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1. Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

Author

Boen, Rune, Kaufmann, Tobias, van der Meer, Dennis, Frei, Oleksandr, Agartz, Ingrid, Ames, David, Andersson, Micael, Armstrong, Nicola, Artiges, Eric, Atkins, Joshua, Bauer, Jochen, Benedetti, Francesco, Boomsma, Dorret, Brodaty, Henry, Brosch, Katharina, Buckner, Randy, Cairns, Murray, Calhoun, Vince, Caspers, Svenja, Cichon, Sven, Corvin, Aiden, Crespo-Facorro, Benedicto, Dannlowski, Udo, David, Friederike, de Geus, Eco, de Zubicaray, Greig, Desrivières, Sylvane, Doherty, Joanne, Donohoe, Gary, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fisher, Simon, Forstner, Andreas, Fortaner-Uyà, Lidia, Frouin, Vincent, Fukunaga, Masaki, Ge, Tian, Glahn, David, Goltermann, Janik, Grabe, Hans, Green, Melissa, Groenewold, Nynke, Grotegerd, Dominik, Grøntvedt, Gøril, Hahn, Tim, Hashimoto, Ryota, Hehir-Kwa, Jayne, Henskens, Frans, Holmes, Avram, Håberg, Asta, Haavik, Jan, Jacquemont, Sebastien, Jansen, Andreas, Jockwitz, Christiane, Jönsson, Erik, Kikuchi, Masataka, Kircher, Tilo, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David, Liu, Jingyu, Loughnan, Robert, Mather, Karen, McMahon, Katie, McRae, Allan, Medland, Sarah, Meinert, Susanne, Moreau, Clara, Morris, Derek, Mowry, Bryan, Mühleisen, Thomas, Nenadić, Igor, Nöthen, Markus, Nyberg, Lars, Ophoff, Roel, Owen, Michael, Pantelis, Christos, Paolini, Marco, Paus, Tomas, Pausova, Zdenka, Persson, Karin, Quidé, Yann, Marques, Tiago, Sachdev, Perminder, Sando, Sigrid, Schall, Ulrich, Scott, Rodney, Selbæk, Geir, Shumskaya, Elena, Silva, Ana, Sisodiya, Sanjay, Stein, Frederike, Stein, Dan, Straube, Benjamin, Streit, Fabian, Strike, Lachlan, Teumer, Alexander, and Teutenberg, Lea

Subjects
15q11.2 BP1-BP2, 1q21.1 distal, Brain structure, Copy number variants, Intraindividual variability, Magnetic resonance imaging, Humans, Chromosome Deletion, Brain, Magnetic Resonance Imaging, Abnormalities, Multiple, Chromosomes, Human, Pair 15, DNA Copy Number Variations
Abstract

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individuals regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

Published
2024

2. Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Author

Palmer, Duncan S, Howrigan, Daniel P, Chapman, Sinéad B, Adolfsson, Rolf, Bass, Nick, Blackwood, Douglas, Boks, Marco PM, Chen, Chia-Yen, Churchhouse, Claire, Corvin, Aiden P, Craddock, Nicholas, Curtis, David, Di Florio, Arianna, Dickerson, Faith, Freimer, Nelson B, Goes, Fernando S, Jia, Xiaoming, Jones, Ian, Jones, Lisa, Jonsson, Lina, Kahn, Rene S, Landén, Mikael, Locke, Adam E, McIntosh, Andrew M, McQuillin, Andrew, Morris, Derek W, O’Donovan, Michael C, Ophoff, Roel A, Owen, Michael J, Pedersen, Nancy L, Posthuma, Danielle, Reif, Andreas, Risch, Neil, Schaefer, Catherine, Scott, Laura, Singh, Tarjinder, Smoller, Jordan W, Solomonson, Matthew, Clair, David St, Stahl, Eli A, Vreeker, Annabel, Walters, James TR, Wang, Weiqing, Watts, Nicholas A, Yolken, Robert, Zandi, Peter P, and Neale, Benjamin M

Subjects
Biotechnology, Human Genome, Clinical Research, Serious Mental Illness, Schizophrenia, Brain Disorders, Bipolar Disorder, Mental Health, Genetics, 2.1 Biological and endogenous factors, Aetiology, Mental health, A Kinase Anchor Proteins, Exome, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Exome Sequencing, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Published
2022

3. Rare coding variants in ten genes confer substantial risk for schizophrenia.

Author

Singh, Tarjinder, Poterba, Timothy, Curtis, David, Akil, Huda, Al Eissa, Mariam, Barchas, Jack D, Bass, Nicholas, Bigdeli, Tim B, Breen, Gerome, Bromet, Evelyn J, Buckley, Peter F, Bunney, William E, Bybjerg-Grauholm, Jonas, Byerley, William F, Chapman, Sinéad B, Chen, Wei J, Churchhouse, Claire, Craddock, Nicholas, Cusick, Caroline M, DeLisi, Lynn, Dodge, Sheila, Escamilla, Michael A, Eskelinen, Saana, Fanous, Ayman H, Faraone, Stephen V, Fiorentino, Alessia, Francioli, Laurent, Gabriel, Stacey B, Gage, Diane, Gagliano Taliun, Sarah A, Ganna, Andrea, Genovese, Giulio, Glahn, David C, Grove, Jakob, Hall, Mei-Hua, Hämäläinen, Eija, Heyne, Henrike O, Holi, Matti, Hougaard, David M, Howrigan, Daniel P, Huang, Hailiang, Hwu, Hai-Gwo, Kahn, René S, Kang, Hyun Min, Karczewski, Konrad J, Kirov, George, Knowles, James A, Lee, Francis S, Lehrer, Douglas S, Lescai, Francesco, Malaspina, Dolores, Marder, Stephen R, McCarroll, Steven A, McIntosh, Andrew M, Medeiros, Helena, Milani, Lili, Morley, Christopher P, Morris, Derek W, Mortensen, Preben Bo, Myers, Richard M, Nordentoft, Merete, O'Brien, Niamh L, Olivares, Ana Maria, Ongur, Dost, Ouwehand, Willem H, Palmer, Duncan S, Paunio, Tiina, Quested, Digby, Rapaport, Mark H, Rees, Elliott, Rollins, Brandi, Satterstrom, F Kyle, Schatzberg, Alan, Scolnick, Edward, Scott, Laura J, Sharp, Sally I, Sklar, Pamela, Smoller, Jordan W, Sobell, Janet L, Solomonson, Matthew, Stahl, Eli A, Stevens, Christine R, Suvisaari, Jaana, Tiao, Grace, Watson, Stanley J, Watts, Nicholas A, Blackwood, Douglas H, Børglum, Anders D, Cohen, Bruce M, Corvin, Aiden P, Esko, Tõnu, Freimer, Nelson B, Glatt, Stephen J, Hultman, Christina M, McQuillin, Andrew, Palotie, Aarno, Pato, Carlos N, Pato, Michele T, Pulver, Ann E, and St Clair, David

Subjects
Humans, Genetic Predisposition to Disease, Receptors, N-Methyl-D-Aspartate, Case-Control Studies, Schizophrenia, Mutation, Exome, Neurodevelopmental Disorders, Human Genome, Biotechnology, Mental Health, Neurosciences, Brain Disorders, Genetics, Serious Mental Illness, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, General Science & Technology
Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P

Published
2022

4. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Author

Blokland, Gabriëlla AM, Grove, Jakob, Chen, Chia-Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Schizophrenia Working Group of the Psychiatric Genomics Consortium, St Clair, David, Lencz, Todd, Mowry, Bryan J, Periyasamy, Sathish, Cairns, Murray J, Tooney, Paul A, Wu, Jing Qin, Kelly, Brian, Kirov, George, Sullivan, Patrick F, Corvin, Aiden, Riley, Brien P, Esko, Tõnu, Milani, Lili, Jönsson, Erik G, Palotie, Aarno, Ehrenreich, Hannelore, Begemann, Martin, Steixner-Kumar, Agnes, Sham, Pak C, Iwata, Nakao, Weinberger, Daniel R, Gejman, Pablo V, Sanders, Alan R, Buxbaum, Joseph D, Rujescu, Dan, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Bramon, Elvira, Murray, Robin M, Pato, Michele T, Lee, Jimmy, Melle, Ingrid, Molden, Espen, Ophoff, Roel A, McQuillin, Andrew, Bass, Nicholas J, Adolfsson, Rolf, Malhotra, Anil K, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Martin, Nicholas G, Fullerton, Janice M, Mitchell, Philip B, Schofield, Peter R, Forstner, Andreas J, Degenhardt, Franziska, Schaupp, Sabrina, Comes, Ashley L, Kogevinas, Manolis, Guzman-Parra, José, Reif, Andreas, Streit, Fabian, Sirignano, Lea, Cichon, Sven, Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Lissowska, Jolanta, Mayoral, Fermin, Müller-Myhsok, Bertram, Świątkowska, Beata, Schulze, Thomas G, Nöthen, Markus M, Rietschel, Marcella, Kelsoe, John, Leboyer, Marion, Jamain, Stéphane, Etain, Bruno, Bellivier, Frank, Vincent, John B, Alda, Martin, O'Donovan, Claire, Cervantes, Pablo, Biernacka, Joanna M, Frye, Mark, McElroy, Susan L, Scott, Laura J, Stahl, Eli A, Landén, Mikael, Hamshere, Marian L, Smeland, Olav B, Djurovic, Srdjan, Vaaler, Arne E, Andreassen, Ole A, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Baune, Bernhard T, Air, Tracy, Preisig, Martin, Uher, Rudolf, Levinson, Douglas F, Weissman, Myrna M, Potash, James B, and Shi, Jianxin

Subjects
Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Endothelial Cells, Humans, Genetic Predisposition to Disease, Receptors, Vascular Endothelial Growth Factor, Sulfurtransferases, Bipolar Disorder, Depressive Disorder, Major, Psychotic Disorders, Schizophrenia, Sex Characteristics, Polymorphism, Single Nucleotide, Female, Male, Genome-Wide Association Study, Bipolar disorder, Genome-wide association study, Genotype-by-sex interaction, Major depressive disorder, Sex differences, Serious Mental Illness, Biotechnology, Mental Health, Genetics, Human Genome, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Mental health, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.MethodsWe conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.ResultsAcross disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).ConclusionsIn the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Published
2022

5. A meta‐analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium

Author

Gutman, Boris A, Erp, Theo GM, Alpert, Kathryn, Ching, Christopher RK, Isaev, Dmitry, Ragothaman, Anjani, Jahanshad, Neda, Saremi, Arvin, Zavaliangos‐Petropulu, Artemis, Glahn, David C, Shen, Li, Cong, Shan, Alnæs, Dag, Andreassen, Ole Andreas, Doan, Nhat Trung, Westlye, Lars T, Kochunov, Peter, Satterthwaite, Theodore D, Wolf, Daniel H, Huang, Alexander J, Kessler, Charles, Weideman, Andrea, Nguyen, Dana, Mueller, Bryon A, Faziola, Lawrence, Potkin, Steven G, Preda, Adrian, Mathalon, Daniel H, Bustillo, Juan, Calhoun, Vince, Ford, Judith M, Walton, Esther, Ehrlich, Stefan, Ducci, Giuseppe, Banaj, Nerisa, Piras, Fabrizio, Piras, Federica, Spalletta, Gianfranco, Canales‐Rodríguez, Erick J, Fuentes‐Claramonte, Paola, Pomarol‐Clotet, Edith, Radua, Joaquim, Salvador, Raymond, Sarró, Salvador, Dickie, Erin W, Voineskos, Aristotle, Tordesillas‐Gutiérrez, Diana, Crespo‐Facorro, Benedicto, Setién‐Suero, Esther, Son, Jacqueline Mayoral, Borgwardt, Stefan, Schönborn‐Harrisberger, Fabienne, Morris, Derek, Donohoe, Gary, Holleran, Laurena, Cannon, Dara, McDonald, Colm, Corvin, Aiden, Gill, Michael, Filho, Geraldo Busatto, Rosa, Pedro GP, Serpa, Mauricio H, Zanetti, Marcus V, Lebedeva, Irina, Kaleda, Vasily, Tomyshev, Alexander, Crow, Tim, James, Anthony, Cervenka, Simon, Sellgren, Carl M, Fatouros‐Bergman, Helena, Agartz, Ingrid, Howells, Fleur, Stein, Dan J, Temmingh, Henk, Uhlmann, Anne, Zubicaray, Greig I, McMahon, Katie L, Wright, Margie, Cobia, Derin, Csernansky, John G, Thompson, Paul M, Turner, Jessica A, and Wang, Lei

Subjects
Brain Disorders, Mental Health, Neurosciences, Schizophrenia, Mental health, Good Health and Well Being, Amygdala, Corpus Striatum, Hippocampus, Humans, Multicenter Studies as Topic, Neuroimaging, Thalamus, schizophrenia, structure, subcortical shape, Cognitive Sciences, Experimental Psychology
Abstract

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.

Published
2022

6. Characterisation of age and polarity at onset in bipolar disorder.

Author

Kalman, Janos L, Olde Loohuis, Loes M, Vreeker, Annabel, McQuillin, Andrew, Stahl, Eli A, Ruderfer, Douglas, Grigoroiu-Serbanescu, Maria, Panagiotaropoulou, Georgia, Ripke, Stephan, Bigdeli, Tim B, Stein, Frederike, Meller, Tina, Meinert, Susanne, Pelin, Helena, Streit, Fabian, Papiol, Sergi, Adams, Mark J, Adolfsson, Rolf, Adorjan, Kristina, Agartz, Ingrid, Aminoff, Sofie R, Anderson-Schmidt, Heike, Andreassen, Ole A, Ardau, Raffaella, Aubry, Jean-Michel, Balaban, Ceylan, Bass, Nicholas, Baune, Bernhard T, Bellivier, Frank, Benabarre, Antoni, Bengesser, Susanne, Berrettini, Wade H, Boks, Marco P, Bromet, Evelyn J, Brosch, Katharina, Budde, Monika, Byerley, William, Cervantes, Pablo, Chillotti, Catina, Cichon, Sven, Clark, Scott R, Comes, Ashley L, Corvin, Aiden, Coryell, William, Craddock, Nick, Craig, David W, Croarkin, Paul E, Cruceanu, Cristiana, Czerski, Piotr M, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Del Zompo, Maria, DePaulo, J Raymond, Djurovic, Srdjan, Edenberg, Howard J, Eissa, Mariam Al, Elvsåshagen, Torbjørn, Etain, Bruno, Fanous, Ayman H, Fellendorf, Frederike, Fiorentino, Alessia, Forstner, Andreas J, Frye, Mark A, Fullerton, Janice M, Gade, Katrin, Garnham, Julie, Gershon, Elliot, Gill, Michael, Goes, Fernando S, Gordon-Smith, Katherine, Grof, Paul, Guzman-Parra, Jose, Hahn, Tim, Hasler, Roland, Heilbronner, Maria, Heilbronner, Urs, Jamain, Stephane, Jimenez, Esther, Jones, Ian, Jones, Lisa, Jonsson, Lina, Kahn, Rene S, Kelsoe, John R, Kennedy, James L, Kircher, Tilo, Kirov, George, Kittel-Schneider, Sarah, Klöhn-Saghatolislam, Farah, Knowles, James A, Kranz, Thorsten M, Lagerberg, Trine Vik, Landen, Mikael, Lawson, William B, Leboyer, Marion, Li, Qingqin S, Maj, Mario, Malaspina, Dolores, Manchia, Mirko, and Mayoral, Fermin

Subjects
Psychiatric Genomics Consortium (PGC) Bipolar Disorder Working Group, International Consortium on Lithium Genetics, Colombia-US Cross Disorder Collaboration in Psychiatric Genetics, Humans, Bipolar Disorder, Depressive Disorder, Major, Age of Onset, Multifactorial Inheritance, Genome-Wide Association Study, Autism Spectrum Disorder, Bipolar disorder, GWAS, age at onset, polarity at onset, polygenic score, Genetics, Mental Health, Prevention, Brain Disorders, Serious Mental Illness, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundStudying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.AimsTo examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.MethodGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.ResultsEarlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.ConclusionsAAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Published
2021

7. Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Author

Lam, Max, Chen, Chia-Yen, Ge, Tian, Xia, Yan, Hill, David W, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Stahl, Eli A, Huckins, Laura, Liewald, David C, Djurovic, Srdjan, Melle, Ingrid, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Koltai, Deborah C, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson B, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Huang, Hailiang, Liu, Chunyu, Malhotra, Anil K, and Lencz, Todd

Subjects
Humans, Nootropic Agents, Cognition, Schizophrenia, Genome-Wide Association Study, Transcriptome, Psychiatry, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

Published
2021

8. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Author

Jia, Xiaoming, Goes, Fernando S, Locke, Adam E, Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U, Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M, Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Gonçalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Juréus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z, Levy, Shawn E, Monson, Eric T, Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zöllner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M, Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A, Richard McCombie, W, McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M, O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B, Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F, Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A, Zandi, Peter P, and Scott, Laura J

Subjects
Humans, Genetic Predisposition to Disease, Bipolar Disorder, Schizophrenia, Polymorphism, Single Nucleotide, Genetic Variation, Genome-Wide Association Study, Exome, Brain Disorders, Prevention, Clinical Research, Human Genome, Serious Mental Illness, Genetics, Mental Health, 2.1 Biological and endogenous factors, Mental health, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

Published
2021

9. Complement genes contribute sex-biased vulnerability in diverse disorders

Author

Arranz, Maria J, Bakker, Steven, Bender, Stephan, Bramon, Elvira, Collier, David A, Crespo-Facorro, Benedicto, Hall, Jeremy, Iyegbe, Conrad, Jablensky, Assen V, Kahn, René S, Kalaydjieva, Luba, Lawrie, Stephen, Lewis, Cathryn M, Lin, Kuang, Linszen, Don H, Mata, Ignacio, McIntosh, Andrew M, Murray, Robin M, Ophoff, Roel A, Van Os, Jim, Powell, John, Rujescu, Dan, Walshe, Muriel, Weisbrod, Matthias, Wiersma, Durk, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris CA, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Giannoulatou, Eleni, Hellenthal, Garrett, Pearson, Richard, Pirinen, Matti, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Edkins, Sarah, Gillman, Matthew, Gray, Emma, Gwilliam, Rhian, Hammond, Naomi, Hunt, Sarah E, Jayakumar, Alagurevathi, Liddle, Jennifer, McCann, Owen T, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Tashakkori-Ghanbaria, Avazeh, Waller, Matthew, Weston, Paul, Whittaker, Pamela, Widaa, Sara, and McCarthy, Mark I

Subjects
Autoimmune Disease, Schizophrenia, Mental Health, Lupus, Genetics, Brain Disorders, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Adult, Alleles, Complement C3, Complement C4, Female, Genetic Predisposition to Disease, HLA Antigens, Haplotypes, Humans, Lupus Erythematosus, Systemic, Major Histocompatibility Complex, Male, Middle Aged, Sex Characteristics, Sjogren's Syndrome, Young Adult, Schizophrenia Working Group of the Psychiatric Genomics Consortium, General Science & Technology
Abstract

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Published
2020

10. The Relationship Between White Matter Microstructure and General Cognitive Ability in Patients With Schizophrenia and Healthy Participants in the ENIGMA Consortium

Author

Holleran, Laurena, Kelly, Sinead, Alloza, Clara, Agartz, Ingrid, Andreassen, Ole A, Arango, Celso, Banaj, Nerisa, Calhoun, Vince, Cannon, Dara, Carr, Vaughan, Corvin, Aiden, Glahn, David C, Gur, Ruben, Hong, Elliot, Hoschl, Cyril, Howells, Fleur M, James, Anthony, Janssen, Joost, Kochunov, Peter, Lawrie, Stephen M, Liu, Jingyu, Martinez, Covadonga, McDonald, Colm, Morris, Derek, Mothersill, David, Pantelis, Christos, Piras, Fabrizio, Potkin, Steven, Rasser, Paul E, Roalf, David, Rowland, Laura, Satterthwaite, Theodore, Schall, Ulrich, Spalletta, Gianfranco, Spaniel, Filip, Stein, Dan J, Uhlmann, Anne, Voineskos, Aristotle, Zalesky, Andrew, van Erp, Theo GM, Turner, Jessica A, Deary, Ian J, Thompson, Paul M, Jahanshad, Neda, and Donohoe, Gary

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Prevention, Neurosciences, Behavioral and Social Science, Clinical Research, Brain Disorders, Serious Mental Illness, Schizophrenia, Mental Health, Mental health, Adult, Anisotropy, Brain, Case-Control Studies, Cognition, Diffusion Tensor Imaging, Factor Analysis, Statistical, Female, Healthy Volunteers, Humans, Intelligence, Male, Middle Aged, Neural Pathways, Principal Component Analysis, Schizophrenic Psychology, Wechsler Scales, White Matter, ENIGMA, Meta-Analysis, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Clinical and health psychology
Abstract

ObjectiveSchizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants.MethodsThe meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition.ResultsMeta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges' g]=0.27, CI=0.17-0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05-0.35) and healthy participant groups (effect size=0.32, CI=0.18-0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18-0.37), the patient group (effect size=0.23, CI=0.09-0.38), and the healthy participant group (effect size=0.31, CI=0.18-0.44).ConclusionsThis study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association.

Published
2020

11. Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Author

Sønderby, Ida E, Gústafsson, Ómar, Doan, Nhat Trung, Hibar, Derrek P, Martin-Brevet, Sandra, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Michael, Armstrong, Nicola J, Bernard, Manon, Blackburn, Nicholas, Blangero, John, Boomsma, Dorret I, Bralten, Janita, Brattbak, Hans-Richard, Brodaty, Henry, Brouwer, Rachel M, Bülow, Robin, Calhoun, Vince, Caspers, Svenja, Cavalleri, Gianpiero, Chen, Chi-Hua, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E, Dale, Anders M, Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco JC, de Zubicaray, Greig I, de Zwarte, Sonja MC, Delanty, Norman, den Braber, Anouk, Desrivières, Sylvane, Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Espeseth, Thomas, Fisher, Simon E, Franke, Barbara, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C, Grabe, Hans, Groenewold, Nynke A, Haavik, Jan, Håberg, Asta, Hashimoto, Ryota, Hehir-Kwa, Jayne Y, Heinz, Andreas, Hillegers, Manon HJ, Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke-Jan, Hulshoff, Hilleke E, Ikeda, Masashi, Jahanshad, Neda, Jernigan, Terry, Jockwitz, Christiane, Johansson, Stefan, Jonsdottir, Gudrun A, Jönsson, Erik G, Kahn, Rene, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Knowles, Emma EM, Kolskår, Knut K, Kwok, John B, Hellard, Stephanie Le, Leu, Costin, Liu, Jingyu, Lundervold, Astri J, Lundervold, Arvid, Martin, Nicholas G, Mather, Karen, Mathias, Samuel R, McCormack, Mark, McMahon, Katie L, McRae, Allan, Milaneschi, Yuri, Moreau, Clara, Morris, Derek, Mothersill, David, Mühleisen, Thomas W, Murray, Robin, Nordvik, Jan E, Nyberg, Lars, Olde Loohuis, Loes M, Ophoff, Roel, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda, Peralta, Juan M, Pike, Bruce, and Prieto, Carlos

Subjects
Intellectual and Developmental Disabilities (IDD), Neurosciences, Brain Disorders, Autism, Biomedical Imaging, Mental Health, Mental health, Adult, Autism Spectrum Disorder, Autistic Disorder, Basal Ganglia, Brain, Chromosome Deletion, Chromosome Disorders, Chromosome Duplication, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Databases, Factual, Female, Globus Pallidus, Humans, Image Processing, Computer-Assisted, Intellectual Disability, Magnetic Resonance Imaging, Male, Middle Aged, Neurodevelopmental Disorders, Organ Size, Putamen, Schizophrenia, 16p11.2 European Consortium, for the ENIGMA-CNV working group, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P

Published
2020

12. The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

Author

Richards, Alexander L, Pardiñas, Antonio F, Frizzati, Aura, Tansey, Katherine E, Lynham, Amy J, Holmans, Peter, Legge, Sophie E, Savage, Jeanne E, Agartz, Ingrid, Andreassen, Ole A, Blokland, Gabriella AM, Corvin, Aiden, Cosgrove, Donna, Degenhardt, Franziska, Djurovic, Srdjan, Espeseth, Thomas, Ferraro, Laura, Gayer-Anderson, Charlotte, Giegling, Ina, van Haren, Neeltje E, Hartmann, Annette M, Hubert, John J, Jönsson, Erik G, Konte, Bettina, Lennertz, Leonhard, Olde Loohuis, Loes M, Melle, Ingrid, Morgan, Craig, Morris, Derek W, Murray, Robin M, Nyman, Håkan, Ophoff, Roel A, van Os, Jim, Petryshen, Tracey L, Quattrone, Diego, Rietschel, Marcella, Rujescu, Dan, Rutten, Bart PF, Streit, Fabian, Strohmaier, Jana, Sullivan, Patrick F, Sundet, Kjetil, Wagner, Michael, Escott-Price, Valentina, Owen, Michael J, Donohoe, Gary, O’Donovan, Michael C, and Walters, James TR

Subjects
Genetics, Prevention, Schizophrenia, Depression, Behavioral and Social Science, Mental Health, Brain Disorders, Serious Mental Illness, Human Genome, 2.1 Biological and endogenous factors, Aetiology, 2.3 Psychological, social and economic factors, Mental health, Bipolar Disorder, Datasets as Topic, Depressive Disorder, Major, Educational Status, Genome-Wide Association Study, Humans, Intelligence, Multifactorial Inheritance, Psychotic Disorders, psychiatry, genomics, intelligence, bioinformatics, GROUP Investigators, EUGEI WP2 Group, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundCognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases.MethodsWe combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases.ResultsPRS for both population IQ (P = 4.39 × 10-28) and EA (P = 1.27 × 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS.ConclusionsCognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

Published
2020

13. GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores

Author

Mullins, Niamh, Bigdeli, Tim B, Børglum, Anders D, Coleman, Jonathan RI, Demontis, Ditte, Mehta, Divya, Power, Robert A, Ripke, Stephan, Stahl, Eli A, Starnawska, Anna, Anjorin, Adebayo, Corvin, Aiden, Sanders, Alan R, Forstner, Andreas J, Reif, Andreas, Koller, Anna C, Świątkowska, Beata, Baune, Bernhard T, Müller-Myhsok, Bertram, Penninx, Brenda WJH, Pato, Carlos, Zai, Clement, Rujescu, Dan, Hougaard, David M, Quested, Digby, Levinson, Douglas F, Binder, Elisabeth B, Byrne, Enda M, Agerbo, Esben, Streit, Fabian, Mayoral, Fermin, Bellivier, Frank, Degenhardt, Franziska, Breen, Gerome, Morken, Gunnar, Turecki, Gustavo, Rouleau, Guy A, Grabe, Hans J, Völzke, Henry, Jones, Ian, Giegling, Ina, Agartz, Ingrid, Melle, Ingrid, Lawrence, Jacob, Walters, James TR, Strohmaier, Jana, Shi, Jianxin, Hauser, Joanna, Biernacka, Joanna M, Vincent, John B, Kelsoe, John, Strauss, John S, Lissowska, Jolanta, Pimm, Jonathan, Smoller, Jordan W, Guzman-Parra, José, Berger, Klaus, Scott, Laura J, Jones, Lisa A, Azevedo, M Helena, Trzaskowski, Maciej, Kogevinas, Manolis, Rietschel, Marcella, Boks, Marco, Ising, Marcus, Grigoroiu-Serbanescu, Maria, Hamshere, Marian L, Leboyer, Marion, Frye, Mark, Nöthen, Markus M, Alda, Martin, Preisig, Martin, Nordentoft, Merete, Boehnke, Michael, O’Donovan, Michael C, Owen, Michael J, Pato, Michele T, Renteria, Miguel E, Budde, Monika, Weissman, Myrna M, Wray, Naomi R, Bass, Nicholas, Craddock, Nicholas, Smeland, Olav B, Andreassen, Ole A, Mors, Ole, Gejman, Pablo V, Sklar, Pamela, McGrath, Patrick, Hoffmann, Per, McGuffin, Peter, Lee, Phil H, Mortensen, Preben Bo, Kahn, René S, Ophoff, Roel A, Adolfsson, Rolf, Van der Auwera, Sandra, Djurovic, Srdjan, Kloiber, Stefan, and Heilmann-Heimbach, Stefanie

Subjects
Prevention, Suicide, Serious Mental Illness, Schizophrenia, Human Genome, Depression, Mental Health, Genetics, Brain Disorders, Aetiology, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Bipolar Disorder, Case-Control Studies, Depressive Disorder, Major, Female, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Risk Factors, Suicide, Attempted, M.R.C.Psych, Dr.Med.Sc, Dipl.-Psych, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Mood Disorders, Polygenic Risk Scoring, Psychiatric Genomics Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveMore than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.MethodsThe samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.ResultsThree genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).ConclusionsThis study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

Published
2019

14. Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Author

Lam, Max, Hill, W David, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Stahl, Eli, Huckins, Laura, Liewald, David C, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, and Lencz, Todd

Subjects
Humans, Genetic Predisposition to Disease, Cognition, Cognition Disorders, Schizophrenia, Synaptic Transmission, Polymorphism, Single Nucleotide, Adult, Educational Status, Genome-Wide Association Study, Neurodevelopmental Disorders, GWAS, cognitive ability, educational attainment, genetic correlation, pathways, pleiotropy, schizophrenia, Serious Mental Illness, Neurosciences, Biotechnology, Mental Health, Genetics, Brain Disorders, Prevention, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Mental health, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Published
2019

15. Population‐based identity‐by‐descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Author

Harold, Denise, Connolly, Siobhan, Riley, Brien P, Kendler, Kenneth S, McCarthy, Shane E, McCombie, William R, Richards, Alex, Owen, Michael J, O'Donovan, Michael C, Walters, James, Donnelly, Peter, Bates, Lesley, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris CA, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Hopkins, Lucinda, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Ripke, Stephan, Neale, Benjamin M, Walters, James TR, Farh, Kai‐How, Holmans, Peter A, Lee, Phil, Bulik‐Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Chan, Raymond CK, and Chan, Ronald YL

Subjects
Biological Sciences, Genetics, Clinical Research, Schizophrenia, Brain Disorders, Human Genome, Prevention, Serious Mental Illness, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Adult, Case-Control Studies, Chromosome Mapping, DNA Copy Number Variations, Databases, Genetic, Exome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Male, Middle Aged, Risk Factors, Sequence Analysis, DNA, Exome Sequencing, GWAS, IBD mapping, rare variants, Wellcome Trust Case Control Consortium 2, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Clinical Sciences, Neurosciences, Clinical sciences
Abstract

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

Published
2019

16. Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018)

Author

Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Glahn, David C, Malhotra, Anil K, and Lencz, Todd

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Clinical Sciences, Human Genome, Genetics, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Cognition, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Nootropic Agents, Polymorphism, Single Nucleotide, GWAS, general cognitive ability, nootropics, gene expression, neurodevelopment, synapse, calcium channel, potassium channel, cerebellum, Paediatrics and Reproductive Medicine, Cognitive Sciences, Genetics & Heredity, Clinical sciences, Reproductive medicine
Abstract

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

Published
2018

17. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Author

Savage, Jeanne E, Jansen, Philip R, Stringer, Sven, Watanabe, Kyoko, Bryois, Julien, de Leeuw, Christiaan A, Nagel, Mats, Awasthi, Swapnil, Barr, Peter B, Coleman, Jonathan RI, Grasby, Katrina L, Hammerschlag, Anke R, Kaminski, Jakob A, Karlsson, Robert, Krapohl, Eva, Lam, Max, Nygaard, Marianne, Reynolds, Chandra A, Trampush, Joey W, Young, Hannah, Zabaneh, Delilah, Hägg, Sara, Hansell, Narelle K, Karlsson, Ida K, Linnarsson, Sten, Montgomery, Grant W, Muñoz-Manchado, Ana B, Quinlan, Erin B, Schumann, Gunter, Skene, Nathan G, Webb, Bradley T, White, Tonya, Arking, Dan E, Avramopoulos, Dimitrios, Bilder, Robert M, Bitsios, Panos, Burdick, Katherine E, Cannon, Tyrone D, Chiba-Falek, Ornit, Christoforou, Andrea, Cirulli, Elizabeth T, Congdon, Eliza, Corvin, Aiden, Davies, Gail, Deary, Ian J, DeRosse, Pamela, Dickinson, Dwight, Djurovic, Srdjan, Donohoe, Gary, Conley, Emily Drabant, Eriksson, Johan G, Espeseth, Thomas, Freimer, Nelson A, Giakoumaki, Stella, Giegling, Ina, Gill, Michael, Glahn, David C, Hariri, Ahmad R, Hatzimanolis, Alex, Keller, Matthew C, Knowles, Emma, Koltai, Deborah, Konte, Bettina, Lahti, Jari, Le Hellard, Stephanie, Lencz, Todd, Liewald, David C, London, Edythe, Lundervold, Astri J, Malhotra, Anil K, Melle, Ingrid, Morris, Derek, Need, Anna C, Ollier, William, Palotie, Aarno, Payton, Antony, Pendleton, Neil, Poldrack, Russell A, Räikkönen, Katri, Reinvang, Ivar, Roussos, Panos, Rujescu, Dan, Sabb, Fred W, Scult, Matthew A, Smeland, Olav B, Smyrnis, Nikolaos, Starr, John M, Steen, Vidar M, Stefanis, Nikos C, Straub, Richard E, Sundet, Kjetil, Tiemeier, Henning, Voineskos, Aristotle N, Weinberger, Daniel R, Widen, Elisabeth, Yu, Jin, Abecasis, Goncalo, Andreassen, Ole A, Breen, Gerome, and Christiansen, Lene

Subjects
Biological Sciences, Genetics, Brain Disorders, Mental Health, Human Genome, Biotechnology, Neurosciences, Underpinning research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Mental health, Neurological, Adolescent, Brain, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intelligence, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Published
2018

18. Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

Author

Lam, Max, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Liewald, David C, Starr, John M, Djurovic, Srdjan, Melle, Ingrid, Sundet, Kjetil, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Attix, Deborah K, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Arking, Dan E, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson A, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Malhotra, Anil K, and Lencz, Todd

Subjects
Biological Sciences, Genetics, Mental Health, Aging, Brain Disorders, Biotechnology, Autoimmune Disease, Neurosciences, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, Mental health, Neurological, Cefotaxime, Cognition, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Nootropic Agents, Polymorphism, Single Nucleotide, Synapses, GWAS, calcium channel, cerebellum, gene expression, general cognitive ability, neurodevelopment, nootropics, potassium channel, synapse, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

Published
2017

19. Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex.

Author

Guadalupe, Tulio, Mathias, Samuel R, vanErp, Theo GM, Whelan, Christopher D, Zwiers, Marcel P, Abe, Yoshinari, Abramovic, Lucija, Agartz, Ingrid, Andreassen, Ole A, Arias-Vásquez, Alejandro, Aribisala, Benjamin S, Armstrong, Nicola J, Arolt, Volker, Artiges, Eric, Ayesa-Arriola, Rosa, Baboyan, Vatche G, Banaschewski, Tobias, Barker, Gareth, Bastin, Mark E, Baune, Bernhard T, Blangero, John, Bokde, Arun LW, Boedhoe, Premika SW, Bose, Anushree, Brem, Silvia, Brodaty, Henry, Bromberg, Uli, Brooks, Samantha, Büchel, Christian, Buitelaar, Jan, Calhoun, Vince D, Cannon, Dara M, Cattrell, Anna, Cheng, Yuqi, Conrod, Patricia J, Conzelmann, Annette, Corvin, Aiden, Crespo-Facorro, Benedicto, Crivello, Fabrice, Dannlowski, Udo, de Zubicaray, Greig I, de Zwarte, Sonja MC, Deary, Ian J, Desrivières, Sylvane, Doan, Nhat Trung, Donohoe, Gary, Dørum, Erlend S, Ehrlich, Stefan, Espeseth, Thomas, Fernández, Guillén, Flor, Herta, Fouche, Jean-Paul, Frouin, Vincent, Fukunaga, Masaki, Gallinat, Jürgen, Garavan, Hugh, Gill, Michael, Suarez, Andrea Gonzalez, Gowland, Penny, Grabe, Hans J, Grotegerd, Dominik, Gruber, Oliver, Hagenaars, Saskia, Hashimoto, Ryota, Hauser, Tobias U, Heinz, Andreas, Hibar, Derrek P, Hoekstra, Pieter J, Hoogman, Martine, Howells, Fleur M, Hu, Hao, Hulshoff Pol, Hilleke E, Huyser, Chaim, Ittermann, Bernd, Jahanshad, Neda, Jönsson, Erik G, Jurk, Sarah, Kahn, Rene S, Kelly, Sinead, Kraemer, Bernd, Kugel, Harald, Kwon, Jun Soo, Lemaitre, Herve, Lesch, Klaus-Peter, Lochner, Christine, Luciano, Michelle, Marquand, Andre F, Martin, Nicholas G, Martínez-Zalacaín, Ignacio, Martinot, Jean-Luc, Mataix-Cols, David, Mather, Karen, McDonald, Colm, McMahon, Katie L, Medland, Sarah E, Menchón, José M, Morris, Derek W, Mothersill, Omar, Maniega, Susana Munoz, and Mwangi, Benson

Subjects
Brain, Humans, Magnetic Resonance Imaging, Organ Size, Aging, Sex Characteristics, Quantitative Trait, Heritable, Adolescent, Adult, Aged, Middle Aged, Female, Male, Functional Laterality, Meta-Analysis as Topic, Young Adult, Age, Enigma, Handedness, Heritability, Meta-analysis, Sex, Subcortical brain asymmetry, Quantitative Trait, Heritable, Medical and Health Sciences, Psychology and Cognitive Sciences, Experimental Psychology
Abstract

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

Published
2017

20. New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis

Author

Lee, S Hong, Byrne, Enda M, Hultman, Christina M, Kähler, Anna, Vinkhuyzen, Anna AE, Ripke, Stephan, Andreassen, Ole A, Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X, McGrath, John J, Mehta, Divya, Stahl, Eli A, Zhao, Qiongyi, Kendler, Kenneth S, Sullivan, Patrick F, Price, Alkes L, O’Donovan, Michael, Okada, Yukinori, Mowry, Bryan J, Raychaudhuri, Soumya, Wray, Naomi R, Byerley, William, Cahn, Wiepke, Cantor, Rita M, Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V, Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F, Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W, Nöthen, Markus M, O’Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N, Pato, Michele T, Pickard, Benjamin S, Posthuma, Danielle, Rasmussen, Henrik B, Rietschel, Marcella, Rujescu, Dan, Schulze, Thomas G, Silverman, Jeremy M, Thirumalai, Srinivasa, Werge, Thomas, Agartz, Ingrid, Amin, Farooq, Azevedo, Maria H, Bass, Nicholas, Black, Donald W, Blackwood, Douglas HR, Bruggeman, Richard, Buccola, Nancy G, Choudhury, Khalid, Cloninger, Robert C, Corvin, Aiden, Craddock, Nicholas, Daly, Mark J, Datta, Susmita, Donohoe, Gary J, Duan, Jubao, Dudbridge, Frank, Fanous, Ayman, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Gill, Michael, Gurling, Hugh, De Haan, Lieuwe, Hamshere, Marian L, Hartmann, Annette M, Holmans, Peter A, Kahn, René S, Keller, Matthew C, Kenny, Elaine, Kirov, George K, Krabbendam, Lydia, Krasucki, Robert, Lawrence, Jacob, Lencz, Todd, Levinson, Douglas F, Lieberman, Jeffrey A, Lin, Dan-Yu, Linszen, Don H, Magnusson, Patrik KE, Maier, Wolfgang, and Malhotra, Anil K

Subjects
Epidemiology, Health Sciences, Human Genome, Mental Health, Brain Disorders, Autoimmune Disease, Schizophrenia, Clinical Research, Arthritis, Serious Mental Illness, Genetics, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Mental health, Adolescent, Adult, Arthritis, Rheumatoid, Cohort Studies, Cross-Sectional Studies, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International, Schizophrenia Working Group of the Psychiatric Genomics Consortium Authors, Schizophrenia Working Group of the Psychiatric Genomics Consortium Collaborators, Rheumatoid Arthritis Consortium International Authors, Rheumatoid Arthritis Consortium International Collaborators, Statistics, Public Health and Health Services, Public health
Abstract

BackgroundA long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders.MethodsWe use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born.ResultsWe estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090).ConclusionsOur results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.

Published
2015

21. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Author

Vilhjálmsson, Bjarni J, Yang, Jian, Finucane, Hilary K, Gusev, Alexander, Lindström, Sara, Ripke, Stephan, Genovese, Giulio, Loh, Po-Ru, Bhatia, Gaurav, Do, Ron, Hayeck, Tristan, Won, Hong-Hee, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Neale, Benjamin M, Corvin, Aiden, Walters, James TR, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Fromer, Menachem, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodrguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, and Grove, Jakob

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Schizophrenia, Mental Health, Brain Disorders, Serious Mental Illness, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Models, Theoretical, Multifactorial Inheritance, Multiple Sclerosis, Phenotype, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

Published
2015

22. Common genetic variants influence human subcortical brain structures

Author

Hibar, Derrek P, Stein, Jason L, Renteria, Miguel E, Arias-Vasquez, Alejandro, Desrivières, Sylvane, Jahanshad, Neda, Toro, Roberto, Wittfeld, Katharina, Abramovic, Lucija, Andersson, Micael, Aribisala, Benjamin S, Armstrong, Nicola J, Bernard, Manon, Bohlken, Marc M, Boks, Marco P, Bralten, Janita, Brown, Andrew A, Mallar Chakravarty, M, Chen, Qiang, Ching, Christopher RK, Cuellar-Partida, Gabriel, den Braber, Anouk, Giddaluru, Sudheer, Goldman, Aaron L, Grimm, Oliver, Guadalupe, Tulio, Hass, Johanna, Woldehawariat, Girma, Holmes, Avram J, Hoogman, Martine, Janowitz, Deborah, Jia, Tianye, Kim, Sungeun, Klein, Marieke, Kraemer, Bernd, Lee, Phil H, Olde Loohuis, Loes M, Luciano, Michelle, Macare, Christine, Mather, Karen A, Mattheisen, Manuel, Milaneschi, Yuri, Nho, Kwangsik, Papmeyer, Martina, Ramasamy, Adaikalavan, Risacher, Shannon L, Roiz-Santiañez, Roberto, Rose, Emma J, Salami, Alireza, Sämann, Philipp G, Schmaal, Lianne, Schork, Andrew J, Shin, Jean, Strike, Lachlan T, Teumer, Alexander, van Donkelaar, Marjolein MJ, van Eijk, Kristel R, Walters, Raymond K, Westlye, Lars T, Whelan, Christopher D, Winkler, Anderson M, Zwiers, Marcel P, Alhusaini, Saud, Athanasiu, Lavinia, Ehrlich, Stefan, Hakobjan, Marina MH, Hartberg, Cecilie B, Haukvik, Unn K, Heister, Angelien JGAM, Hoehn, David, Kasperaviciute, Dalia, Liewald, David CM, Lopez, Lorna M, Makkinje, Remco RR, Matarin, Mar, Naber, Marlies AM, Reese McKay, D, Needham, Margaret, Nugent, Allison C, Pütz, Benno, Royle, Natalie A, Shen, Li, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia SL, van Hulzen, Kimm JE, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Cichon, Sven, Corvin, Aiden, Curran, Joanne E, and Czisch, Michael

Subjects
Biological Psychology, Biological Sciences, Genetics, Psychology, Brain Disorders, Human Genome, Mental Health, Neurosciences, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Mental health, Adolescent, Adult, Aged, Aged, 80 and over, Aging, Apoptosis, Brain, Caudate Nucleus, Child, Female, Gene Expression Regulation, Developmental, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Membrane Proteins, Middle Aged, Organ Size, Putamen, Sex Characteristics, Skull, Young Adult, Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN, IMAGEN, SYS, General Science & Technology
Abstract

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Published
2015

23. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author

O'Dushlaine, Colm, Rossin, Lizzy, Lee, Phil H, Duncan, Laramie, Parikshak, Neelroop N, Newhouse, Stephen, Ripke, Stephan, Neale, Benjamin M, Purcell, Shaun M, Posthuma, Danielle, Nurnberger, John I, Lee, S Hong, Faraone, Stephen V, Perlis, Roy H, Mowry, Bryan J, Thapar, Anita, Goddard, Michael E, Witte, John S, Absher, Devin, Agartz, Ingrid, Akil, Huda, Amin, Farooq, Andreassen, Ole A, Anjorin, Adebayo, Anney, Richard, Anttila, Verneri, Arking, Dan E, Asherson, Philip, Azevedo, Maria H, Backlund, Lena, Badner, Judith A, Bailey, Anthony J, Banaschewski, Tobias, Barchas, Jack D, Barnes, Michael R, Barrett, Thomas B, Bass, Nicholas, Battaglia, Agatino, Bauer, Michael, Bayes, Monica, Bellivier, Frank, Bergen, Sarah E, Berrettini, Wade, Betancur, Catalina, Bettecken, Thomas, Biederman, Joseph, Binder, Elisabeth B, Black, Donald W, Blackwood, Douglas HR, Bloss, Cinnamon S, Boehnke, Michael, Boomsma, Dorret I, Breuer, Rene, Bruggeman, Richard, Cormican, Paul, Buccola, Nancy G, Buitelaar, Jan K, Bunney, William E, Buxbaum, Joseph D, Byerley, William F, Byrne, Enda M, Caesar, Sian, Cahn, Wiepke, Cantor, Rita M, Casas, Miguel, Chakravarti, Aravinda, Chambert, Kimberly, Choudhury, Khalid, Cichon, Sven, Mattheisen, Manuel, Cloninger, C Robert, Collier, David A, Cook, Edwin H, Coon, Hilary, Cormand, Bru, Corvin, Aiden, Coryell, William H, Craig, David W, Craig, Ian W, Crosbie, Jennifer, Cuccaro, Michael L, Curtis, David, Czamara, Darina, Datta, Susmita, Dawson, Geraldine, Day, Richard, De Geus, Eco J, Degenhardt, Franziska, Djurovic, Srdjan, Donohoe, Gary J, Doyle, Alysa E, Duan, Jubao, Dudbridge, Frank, Duketis, Eftichia, Ebstein, Richard P, Edenberg, Howard J, Elia, Josephine, Ennis, Sean, Etain, Bruno, and Fanous, Ayman

Subjects
Human Genome, Brain Disorders, Serious Mental Illness, Schizophrenia, Genetics, Depression, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Brain, Databases, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study, Histones, Humans, Mental Disorders, Signal Transduction, Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium, Neurosciences, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

Published
2015

24. Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

Author

Gusev, Alexander, Lee, S Hong, Trynka, Gosia, Finucane, Hilary, Vilhjálmsson, Bjarni J, Xu, Han, Zang, Chongzhi, Ripke, Stephan, Bulik-Sullivan, Brendan, Stahl, Eli, Kähler, Anna K, Hultman, Christina M, Purcell, Shaun M, McCarroll, Steven A, Daly, Mark J, Pasaniuc, Bogdan, Sullivan, Patrick F, Neale, Benjamin M, Wray, Naomi R, Raychaudhuri, Soumya, Price, Alkes, Corvin, Aiden, Walters, James TR, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Børglum, Anders D, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, and Georgieva, Lyudmila

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Prevention, Computer Simulation, Genetic Diseases, Inborn, Genetic Variation, Genome-Wide Association Study, Humans, Inheritance Patterns, Models, Genetic, Open Reading Frames, Regulatory Elements, Transcriptional, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg(2)) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg(2) from imputed SNPs (5.1× enrichment; p = 3.7 × 10(-17)) and 38% (SE = 4%) of hg(2) from genotyped SNPs (1.6× enrichment, p = 1.0 × 10(-4)). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained

Published
2014

25. Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia.

Author

Ruderfer, Douglas M, Fanous, Ayman H, Ripke, Stephan, McQuillin, Andrew, Amdur, Richard L, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Gejman, Pablo V, O'Donovan, Michael C, Andreassen, Ole A, Djurovic, Srdjan, Hultman, Christina M, Kelsoe, John R, Jamain, Stephane, Landén, Mikael, Leboyer, Marion, Nimgaonkar, Vishwajit, Nurnberger, John, Smoller, Jordan W, Craddock, Nick, Corvin, Aiden, Sullivan, Patrick F, Holmans, Peter, Sklar, Pamela, and Kendler, Kenneth S

Subjects
Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Humans, Genetic Predisposition to Disease, Calcium Channels, L-Type, Cell Cycle Proteins, Nuclear Proteins, Factor Analysis, Statistical, Odds Ratio, Case-Control Studies, Bipolar Disorder, Schizophrenia, Schizophrenic Psychology, Phenotype, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Phosphatidylinositol 3-Kinases, bipolar, clinical symptoms, cross disorder, polygenic, schizophrenia, Calcium Channels, L-Type, Factor Analysis, Statistical, Polymorphism, Single Nucleotide, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.

Published
2014

26. Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the ZNF804A Pathway

Author

Nicodemus, Kristin K, Hargreaves, April, Morris, Derek, Anney, Richard, Gill, Michael, Corvin, Aiden, and Donohoe, Gary

Subjects
Mental Health, Schizophrenia, Serious Mental Illness, Genetics, Clinical Research, Behavioral and Social Science, Neurosciences, Brain Disorders, Prevention, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Aetiology, Mental health, Adult, Cognition Disorders, Epistasis, Genetic, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Memory, Short-Term, Middle Aged, Multifactorial Inheritance, Neural Pathways, Neuropsychological Tests, Polymorphism, Single Nucleotide, Psychotic Disorders, Zinc Fingers, Schizophrenia Psychiatric Genome-wide Association Study (GWAS) Consortium, Wellcome Trust Case Control Consortium 2, Other Medical and Health Sciences, Psychology, Cognitive Sciences
Abstract

ImportanceWe investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained.ObjectivesTo (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score.Design, setting, and participantsPatients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis).Main outcomes and measuresParticipants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition.ResultsHigher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants.Conclusions and relevanceThese data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.

Published
2014

27. Biological insights from 108 schizophrenia-associated genetic loci

Author

Ripke, Stephan, Neale, Benjamin M, Corvin, Aiden, Walters, James TR, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A Jr, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Hougaard, David M, Ikeda, Masashi, and Joa, Inge

Subjects
Human Genome, Brain Disorders, Serious Mental Illness, Prevention, Schizophrenia, Genetics, Neurosciences, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Mental health, Alleles, Brain, Enhancer Elements, Genetic, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Glutamic Acid, Humans, Immunity, Multifactorial Inheritance, Mutation, Odds Ratio, Polymorphism, Single Nucleotide, Synaptic Transmission, Schizophrenia Working Group of the Psychiatric Genomics Consortium, General Science & Technology
Abstract

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

Published
2014

28. Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Author

Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden P, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris CA, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard D, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Tashakkori-Ghanbaria, Avazeh, Waller, Matthew J, Weston, Paul, Widaa, Sara, Whittaker, Pamela, and McCarthy, Mark I

Subjects
Mental health, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Schizophrenia, Sweden, Multicenter Genetic Studies of Schizophrenia Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Published
2013

29. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

Author

Absher, Devin, Agartz, Ingrid, Akil, Huda, Amin, Farooq, Andreassen, Ole, Anjorin, Adebayo, Anney, Richard, Anttila, Verneri, Arking, Dan, Asherson, Philip, Azevedo, Maria, Backlund, Lena, Badner, Judith, Bailey, Anthony, Banaschewski, Tobias, Barchas, Jack, Barnes, Michael, Barrett, Thomas, Bass, Nicholas, Battaglia, Agatino, Bauer, Michael, Bayés, Mònica, Bellivier, Frank, Bergen, Sarah, Berrettini, Wade, Betancur, Catalina, Bettecken, Thomas, Biederman, Joseph, Binder, Elisabeth, Black, Donald, Blackwood, Douglas, Boehnke, Michael, Boomsma, Dorret, Breen, Gerome, Breuer, René, Bruggeman, Richard, Cormican, Paul, Buccola, Nancy, Buitelaar, Jan, Bunney, William, Buxbaum, Joseph, Byerley, William, Byrne, Enda, Caesar, Sian, Cahn, Wiepke, Cantor, Rita, Casas, Miguel, Chakravarti, Aravinda, Chambert, Kimberly, Choudhury, Khalid, Cichon, Sven, Cloninger, C, Collier, David, Cook, Edwin, Coon, Hilary, Cormand, Bru, Corvin, Aiden, Coryell, William, Craig, David, Craig, Ian, Crosbie, Jennifer, Cuccaro, Michael, Curtis, David, Czamara, Darina, Datta, Susmita, Dawson, Geraldine, Day, Richard, De Geus, Eco, Degenhardt, Franziska, Djurovic, Srdjan, Donohoe, Gary, Doyle, Alysa, Duan, Jubao, Dudbridge, Frank, Duketis, Eftichia, Ebstein, Richard, Edenberg, Howard, Elia, Josephine, Ennis, Sean, Etain, Bruno, Fanous, Ayman, Farmer, Anne, Ferrier, I, Flickinger, Matthew, Fombonne, Eric, Foroud, Tatiana, Frank, Josef, Franke, Barbara, Fraser, Christine, Freedman, Robert, Giegling, Ina, Gill, Michael, Gordon, Scott, Gordon-Smith, Katherine, Green, Elaine, Greenwood, Tiffany, Grice, Dorothy, Gross, Magdalena, Grozeva, Detelina, and Guan, Weihua

Subjects
Adult, Attention Deficit Disorder with Hyperactivity, Bipolar Disorder, Child, Child Development Disorders, Pervasive, Crohn Disease, Depressive Disorder, Major, Genetic Heterogeneity, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Inheritance Patterns, Mental Disorders, Polymorphism, Single Nucleotide, Schizophrenia
Abstract

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohns disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Published
2013

30. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.

Author

Vacic, Vladimir, McCarthy, Shane, Malhotra, Dheeraj, Murray, Fiona, Chou, Hsun-Hua, Peoples, Aine, Makarov, Vladimir, Yoon, Seungtai, Bhandari, Abhishek, Corominas, Roser, Iakoucheva, Lilia M, Krastoshevsky, Olga, Krause, Verena, Larach-Walters, Verónica, Welsh, David K, Craig, David, Kelsoe, John R, Gershon, Elliot S, Leal, Suzanne M, Dell Aquila, Marie, Morris, Derek W, Gill, Michael, Corvin, Aiden, Insel, Paul A, McClellan, Jon, King, Mary-Claire, Karayiorgou, Maria, Levy, Deborah L, DeLisi, Lynn E, and Sebat, Jonathan

Subjects
Cell Line, Chromosomes, Human, Pair 7, Humans, Genetic Predisposition to Disease, Cyclic AMP, Cohort Studies, Reproducibility of Results, Pedigree, Schizophrenia, Signal Transduction, Transcription, Genetic, Gene Dosage, Inheritance Patterns, Genes, Duplicate, Female, Male, Receptors, Vasoactive Intestinal Peptide, Type II, Genome-Wide Association Study, DNA Copy Number Variations, General Science & Technology
Abstract

Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.

Published
2011

31. Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Author

Trubetskoy, Vassily, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Braun, Alice, Kraft, Julia, Skarabis, Nora, Walter, Henrik, Ripke, Stephan, Pardiñas, Antonio F., Dennison, Charlotte A., Hall, Lynsey S., Harwood, Janet C., Richards, Alexander L., Legge, Sophie E., Lynham, Amy, Williams, Nigel M., Bray, Nicholas J., Escott-Price, Valentina, Kirov, George, Holmans, Peter A., Pocklington, Andrew J., Owen, Michael J., Walters, James T. R., O’Donovan, Michael C., Qi, Ting, Sidorenko, Julia, Wu, Yang, Zeng, Jian, Gratten, Jacob, Visscher, Peter M., Yang, Jian, Wray, Naomi R., Bigdeli, Tim B., Fanous, Ayman H., Bryois, Julien, Bergen, Sarah E., Kähler, Anna K., Magnusson, Patrik K. E., Hultman, Christina M., Sullivan, Patrick F., Chen, Chia-Yen, Atkinson, Elizabeth G., Goldstein, Jacqueline I., Howrigan, Daniel P., Martin, Alicia R., Daly, Mark J., Huang, Hailiang, Neale, Benjamin M., Ge, Tian, Lam, Max, Belliveau, Richard A., Chambert, Kimberley D., Genovese, Giulio, Lee, Phil H., Pietiläinen, Olli, McCarroll, Steven A., Moran, Jennifer L., Smoller, Jordan W., Brown, Tyler C., Feng, Guoping, Hyman, Steven E., Sheng, Morgan, Chong, Siow Ann, Subramaniam, Mythily, Lencz, Todd, Malhotra, Anil K., Watanabe, Kyoko, Frei, Oleksandr, Agartz, Ingrid, Athanasiu, Lavinia, Melle, Ingrid, Andreassen, Ole A., Steen, Nils Eiel, DeLisi, Lynn E., Mesholam-Gately, Raquelle I., Seidman, Larry J., Koopmans, Frank, Magnusson, Sigurdur, Stefánsson, Hreinn, Stefansson, Kari, Grove, Jakob, Agerbo, Esben, Als, Thomas D., Bybjerg-Grauholm, Jonas, Demontis, Ditte, Hougaard, David M., Mors, Ole, Mortensen, Preben B., Nordentoft, Merete, Børglum, Anders D., Mattheisen, Manuel, Kim, Minsoo, Gandal, Michael J., Li, Zhiqiang, Shi, Yongyong, Zhou, Wei, Qin, Shengying, Voloudakis, Georgios, Zhang, Wen, Roussos, Panos, Adams, Mark, McIntosh, Andrew, Söderman, Erik, Jönsson, Erik G., McGrath, John J., Al Eissa, Mariam, Bass, Nicholas J., Fiorentino, Alessia, O’Brien, Niamh Louise, Pimm, Jonathan, Sharp, Sally Isabel, McQuillin, Andrew, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z., Bruggeman, Richard, Alptekin, Köksal, Amin, Farooq, Arolt, Volker, Lencer, Rebecca, Rothermundt, Matthias, Baune, Bernhard T., Arrojo, Manuel, Azevedo, Maria Helena, Bacanu, Silviu A., Webb, Bradley T., Wormley, Brandon K., Riley, Brien P., Kendler, Kenneth S., Begemann, Martin, Mitjans, Marina, Steixner-Kumar, Agnes A., Ehrenreich, Hannelore, Bene, Judit, Benyamin, Beben, Blasi, Giuseppe, Rampino, Antonio, Torretta, Silvia, Bertolino, Alessandro, Bobes, Julio, Bonassi, Stefano, Bressan, Rodrigo Affonseca, Gadelha, Ary, Noto, Cristiano, Ota, Vanessa Kiyomi, Santoro, Marcos Leite, Belangero, Sintia Iole, Bromet, Evelyn J., Buckley, Peter F., Buckner, Randy L., Cahn, Wiepke, Kahn, René S., Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Schall, Ulrich, Calkins, Monica E., Gur, Raquel E., Gur, Ruben C., Turetsky, Bruce I., Carr, Vaughan J., Castle, David, Harvey, Carol, Catts, Stanley V., Chan, Raymond C. K., Chaumette, Boris, Kebir, Oussama, Krebs, Marie-Odile, Cheng, Wei, Cheung, Eric F. C., Cohen, David, Consoli, Angèle, Giannitelli, Marianna, Laurent-Levinson, Claudine, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Quattrone, Diego, Breen, Gerome, Collier, David A., Di Forti, Marta, Vassos, Evangelos, Mondelli, Valeria, van Amelsvoort, Therese, Murray, Robin M., Davidson, Michael, Davis, Kenneth L., Haroutunian, Vahram, Malaspina, Dolores, Reichenberg, Abraham, Siever, Larry J., Silverman, Jeremy M., Buxbaum, Joseph D., de Haan, Lieuwe, Degenhardt, Franziska, Forstner, Andreas, Nöthen, Markus M., Dickerson, Faith, Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Gejman, Pablo V., Sanders, Alan R., Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanás, Lourdes, Peñas, Javier González, González-Pinto, Ana, Molto, María Dolores, Moreno, Carmen, Parellada, Mara, Sanjuan, Julio, Crepo-Facorro, Benedicto, Mata, Ignacio, Arango, Celso, Faraone, Stephen V., Frank, Josef, Streit, Fabian, Witt, Stephanie H., Rietschel, Marcella, Freimer, Nelson B., Ophoff, Roel A., Fromer, Menachem, Stahl, Eli A., Frustaci, Alessandra, Gershon, Elliot S., Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Giusti-Rodríguez, Paola, Szatkiewicz, Jin P., Godard, Stephanie, González Peñas, Javier, Gopal, Srihari, Savitz, Adam, Li, Qingqin S., Green, Michael F., Nuechterlein, Keith H., Sugar, Catherine A., Greenwood, Tiffany A., Light, Gregory A., Swerdlow, Neal R., Braff, David, Guillin, Olivier, Campion, Dominique, Gülöksüz, Sinan, Luykx, Jurjen J., Rutten, Bart P. F., van Winkel, Ruud, Gutiérrez, Blanca, Hahn, Eric, Hakonarson, Hakon, Pellegrino, Renata, Pantelis, Christos, Hayward, Caroline, Henskens, Frans A., Kelly, Brian J., Herms, Stefan, Hoffmann, Per, Ikeda, Masashi, Iwata, Nakao, Iyegbe, Conrad, van Os, Jim, Joa, Inge, Julià, Antonio, Marsal, Sara, Kam-Thong, Tony, Rautanen, Anna, Kamatani, Yoichiro, Karachanak-Yankova, Sena, Toncheva, Draga, Keller, Matthew C., Khrunin, Andrey, Limborska, Svetlana, Slominsky, Petr, Kim, Sung-Wan, Klovins, Janis, Nikitina-Zake, Liene, Kondratiev, Nikolay, Golimbet, Vera, Kubo, Michiaki, Kučinskas, Vaidutis, Kučinskiene, Zita Ausrele, Kusumawardhani, Agung, Kuzelova-Ptackova, Hana, Landi, Stefano, Lazzeroni, Laura C., Levinson, Douglas F., Petryshen, Tracey L., Lehrer, Douglas S., Lerer, Bernard, Li, Miaoxin, Lieberman, Jeffrey, Stroup, T. Scott, Liu, Chih-Min, Hwu, Hai-Gwo, Lönnqvist, Jouko, Loughland, Carmel M., Lubinski, Jan, Bakker, Steven, Kahn, René, Macek, Milan, Mackinnon, Andrew, Maher, Brion S., Maier, Wolfgang, Atbaşoğlu, Eşref Cem, Mallet, Jacques, Marder, Stephen R., Martorell, Lourdes, Muntané, Gerard, Vilella, Elisabet, Meier, Sandra, Schulze, Thomas G., McCarley, Robert W., McDonald, Colm, Donohoe, Gary, Morris, Derek W., Periyasamy, Sathish, Mowry, Bryan J., Medeiros, Helena, Sobell, Janet L., Melegh, Bela, Metspalu, Andres, Milani, Lili, Esko, Tõnu, Michie, Patricia T., Milanova, Vihra, Molden, Espen, Molina, Esther, Morley, Christopher P., Murphy, Kieran C., Myin-Germeys, Inez, Nenadić, Igor, Nestadt, Gerald, Pulver, Ann E., O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Freedman, Robert, Paunio, Tiina, Perkins, Diana O., Pfuhlmann, Bruno, Benner, Christian, Pirinen, Matti, Palotie, Aarno, Porteous, David, Powell, John, Quested, Digby, Radant, Allen D., Tsuang, Debby W., Rapaport, Mark H., Roe, Cheryl, Liu, Chunyu, Roffman, Joshua L., Roth, Julian, Gawlik, Micha, Saker-Delye, Safaa, Salomaa, Veikko, Suvisaari, Jaana, Shi, Jianxin, Sigurdsson, Engilbert, Sim, Kang, So, Hon-Cheong, Stain, Helen J., Stögmann, Elisabeth, Zimprich, Fritz, Stone, William S., Straub, Richard E., Hyde, Thomas, Jaffe, Andrew, Weinberger, Daniel R., Strengman, Eric, Svrakic, Dragan M., Cloninger, C. Robert, Ta, Thi Minh Tam, Takahashi, Atsushi, Terao, Chikashi, Thibaut, Florence, Tosato, Sarah, Tura, Gian Battista, Üçok, Alp, Vaaler, Arne, Veijola, Juha, Waddington, John, Waterreus, Anna, Morgan, Vera A., Jablensky, Assen V., Weiser, Mark, Wu, Jing Qin, Xu, Zhida, Yolken, Robert, Zai, Clement C., Kennedy, James L., Zhu, Feng, Saka, Meram C., Ayub, Muhammad, Black, Donald W., Buccola, Nancy G., Byerley, William F., Chen, Wei J., Crespo-Facorro, Benedicto, Galletly, Cherrie, Gennarelli, Massimo, Müller-Myhsok, Bertram, Neil, Amanda L., Pato, Michele T., Pato, Carlos N., Wang, Shi-Heng, Xu, Shuhua, Adolfsson, Rolf, Bramon, Elvira, Cervilla, Jorge A., Cichon, Sven, Corvin, Aiden, Gill, Michael, Curtis, David, Domenici, Enrico, Gareeva, Anna, Khusnutdinova, Elza, Glatt, Stephen J., Hong, Kyung Sue, Knowles, James A., Lee, Jimmy, Liu, Jianjun, Malhotra, Dheeraj, Menezes, Paulo R., Nimgaonkar, Vishwajit, Paciga, Sara A., Rivera, Margarita, Schwab, Sibylle G., Serretti, Alessandro, Sham, Pak C., Clair, David St, Tsuang, Ming T., Vawter, Marquis P., Werge, Thomas, Wildenauer, Dieter B., Yu, Xin, Yue, Weihua, Verhage, Matthijs, Sahasrabudhe, Dnyanada, Toonen, Ruud F., Posthuma, Danielle, Dai, Nan, Wenwen, Qin, Wildenauer, D. B., Agiananda, Feranindhya, Amir, Nurmiati, Antoni, Ronald, Arsianti, Tiana, Asmarahadi, Asmarahadi, Diatri, H., Djatmiko, Prianto, Irmansyah, Irmansyah, Khalimah, Siti, Kusumadewi, Irmia, Kusumaningrum, Profitasari, Lukman, Petrin R., Nasrun, Martina W., Safyuni, N. S., Prasetyawan, Prasetyawan, Semen, G., Siste, Kristiana, Tobing, Heriani, Widiasih, Natalia, Wiguna, Tjhin, Wulandari, D., Evalina, None, Hananto, A. J., Ismoyo, Joni H., Marini, T. M., Henuhili, Supiyani, Reza, Muhammad, Yusnadewi, Suzy, Abyzov, Alexej, Akbarian, Schahram, van Bakel, Harm, Breen, Michael, Charney, Alex, Dracheva, Stella, Girdhar, Kiran, Hoffman, Gabriel, Jiang, Yan, Pinto, Dalila, Purcell, Shaun, Roussos, Panagiotis, Wiseman, Jennifer, Ashley-Koch, Allison, Crawford, Gregory, Reddy, Tim, Brown, Miguel, Grennan, Kay, Carlyle, Becky, Emani, Prashant, Galeev, Timur, Gerstein, Mark, Gu, Mengting, Guerra, Brittney, Gursoy, Gamze, Kitchen, Robert, Lee, Donghoon, Li, Mingfeng, Liu, Shuang, Navarro, Fabio, Pan, Xinghua, Pochareddy, Sirisha, Rozowsky, Joel, Sestan, Nenad, Sethi, Anurag, Shi, Xu, Szekely, Anna, Wang, Daifeng, Warrell, Jonathan, Weissman, Sherman, Wu, Feinan, Xu, Xuming, Coetzee, Gerard, Farnham, Peggy, Lay, Fides, Rhie, Suhn, Witt, Heather, Wood, Shannon, Yao, Lijing, Gandal, Mike, Polioudakis, Damon, Swarup, Vivek, Won, Hyejung, Giase, Gina, Jiang, Shan, Kefi, Amira, Shieh, Annie, Goes, Fernando, Zandi, Peter, Kim, Yunjung, Mattei, Eugenio, Purcaro, Michael, Pratt, Henry, Peters, Mette A., Sanders, Stephan, Weng, Zhiping, White, Kevin, Arranz, Maria J., Lewis, Cathryn, Lin, Kuang, Walshe, Muriel, Bender, Stephan, Weisbrod, Matthias, Hall, Jeremy, Lawrie, Stephen, Linszen, Don H., Achsel, Tilmann, Bagni, Claudia, Andres-Alonso, Maria, Kreutz, Michael R., Bayés, Àlex, Biederer, Thomas, Brose, Nils, Chua, John Jia En, Coba, Marcelo P., Cornelisse, L. Niels, van Weering, Jan R. T., de Jong, Arthur P. H., MacGillavry, Harold D., de Juan-Sanz, Jaime, Dieterich, Daniela C., Pielot, Rainer, Smalla, Karl-Heinz, Gundelfinger, Eckart D., Goldschmidt, Hana L., Huganir, Richard L., Hoogenraad, Casper, Imig, Cordelia, Jahn, Reinhard, Jung, Hwajin, Kim, Eunjoon, Kaeser, Pascal S., Lipstein, Noa, Malenka, Robert, McPherson, Peter S., O’Connor, Vincent, Ryan, Timothy A., Sala, Carlo, Verpelli, Chiara, Smit, August B., Südhof, Thomas C., Thomas, Paul D., Medical Research Council (UK), National Natural Science Foundation of China, Royal Society (UK), Chinese Academy of Sciences, Shanghai Science and Technology Committee, Research Council of Norway, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Comunidad de Madrid, Fundación Alicia Koplowitz, Fundación Alonso Lozano, Mental Health Research UK, Wellcome Trust, Brain and Behavior Research Foundation, NIHR Biomedical Research Centre (UK), University College London, Generalitat Valenciana, Internal medicine, Human genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, RS: MHeNs - R3 - Neuroscience, MUMC+: MA Psychiatrie (3), MUMC+: MA Med Staf Spec Psychiatrie (9), MUMC+: Hersen en Zenuw Centrum (3), Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Benyamin, Beben, O'Donovan, Michael C, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Molecular and Cellular Neurobiology, Functional Genomics, and Complex Trait Genetics

Subjects
Genetics of the nervous system, Schizophrenia/genetics, VARIANTS, PROFILE, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, DISEASE, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, Alleles, Genomics, Genome-Wide Association Study, Schizophrenia, Polymorphism, RISK, ARCHITECTURE, Science & Technology, Multidisciplinary, MUTATIONS, Genetic Predisposition to Disease/genetics, Settore BIO/13, Single Nucleotide, ASSOCIATION, Polymorphism, Single Nucleotide/genetics, STATISTICS, Multidisciplinary Sciences, INDIVIDUALS, Science & Technology - Other Topics, Diseases of the nervous system, ddc:500, Single Nucleotide/genetics, INTEGRATION
Abstract

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., The work at Cardiff University was additionally supported by Medical Research Council Centre grant no. MR/L010305/1 and program grant no. G0800509. S. Xu also gratefully acknowledges the support of the National Natural Science Foundation of China (NSFC) grants (31525014, 91731303, 31771388, 31961130380 and 32041008), the UK Royal Society-Newton Advanced Fellowship (NAF\R1\191094), the Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) and the Strategic Priority Research Program (XDB38000000) of the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). O. A. Andreassen was supported by the Research Council of Norway (283798, 262656, 248980, 273291, 248828, 248778, 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, EU H2020 no. 847776. B. Melegh was supported in part by the National Scientific Research Program (NKFIH) K 138669. S. V. Faraone is supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreements 667302 and 728018 and NIMH grants 5R01MH101519 and U01 MH109536-01. S. I. Belangero was supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo), grant numbers: 2010/08968-6; 2014/07280-1 2011/50740-5 (including R. A. Bressan). The Singapore team (J. Lee, J. Liu, K. Sim, S. A. Chong and M. Subramanian) acknowledges the National Medical Research Council Translational and Clinical Research Flagship Programme (grant no.: NMRC/TCR/003/2008). M. Macek was supported by LM2018132, CZ.02.1.01/0.0/0.0/18_046/0015515 and IP6003 –VZFNM00064203. C. Arango has been funded by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF Funds from the European Commission, ‘A way of making Europe’, CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement no 115916, project PRISM; and grant agreement no. 777394, project AIMS-2-TRIALS), Fundación Familia Alonso and Fundación Alicia Koplowitz. E. Bramon acknowledges support from the National Institute of Health Research UK (grant NIHR200756); Mental Health Research UK John Grace QC Scholarship 2018; an ESRC collaborative award 2020; BMA Margaret Temple Fellowship 2016; Medical Research Council New Investigator Award (G0901310); MRC Centenary Award (G1100583); MRC project grant G1100583; National Institute of Health Research UK post-doctoral fellowship (PDA/02/06/016); NARSAD Young Investigator awards 2005 and 2008; Wellcome Trust Research Training Fellowship; Wellcome Trust Case Control Consortium awards (085475/B/08/Z, 085475/Z/08/Z); European Commission Horizon 2020 (747429); NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King’s College London; and NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London (UCLH BRC - Mental Health Theme). D. Molto is funded by the European Regional Development Fund (ERDF)–Valencian Community 2014–2020, Spain. E. G. Atkinson was supported by the NIMH K01MH121659.

Published
2022

32. A polygenic resilience score moderates the genetic risk for schizophrenia

Author

Hess, Jonathan L, Tylee, Daniel S, Mors, Ole, Duan, Jubao, Dudbridge, Frank, Duncanson, Audrey, Durmishi, Naser, Edkins, Sarah, Ehrenreich, Hannelore, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Esko, Tõnu, Nordentoft, Merete, Essioux, Laurent, Fanous, Ayman H, Farh, Kai-How, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freeman, Colin, Freimer, Nelson B, Friedl, Marion, Hougaard, David M, Friedman, Joseph I, Fromer, Menachem, Gejman, Pablo V, Genovese, Giulio, Georgieva, Lyudmila, Giannoulatou, Eleni, Giegling, Ina, Gill, Michael, Gillman, Matthew, Giusti-Rodríguez, Paola, Byberg-Grauholm, Jonas, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, Gray, Emma, Gurling, Hugh, Gwilliam, Rhian, de Haan, Lieuwe, Hall, Jeremy, Bækvad-Hansen, Marie, Hammer, Christian, Hammond, Naomi, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Hellenthal, Garrett, Henskens, Frans A, Herms, Stefan, Greenwood, Tiffany A, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Huang, Hailiang, Hultman, Christina M, Hunt, Sarah E, Ikeda, Masashi, Iwata, Nakao, Iyegbe, Conrad, Tsuang, Ming T, Jablensky, Assen V, Jankowski, Janusz, Jayakumar, Alagurevathi, Joa, Inge, Jönsson, Erik G, Julià, Antonio, Kähler, Anna K, Kahn, René S, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Curtis, David, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kendler, Kenneth S, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Kirov, George, Klovins, Janis, Knight, Jo, Steinberg, Stacy, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Langford, Cordelia, Laurent, Claudine, Lawrie, Stephen, Lee, S Hong, Lee, Phil, Sigurdsson, Engilbert, Lee, Jimmy, Legge, Sophie E, Lencz, Todd, Lerer, Bernard, Levinson, Douglas F, Lewis, Cathryn M, Li, Tao, Li, Qingqin S, Li, Miaoxin, Liang, Kung-Yee, Mattheisen, Manuel, Stefánsson, Hreinn, Liddle, Jennifer, Lieberman, Jeffrey, Limborska, Svetlana, Lin, Kuang, Linszen, Don H, Liu, Jianjun, Lönnqvist, Jouko, Loughland, Carmel M, Lubinski, Jan, Macek, Milan, Stefánsson, Kári, Magnusson, Patrik K E, Maher, Brion S, Maier, Wolfgang, Malhotra, Anil K, Mallet, Jacques, Markus, Hugh S, Marsal, Sara, Mata, Ignacio, Mathew, Christopher G, Mattingsdal, Morten, Edenberg, Howard J, McCann, Owen T, McCarley, Robert W, McCarroll, Steven A, McCarthy, Mark I, McDonald, Colm, McIntosh, Andrew M, McQuillin, Andrew, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Holmans, Peter, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Moran, Jennifer L, Morris, Derek W, Mowry, Bryan J, Faraone, Stephen V, Müller-Myhsok, Bertram, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Neale, Benjamin M, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Glatt, Stephen J, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, Nöthen, Markus M, O'Callaghan, Eadbhard, O'Donovan, Michael C, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Adolfsson, Rolf, Olsen, Line, Ophoff, Roel A, Van Os, Jim, Owen, Michael J, Palmer, Colin N A, Palotie, Aarno, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Agartz, Ingrid, Pato, Michele T, Pato, Carlos N, Paunio, Tiina, Pearson, Richard, Cairns, Murray J, DeLisi, Lynn E, Gershon, Elliot S, Kelly, Brian J, Lam, Max, Norgren, Nina, Agerbo, Esben, Paciga, Sara A, Tooney, Paul A, Wu, Jing Qin, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pers, Tune H, Petryshen, Tracey L, Pietiläinen, Olli, Pimm, Jonathan, Pirinen, Matti, Albus, Margot, Plomin, Robert, Pocklington, Andrew J, Posthuma, Danielle, Potter, Simon C, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Alexander, Madeline, Rautanen, Anna, Ravindrarajah, Radhi, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Ricketts, Michelle, Rietschel, Marcella, Riley, Brien P, Ripke, Stephan, Roffman, Joshua L, Amin, Farooq, Roussos, Panos, Ruderfer, Douglas M, Rujescu, Dan, Salomaa, Veikko, Sanders, Alan R, Sawcer, Stephen J, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Andreassen, Ole A, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Sham, Pak C, Shi, Jianxin, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Sklar, Pamela, Arranz, Maria J, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Söderman, Erik, Spencer, Chris C A, Clair, David St, Stahl, Eli A, Stogmann, Elisabeth, Strange, Amy, Straub, Richard E, Bacanu, Silviu A, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Su, Zhan, Subramaniam, Mythily, Sullivan, Patrick F, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Tashakkori-Ghanbaria, Avazeh, Bakker, Steven, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Trembath, Richard C, Veijola, Juha, Visscher, Peter M, Viswanathan, Ananth C, Vukcevic, Damjan, Waddington, John, Waller, Matthew, Band, Gavin, Walsh, Dermot, Walshe, Muriel, Walters, James T R, Wang, Qiang, Wang, Dai, Webb, Bradley T, Weinberger, Daniel R, Weisbrod, Matthias, Weiser, Mark, Wendland, Jens R, Barroso, Ines, Weston, Paul, Whittaker, Pamela, Widaa, Sara, Wiersma, Durk, Wildenauer, Dieter B, Williams, Stephanie, Williams, Nigel M, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily H M, Begemann, Martin, Wood, Nicholas W, Wormley, Brandon K, Wray, Naomi R, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Bellenguez, Céline, Research, Lundbeck Foundation Initiative for Integrative Psychiatric, Belliveau, Richard A, Bender, Stephan, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Blackburn, Hannah, Blackwell, Jenefer M, Blackwood, Douglas H R, Børglum, Anders D, Bramon, Elvira, Brown, Matthew A, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Bulik-Sullivan, Brendan, Bumpstead, Suzannah J, Buxbaum, Joseph D, Byerley, William, Cahn, Wiepke, Als, Thomas D, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Casas, Juan P, Catts, Stanley V, Chambert, Kimberley D, Chan, Ronald Y L, Chan, Raymond C K, Grove, Jakob, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cichon, Sven, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Collier, David A, Cormican, Paul, Werge, Thomas, Corvin, Aiden, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Daly, Mark J, Darvasi, Ariel, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Mortensen, Preben Bo, Deloukas, Panos, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Domenici, Enrico, Donnelly, Peter, Donohoe, Gary, Drapeau, Elodie, Dronov, Serge, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Adult Psychiatry, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Hess, Jonathan L, Tylee, Daniel S, Mattheisen, Manuel, Borglum, Anders D, Glatt, Stephen J, Lee, Sand Hong, Schizophrenia Working Group of thePsychiatric Genomics Consortium, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, and Myin-Germeys, Inez

Subjects
Multifactorial Inheritance, Schizophrenia/genetics, Genome-wide association study, Disease, Medical and Health Sciences, 0302 clinical medicine, Risk Factors, schizophrenia, genetics, risk, 2.1 Biological and endogenous factors, genetics, polygenic score, Aetiology, genome wide association study, risk, Genetics, Psychiatry, 0303 health sciences, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Genetic Predisposition to Disease/genetics, Single Nucleotide, Genomics, Biological Sciences, Serious Mental Illness, Polymorphism, Single Nucleotide/genetics, Penetrance, 3. Good health, Psychiatry and Mental health, Mental Health, Mendelian disease, Erfðarannsóknir, Life Sciences & Biomedicine, Single Nucleotide/genetics, Biochemistry & Molecular Biology, Schizophrenia (object-oriented programming), high risk, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Geðklofi, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Polymorphism, Resilience (network), Molecular Biology, resilience, Multifactorial Inheritance/genetics, Alleles, 030304 developmental biology, Science & Technology, Prevention, Human Genome, Psychology and Cognitive Sciences, Neurosciences, Brain Disorders, Lundbeck Foundation Initiative for Integrative Psychiatric Research, schizophrenia, Good Health and Well Being, Schizophrenia, Neurosciences & Neurology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531–538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known “polygenic resilience score” that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder., SJG is supported by grants from the U.S. National Institutes of Health (5R01MH101519, 5R01AG054002), the Sidney R. Baer, Jr. Foundation, and NARSAD: The Brain & Behavior Research Foundation. SVF is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreement number 667302 and NIMH grants 5R01MH101519 and U01 MH109536-01. HJE is supported by grants from the U.S. National Institutes of Health (U10 AA008401; U01 MH109532). Statistical analyses were conducted on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003) along with a supplement from the Dutch Brain Foundation and VU University. The Danish iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) and GEMS2 teams acknowledge funding from The Lundbeck Foundation (grant no R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project no: 294838), the Danish Strategic Research Council and grants from Aarhus University to the iSEQ and CIRRAU centers. The Danish National Biobank resource at Statens Serum Institut was supported by the Novo Nordisk Foundation. Computational resources for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility were provided by the iSEQ center, Aarhus University, Denmark (grant to ADB).

Published
2021

33. Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Author

Pardiñas, Antonio F., Smart, Sophie E., Corvin, Aiden, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S., Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Fanous, Ayman H., Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, Haan, Lieuwe de, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Frank, Josef, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Kelly, Brian, Julià, Antonio, Kahn, René S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, McQuillin, Andrew, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Keong, Jimmy Lee Chee, Lee, S. Hong, Melle, Ingrid, Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Mortensen, Preben B., Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Mowry, Bryan J., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Pato, Carlos N., Morris, Derek W., Mors, Ole, Murphy, Kieran C., Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Periyasamy, Sathish, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O’Callaghan, Eadbhard, O’Dushlaine, Colm, O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Os, Jim Van, Willcocks, Isabella R., Rietschel, Marcella, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietiläinen, Olli, Pimm, Jonathan, Rujescu, Dan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Simonsen, Carmen, Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., St Clair, David, Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon-Cheong, Tooney, Paul, Spencer, Chris C. A., Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Strohmaier, Jana, Stroup, T. Scott, Subramaniam, Mythily, Wu, Jing Qin, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Andreassen, Ole A., Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wong, Emily H. M., Kowalec, Kaarina, Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Blackwood, Douglas H. R., Sullivan, Patrick F., Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V., Gill, Michael, Murray, Robin M., Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jönsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Holmans, Peter A., Owen, Michael J., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., Moran, Jennifer L., Nöthen, Markus M., Ophoff, Roel A., Palotie, Aarno, Petryshen, Tracey L., MacCabe, James H., Posthuma, Danielle, Riley, Brien P., Sham, Pak C., Sklar, Pamela, Clair, David St, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., Agbedjro, Deborah, O’Donovan, Michael C., Stahl, Daniel, Kapur, Shitij, Millgate, Edward, Kepinska, Adrianna, Kravariti, Eugenia, Ajnakina, Olesya, Alameda, Luis, Barnes, Thomas R. E., Berardi, Domenico, Bonora, Elena, Walters, James T. R., Camporesi, Sara, Cleusix, Martine, Conus, Philippe, Crespo-Facorro, Benedicto, D’Andrea, Giuseppe, Demjaha, Arsime, Do, Kim Q., Doody, Gillian A., Eap, Chin B., Ferchiou, Aziz, Ripke, Stephan, Di Forti, Marta, Guidi, Lorenzo, Homman, Lina, Jenni, Raoul, Joyce, Eileen M., Kassoumeri, Laura, Khadimallah, Inès, Lastrina, Ornella, Muratori, Roberto, Noyan, Handan, Neale, Benjamin M., O’Neill, Francis A., Pignon, Baptiste, Restellini, Romeo, Richard, Jean-Romain, Schürhoff, Franck, Španiel, Filip, Szöke, Andrei, Tarricone, Ilaria, Tortelli, Andrea, Üçok, Alp, Farh, Kai-How, Vázquez-Bourgon, Javier, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Dennison, Charlotte A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A ., Lynham, Amy J., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Legge, Sophie E., Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberly D., Chan, Raymond C. K., Chen, Ronald Y. L., Chen, Eric Y. H., Cheng, Wei, Baune, Bernhard T., Cheung, Eric F. C., Chong, Siow Ann, Cloninger, C. Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Bigdeli, Tim B., Davis, Kenneth L., Degenhardt, Franziska, Favero, Jurgen Del, DeLisi, Lynn E., Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Cairns, Murray J., Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Farrell, Martilias S., Franke, Lude, Freedman, Robert, Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC), Ripke, S., Neale, B.M., Farh, K.H., Lee, P., Bulik-Sullivan, B., Collier, D.A., Huang, H., Pers, T.H., Agartz, I., Agerbo, E., Albus, M., Alexander, M., Amin, F., Bacanu, S.A., Begemann, M., Belliveau, R.A., Bene, J., Bergen, S.E., Bevilacqua, E., Black, D.W., Bruggeman, R., Buccola, N.G., Buckner, R.L., Byerley, W., Cahn, W., Cai, G., Campion, D., Cantor, R.M., Carr, V.J., Carrera, N., Catts, S.V., Chambert, K.D., Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W., Cheung, EFC, Chong, S.A., Cloninger, C.R., Cohen, D., Cohen, N., Cormican, P., Craddock, N., Crowley, J.J., Curtis, D., Davidson, M., Davis, K.L., Degenhardt, F., Favero, J.D., DeLisi, L.E., Demontis, D., Dikeos, D., Dinan, T., Djurovic, S., Donohoe, G., Drapeau, E., Duan, J., Dudbridge, F., Durmishi, N., Eichhammer, P., Eriksson, J., Escott-Price, V., Essioux, L., Farrell, M.S., Franke, L., Freedman, R., Freimer, N.B., Friedl, M., Friedman, J.I., Fromer, M., Genovese, G., Georgieva, L., Gershon, E.S., Giegling, I., Giusti-Rodríguez, P., Godard, S., Goldstein, J.I., Golimbet, V., Gopal, S., Gratten, J., Haan, L., Hammer, C., Hamshere, M.L., Hansen, M., Hansen, T., Haroutunian, V., Hartmann, A.M., Henskens, F.A., Herms, S., Hirschhorn, J.N., Hoffmann, P., Hofman, A., Hollegaard, M.V., Hougaard, D.M., Ikeda, M., Joa, I., Julià, A., Kahn, R.S., Kalaydjieva, L., Karachanak-Yankova, S., Karjalainen, J., Kavanagh, D., Keller, M.C., Kennedy, J.L., Khrunin, A., Kim, Y., Klovins, J., Knowles, J.A., Konte, B., Kucinskas, V., Kucinskiene, Z.A., Kuzelova-Ptackova, H., Kähler, A.K., Laurent, C., Keong, JLC, Lee, S.H., Lerer, B., Li, M., Li, T., Liang, K.Y., Lieberman, J., Limborska, S., Loughland, C.M., Lubinski, J., Lönnqvist, J., Macek, M., Magnusson, PKE, Maher, B.S., Maier, W., Mallet, J., Marsal, S., Mattheisen, M., Mattingsdal, M., McCarley, R.W., McDonald, C., McIntosh, A.M., Meier, S., Meijer, C.J., Melegh, B., Melle, I., Mesholam-Gately, R.I., Metspalu, A., Michie, P.T., Milani, L., Milanova, V., Mokrab, Y., Morris, D.W., Mors, O., Murphy, K.C., Myin-Germeys, I., Müller-Myhsok, B., Nelis, M., Nenadic, I., Nertney, D.A., Nestadt, G., Nicodemus, K.K., Nikitina-Zake, L., Nisenbaum, L., Nordin, A., O'Callaghan, E., O'Dushlaine, C., O'Neill, F.A., Oh, S.Y., Olincy, A., Olsen, L., Os, J.V., Pantelis, C., Papadimitriou, G.N., Papiol, S., Parkhomenko, E., Pato, M.T., Paunio, T., Pejovic-Milovancevic, M., Perkins, D.O., Pietiläinen, O., Pimm, J., Pocklington, A.J., Powell, J., Price, A., Pulver, A.E., Purcell, S.M., Quested, D., Rasmussen, H.B., Reichenberg, A., Reimers, M.A., Richards, A.L., Roffman, J.L., Roussos, P., Ruderfer, D.M., Salomaa, V., Sanders, A.R., Schall, U., Schubert, C.R., Schulze, T.G., Schwab, S.G., Scolnick, E.M., Scott, R.J., Seidman, L.J., Shi, J., Sigurdsson, E., Silagadze, T., Silverman, J.M., Sim, K., Slominsky, P., Smoller, J.W., So, H.C., Spencer, CCA, Stahl, E.A., Stefansson, H., Steinberg, S., Stogmann, E., Straub, R.E., Strengman, E., Strohmaier, J., Stroup, T.S., Subramaniam, M., Suvisaari, J., Svrakic, D.M., Szatkiewicz, J.P., Söderman, E., Thirumalai, S., Toncheva, D., Tosato, S., Veijola, J., Waddington, J., Walsh, D., Wang, D., Wang, Q., Webb, B.T., Weiser, M., Wildenauer, D.B., Williams, N.M., Williams, S., Witt, S.H., Wolen, A.R., Wong, EHM, Wormley, B.K., Xi, H.S., Zai, C.C., Zheng, X., Zimprich, F., Wray, N.R., Stefansson, K., Visscher, P.M., Adolfsson, R., Blackwood, DHR, Bramon, E., Buxbaum, J.D., Børglum, A.D., Cichon, S., Darvasi, A., Domenici, E., Ehrenreich, H., Esko, T., Gejman, P.V., Gill, M., Gurling, H., Hultman, C.M., Iwata, N., Jablensky, A.V., Jönsson, E.G., Kendler, K.S., Kirov, G., Knight, J., Lencz, T., Levinson, D.F., Li, Q.S., Liu, J., Malhotra, A.K., McCarroll, S.A., Moran, J.L., Mortensen, P.B., Nöthen, M.M., Ophoff, R.A., Palotie, A., Petryshen, T.L., Posthuma, D., Riley, B.P., Sham, P.C., Sklar, P., Clair, D.S., Weinberger, D.R., Wendland, J.R., Werge, T., Daly, M.J., Agbedjro, D., Stahl, D., Kapur, S., Millgate, E., Kepinska, A., Kravariti, E., Medical Research Council (UK), Cardiff University, Welsh Government, Health and Care Research Wales, European Commission, Academy of Medical Sciences (UK), Research Council of Norway, K. G. Jebsen Centres for Medical Research, National Institute for Health Research (UK), University College London, Government of Canada, University of Manitoba, Swedish Research Council, National Institute of Mental Health (US), Kings College London, Public Health Agency (Northern Ireland), The Psychiatry Research Trust, Maudsley Charity, Swiss National Science Foundation, Fondation Alamaya, Ministry of Health of the Czech Republic, Instituto de Salud Carlos III, Plan Nacional sobre Drogas (España), Fundació Seny, Fundación Marques de Valdecilla, Ministerio de Economía y Competitividad (España), Wellcome Trust, and Universidad de Cantabria

Subjects
Male, endocrine system, Multifactorial Inheritance, animal structures, Psychiatry and Behavioral Health, Online First, Humans, Genetic Predisposition to Disease, ddc:610, Neurogenetics, Medicinsk genetik, Original Investigation, Research, Schizophrenia Sprectum and Other Psychotic Disorders, Featured, Genetics and genomics, Psychiatry and Mental health, Neurology, Psychotic Disorders, Schizophrenia, Female, Medical Genetics, hormones, hormone substitutes, and hormone antagonists, Comments, Genome-Wide Association Study
Abstract

[Importance] About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts., [Objective] To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples., [Design, Setting, and Participants] Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G])., [Main Outcomes and Measures] GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition., [Results] The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04)., [Conclusions and Relevance] In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance., This work was supported by Medical Research Council Centre grant MR/L010305/1, Medical Research Council Program grant MR/P005748/1, and Medical Research Council Project grants MR/L011794/1 and MC_PC_17212 to Cardiff University and by the National Centre for Mental Health, funded by the Welsh Government through Health and Care Research Wales. This work acknowledges the support of the Supercomputing Wales project, which is partially funded by the European Regional Development Fund via the Welsh Government. Dr Pardiñas was supported by an Academy of Medical Sciences Springboard Award (SBF005\1083). Dr Andreassen was supported by the Research Council of Norway (grants 283798, 262656, 248980, 273291, 248828, 248778, and 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, and the European Union’s Horizon 2020 Research and Innovation Programme (grant 847776). Dr Ajnakina was supported by an National Institute for Health Research postdoctoral fellowship (PDF-2018-11-ST2-020). Dr Joyce was supported by the University College London Hospitals/UCL University College London Biomedical Research Centre. Dr Kowalec received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement (793530) from the government of Canada Banting postdoctoral fellowship programme and the University of Manitoba. Dr Sullivan was supported by the Swedish Research Council (Vetenskapsrådet, D0886501), the European Union’s Horizon 2020 programme (COSYN, 610307) and the US National Institute of Mental Health (U01 MH109528 and R01 MH077139). The Psychiatric Genomics Consortium was partly supported by the National Institute Of Mental Health (grants R01MH124873). The Sweden Schizophrenia Study was supported by the National Institute Of Mental Health (grant R01MH077139). The STRATA consortium was supported by a Stratified Medicine Programme grant to Dr MacCabe from the Medical Research Council (grant MR/L011794/1), which funded the research and supported Drs Pardiñas, Smart, Kassoumeri, Murray, Walters, and MacCabe. Dr Smart was supported by a Collaboration for Leadership in Applied Health Research and Care South London at King’s College Hospital National Health Service Foundation Trust. The AESOP (US) cohort was funded by the UK Medical Research Council (grant G0500817). The Belfast (UK) cohort was funded by the Research and Development Office of Northern Ireland. The Bologna (Italy) cohort was funded by the European Community’s Seventh Framework program (HEALTH-F2-2010–241909, project EU-GEI). The Genetics and Psychosis project (London, UK) cohort was funded by the UK National Institute of Health Research Specialist Biomedical Research Centre for Mental Health, South London and the Maudsley National Health Service Mental Health Foundation Trust (SLAM) and the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London; Psychiatry Research Trust; Maudsley Charity Research Fund; and the European Community’s Seventh Framework program (HEALTH-F2-2009-241909, project EU-GEI). The Lausanne (Switzerland) cohort was funded by the Swiss National Science Foundation (grants 320030_135736/1, 320030-120686, 324730-144064, 320030-173211, and 171804); the National Center of Competence in Research Synaptic Bases of Mental Diseases from the Swiss National Science Foundation (grant 51AU40_125759); and Fondation Alamaya. The Oslo (Norway) cohort was funded by the Research Council of Norway (grant 223273/F50, under the Centers of Excellence funding scheme, 300309, 283798) and the South-Eastern Norway Regional Health Authority (grants 2006233, 2006258, 2011085, 2014102, 2015088, and 2017-112). The Paris (France) cohort was funded by European Community’s Seventh Framework program (HEALTH-F2-2010–241909, project EU-GEI). The Prague (Czech Republic) cohort was funded by the Ministry of Health of the Czech Republic (grant NU20-04-00393). The Santander (Spain) cohort was funded by the following grants to Dr Crespo-Facorro: Instituto de Salud Carlos III (grants FIS00/3095, PI020499, PI050427, and PI060507), Plan Nacional de Drogas Research (grant 2005-Orden sco/3246/2004), SENY Fundatio Research (grant 2005-0308007), Fundacion Marques de Valdecilla (grant A/02/07, API07/011) and Ministry of Economy and Competitiveness and the European Fund for Regional Development (grants SAF2016-76046-R and SAF2013-46292-R). The West London (UK) cohort was funded by The Wellcome Trust (grants 042025, 052247, and 064607).

Published
2022

34. Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders

Author

Andlauer, Till F M, Guzman-Parra, Jose, Orozco Diaz, Guillermo, Freimer, Nelson B, Frisén, Louise, Gade, Katrin, Gage, Diane, Garnham, Julie, Giambartolomei, Claudia, Pedersen, Marianne Giørtz, Goldstein, Jaqueline, Gordon, Scott D, Gordon-Smith, Katherine, de Diego-Otero, Yolanda, Green, Elaine K, Green, Melissa J, Greenwood, Tiffany A, Grove, Jakob, Guan, Weihua, Parra, José Guzman, Hamshere, Marian L, Hautzinger, Martin, Heilbronner, Urs, Herms, Stefan, Moreno-Küstner, Berta, Hipolito, Maria, Hoffmann, Per, Holland, Dominic, Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S, Juréus, Anders, Kandaswamy, Radhika, Karlsson, Robert, Kennedy, James L, Auburger, Georg, Kittel-Schneider, Sarah, Knowles, James A, Kogevinas, Manolis, Koller, Anna C, Kupka, Ralph, Lavebratt, Catharina, Lawrence, Jacob, Lawson, William B, Leber, Markus, Lee, Phil H, Degenhardt, Franziska, Levy, Shawn E, Li, Jun Z, Liu, Chunyu, Lucae, Susanne, Maaser, Anna, MacIntyre, Donald J, Mahon, Pamela B, Maier, Wolfgang, Martinsson, Lina, McCarroll, Steve, Heilmann-Heimbach, Stefanie, McGuffin, Peter, McInnis, Melvin G, McKay, James D, Medeiros, Helena, Medland, Sarah E, Meng, Fan, Milani, Lili, Montgomery, Grant W, Morris, Derek W, Mühleisen, Thomas W, Mullins, Niamh, Nguyen, Hoang, Nievergelt, Caroline M, Adolfsson, Annelie Nordin, Nwulia, Evaristus A, O'Donovan, Claire, Loohuis, Loes M Olde, Ori, Anil P S, Oruc, Lilijana, Ösby, Urban, Perlis, Roy H, Perry, Amy, Pfennig, Andrea, Potash, James B, Purcell, Shaun M, Regeer, Eline J, Reif, Andreas, Reinbold, Céline S, Rice, John P, Richards, Alexander L, Frank, Josef, Rivas, Fabio, Rivera, Margarita, Roussos, Panos, Ruderfer, Douglas M, Ryu, Euijung, Sánchez-Mora, Cristina, Schatzberg, Alan F, Scheftner, William A, Schork, Nicholas J, Weickert, Cynthia Shannon, Foo, Jerome C, Shehktman, Tatyana, Shilling, Paul D, Sigurdsson, Engilbert, Slaney, Claire, Smeland, Olav B, Sobell, Janet L, Hansen, Christine Søholm, Spijker, Anne T, Clair, David St, Steffens, Michael, Streit, Fabian, Treutlein, Jens, Strauss, John S, Strohmaier, Jana, Szelinger, Szabolcs, Thompson, Robert C, EThorgeirsson, Thorgeir, Vedde, Helmut, Wang, Weiqing, Watson, Stanley J, Witt, Stephanie H, Weickert, Thomas W, Xi, Simon, Xu, Wei, Young, Allan H, Zandi, Peter, Zhang, Peng, Zollner, Sebastian, Adolfsson, Rolf, Agartz, Ingrid, Cichon, Sven, Alda, Martin, Backlund, Lena, Baune, Bernhard T, Bellivier, Frank, Berrettini, Wade H, Biernacka, Joanna M, Blackwood, Douglas H R, Boehnke, Michael, Børglum, Anders D, Corvin, Aiden, Craddock, Nicholas, Daly, Mark J, Dannlowski, Udo, Esko, Tõnu, Etain, Bruno, Frye, Mark, Fullerton, Janice M, Gershon, Elliot S, Gill, Michael, Goes, Fernando, Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Hougaard, David M, Hultman, Christina M, Jones, Ian, Jones, Lisa A, Kahn, René S, Kirov, George, Landén, Mikael, Leboyer, Marion, Mayoral, Fermín, Lewis, Cathryn M, Li, Qingqin S, Lissowska, Jolanta, Martin, Nicholas G, Mayoral, Fermin, McElroy, Susan L, McIntosh, Andrew M, McMahon, Francis J, Melle, Ingrid, Metspalu, Andres, Müller-Myhsok, Bertram, Mitchell, Philip B, Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Myers, Richard M, Neale, Benjamin M, Nimgaonkar, Vishwajit, Nordentoft, Merete, Nöthen, Markus M, Forstner, Andreas J, O'Donovan, Michael C, Oedegaard, Ketil J, Owen, Michael J, Paciga, Sara A, Pato, Carlos, Pato, Michele T, Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Ribasés, Marta, Rietschel, Marcella, Rouleau, Guy A, Schalling, Martin, Schofield, Peter R, Schulze, Thomas G, Serretti, Alessandro, Smoller, Jordan W, Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Sullivan, Patrick F, Turecki, Gustavo, Vaaler, Arne E, Vieta, Eduard, Vincent, John B, Werge, Thomas, Nurnberger, John I, Wray, Naomi R, Florio, Arianna Di, Edenberg, Howard J, Stahl, Eli A, Ophoff, Roel A, Scott, Laura J, Andreassen, Ole A, Kelsoe, John, Sklar, Pamela, Ripke, Stephan, Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M, Breen, Gerome, Abdellaoui, Abdel, Adams, Mark J, Agerbo, Esben, Air, Tracy M, Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T F, Bigdeli, Tim B, Binder, Elisabeth B, Bryois, Julien, Buttenschøn, Henriette N, Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane Hvarregaard, Clarke, Toni-Kim, Coleman, Jonathan R I, Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, McQuillin, Andrew, Craddock, Nick, Crawford, Gregory E, Davies, Gail, Deary, Ian J, Derks, Eske M, Direk, Nese, Dolan, Conor V, Dunn, Erin C, Eley, Thalia C, Escott-Price, Valentina, Kiadeh, Farnush Farhadi Hassan, Finucane, Hilary K, Gaspar, Héléna A, Goes, Fernando S, Trubetskoy, Vassily, Hall, Lynsey S, Hansen, Thomas F, Hickie, Ian B, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Howard, David M, Ising, Marcus, Jansen, Rick, Jorgenson, Eric, Kohane, Isaac S, Kraft, Julia, Wang, Yunpeng, Kretzschmar, Warren W, Kutalik, Zoltán, Li, Yihan, Lind, Penelope A, MacKinnon, Dean F, Maier, Robert M, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, Mehta, Divya, Middeldorp, Christel M, Mihailov, Evelin, Milaneschi, Yuri, Mondimore, Francis M, Mostafavi, Sara, Nauck, Matthias, Ng, Bernard, Nivard, Michel G, Nyholt, Dale R, O'Reilly, Paul F, Oskarsson, Hogni, Painter, Jodie N, González, Maria José, de Leeuw, Christiaan A, Pedersen, Carsten Bøcker, Peterson, Roseann E, Pettersson, Erik, Peyrot, Wouter J, Pistis, Giorgio, Quiroz, Jorge A, Qvist, Per, Steinberg, Stacy, Riley, Brien P, Mirza, Saira Saeed, Schoevers, Robert, Schulte, Eva C, Shen, Ling, Shi, Jianxin, Shyn, Stanley I, Sinnamon, Grant C B, Pavlides, Jennifer M Whitehead, Smit, Johannes H, Smith, Daniel J, Tansey, Katherine E, Teismann, Henning, Teumer, Alexander, Thompson, Wesley, Thomson, Pippa A, Thorgeirsson, Thorgeir E, Traylor, Matthew, Uitterlinden, André G, Umbricht, Daniel, Van der Auwera, Sandra, van Hemert, Albert M, Viktorin, Alexander, Pers, Tune H, Visscher, Peter M, Webb, Bradley T, Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Wu, Yang, Xi, Hualin S, Yang, Jian, Holmans, Peter A, Zhang, Futao, Arolt, Volker, Berger, Klaus, Boomsma, Dorret I, de Geus, E. J. C., DePaulo, J Raymond, Domenici, Enrico, Abbott, Liam, Domschke, Katharina, Grabe, Hans J, Hamilton, Steven P, Hayward, Caroline, Heath, Andrew C, Kendler, Kenneth S, Kloiber, Stefan, Lewis, Glyn, Madden, Pamela A F, Magnusson, Patrik K, Akil, Huda, Pedersen, Nancy L, Penninx, Brenda W J H, Porteous, David J, Preisig, Martin, Albani, Diego, Schaefer, Catherine, Tiemeier, Henning, Uher, Rudolf, Völzke, Henry, Weissman, Myrna M, Gil Flores, Susana, Alliey-Rodriguez, Ney, Levinson, Douglas F, Als, Thomas D, Anjorin, Adebayo, Antilla, Verneri, Awasthi, Swapnil, Badner, Judith A, Barchas, Jack D, Bass, Nicholas, Bauer, Michael, Cabaleiro Fabeiro, Francisco J, Belliveau, Richard, Bergen, Sarah E, Bøen, Erlend, Boks, Marco, Boocock, James, Budde, Monika, Bunney, William, Burmeister, Margit, Del Río Noriega, Francisco, Byerley, William, Casas, Miquel, Cerrato, Felecia, Cervantes, Pablo, Chambert, Kimberly, Charney, Alexander W, Chen, Danfeng, Churchhouse, Claire, Coryell, William, Perez, Fermin Perez, Craig, David W, Cruceanu, Cristiana, Czerski, Piotr M, Dale, Anders M, de Jong, Simone, Del-Favero, Jurgen, Djurovic, Srdjan, Dobbyn, Amanda L, Haro González, Jesus, Dumont, Ashley, Elvsåshagen, Torbjørn, Fan, Chun Chieh, Fischer, Sascha B, Flickinger, Matthew, Foroud, Tatiana M, Forty, Liz, Fraser, Christine, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, Epidemiology and Data Science, APH - Digital Health, Andlauer T.F.M., Guzman-Parra J., Streit F., Strohmaier J., Gonzalez M.J., Gil Flores S., Cabaleiro Fabeiro F.J., del Rio Noriega F., Perez F.P., Haro Gonzalez J., Orozco Diaz G., de Diego-Otero Y., Moreno-Kustner B., Auburger G., Degenhardt F., Heilmann-Heimbach S., Herms S., Hoffmann P., Frank J., Foo J.C., Treutlein J., Witt S.H., Cichon S., Kogevinas M., Stahl E.A., Breen G., Forstner A.J., McQuillin A., Ripke S., Trubetskoy V., Mattheisen M., Wang Y., Coleman J.R.I., Gaspar H.A., de Leeuw C.A., Steinberg S., Pavlides J.M.W., Trzaskowski M., Pers T.H., Holmans P.A., Abbott L., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Anjorin A., Antilla V., Awasthi S., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Belliveau R., Bergen S.E., Pedersen C.B., Boen E., Boks M., Boocock J., Budde M., Bunney W., Burmeister M., Bybjerg-Grauholm J., Byerley W., Casas M., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Churchhouse C., Clarke T.-K., Coryell W., Craig D.W., Cruceanu C., Czerski P.M., Dale A.M., de Jong S., Del-Favero J., DePaulo J.R., Djurovic S., Dobbyn A.L., Dumont A., Elvsashagen T., Escott-Price V., Fan C.C., Fischer S.B., Flickinger M., Foroud T.M., Forty L., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Pedersen M.G., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Parra J.G., Hamshere M.L., Hautzinger M., Heilbronner U., Hipolito M., Holland D., Huckins L., Jamain S., Johnson J.S., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Koller A.C., Kupka R., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Liu C., Lucae S., Maaser A., MacIntyre D.J., Mahon P.B., Maier W., Martinsson L., McCarroll S., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Meng F., Milani L., Montgomery G.W., Morris D.W., Muhleisen T.W., Mullins N., Nguyen H., Nievergelt C.M., Adolfsson A.N., Nwulia E.A., O'Donovan C., Loohuis L.M.O., Ori A.P.S., Oruc L., Osby U., Perlis R.H., Perry A., Pfennig A., Potash J.B., Purcell S.M., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Richards A.L., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schork N.J., Weickert C.S., Shehktman T., Shilling P.D., Sigurdsson E., Slaney C., Smeland O.B., Sobell J.L., Hansen C.S., Spijker A.T., Clair D.S., Steffens M., Strauss J.S., Szelinger S., Thompson R.C., EThorgeirsson T., Vedde H., Wang W., Watson S.J., Weickert T.W., Xi S., Xu W., Young A.H., Zandi P., Zhang P., Zollner S., Adolfsson R., Agartz I., Alda M., Backlund L., Baune B.T., Bellivier F., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Borglum A.D., Corvin A., Craddock N., Daly M.J., Dannlowski U., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., Gill M., Goes F., Grigoroiu-Serbanescu M., Hauser J., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Posthuma D., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Werge T., Nurnberger J.I., Wray N.R., Florio A.D., Edenberg H.J., Ophoff R.A., Scott L.J., Andreassen O.A., Kelsoe J., Sklar P., Byrne E.M., Abdellaoui A., Adams M.J., Air T.M., Bacanu S.-A., Beekman A.T.F., Bigdeli T.B., Binder E.B., Bryois J., Buttenschon H.N., Cai N., Castelao E., Christensen J.H., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Deary I.J., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Kiadeh F.F.H., Finucane H.K., Goes F.S., Hall L.S., Hansen T.F., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Howard D.M., Ising M., Jansen R., Jorgenson E., Kohane I.S., Hill, Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacKinnon D.F., Maier R.M., Marchini J., Mbarek H., McGrath P., Mehta D., Middeldorp C.M., Mihailov E., Milaneschi Y., Mondimore F.M., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Painter J.N., Peterson R.E., Pettersson E., Peyrot W.J., Pistis G., Quiroz J.A., Qvist P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Shi J., Shyn S.I., Sinnamon G.C.B., Smit J.H., Smith D.J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Uitterlinden A.G., Umbricht D., Van der Auwera S., van Hemert A.M., Viktorin A., Visscher P.M., Webb B.T., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Berger K., Boomsma D.I., de Geus E.J.C., Domenici E., Domschke K., Grabe H.J., Hamilton S.P., Hayward C., Heath A.C., Kendler K.S., Kloiber S., Lewis G., Madden P.A.F., Magnusson P.K., Pedersen N.L., Penninx B.W.J.H., Porteous D.J., Preisig M., Schaefer C., Tiemeier H., Uher R., Volzke H., Weissman M.M., Levinson D.F., Child and Adolescent Psychiatry / Psychology, Epidemiology, Internal Medicine, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Complex Trait Genetics, and Adult Psychiatry

Subjects
Netherlands Twin Register (NTR), Genetic variants, Bipolar Disorder, Specific risk, Disease, 0302 clinical medicine, Multiplex, Genetic risk, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Depression (differential diagnoses), 0303 health sciences, Depression, ddc, 3. Good health, Geðraskanir, Psychiatry and Mental health, Schizophrenia, Cohort, Major depressive disorder, Case-Control Studie, Human, medicine.medical_specialty, Bipolar disorder, Article, Cellular and Molecular Neuroscience, 03 medical and health sciences, Geðklofi, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Psychiatry, Þunglyndi, Molecular Biology, 030304 developmental biology, Depressive Disorder, Major, Geðhvarfasýki, business.industry, Psychiatric disorder, medicine.disease, Genarannsóknir, Case-Control Studies, Multiple comparisons problem, business, 030217 neurology & neurosurgery
Abstract

Publisher's version, Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development., The study was supported by the German Federal Ministry of Education and Research (BMBF), through the Integrated Network IntegraMent, under the auspices of the e:Med programme (grants 01ZX1314A to MMN and SC; 01ZX1314G to MR; 01ZX1614J to BMM) through grants 01EE1406C to MR and 01EE1409C to MR and SHW, and through ERA-NET NEURON, “SynSchiz—Linking synaptic dysfunction to disease mechanisms in schizophrenia—a multilevel investigation” (01EW1810 to MR) and BMBF grants 01EE1409C and 01EE1406C to MR and SHW; by the German Research Foundation (DFG grants FOR2107; RI908/11-2 to MR; NO246/10-2 to MMN; MU1315/8-2 to BMM; WI 3439/3-2 to SHW), by the Andalusian regional Health and Innovation Government (grants PI-0060-2017, RC-0006-2015 the Nicolas Monarde Programme for YDO and CTS-546) and by the Swiss National Science Foundation (SNSF grant 156791 to SC). MMN is a member of the DFG-funded cluster of excellence ImmunoSensation. The PGC has received major funding from the US National Institute of Mental Health and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320). We thank the research participants and employees of 23andMe, Inc. for their contribution to the MDD meta-analysis published in [14]. We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for the present analyses. See the Supplementary Data for extended Acknowledgements.

Published
2021

35. Characterisation of age and polarity at onset in bipolar disorder

Author

Kalman, Janos, Olde Loohuis, Loes, Vreeker, Annabel, Mcquillin, Andrew, Stahl, Eli, Ruderfer, Douglas, Grigoroiu-Serbanescu, Maria, Panagiotaropoulou, Georgia, Ripke, Stephan, Bigdeli, Tim, Stein, Frederike, Meller, Tina, Meinert, Susanne, Pelin, Helena, Streit, Fabian, Papiol, Sergi, Adams, Mark, Adolfsson, Rolf, Adorjan, Kristina, Agartz, Ingrid, Aminoff, Sofie, Anderson-Schmidt, Heike, Andreassen, Ole, Ardau, Raffaella, Aubry, Jean-Michel, Balaban, Ceylan, Bass, Nicholas, Baune, Bernhard, Bellivier, Frank, Benabarre, Antoni, Bengesser, Susanne, Berrettini, Wade, Boks, Marco, Bromet, Evelyn, Brosch, Katharina, Budde, Monika, Byerley, William, Cervantes, Pablo, Chillotti, Catina, Cichon, Sven, Clark, Scott, Comes, Ashley, Corvin, Aiden, Coryell, William, Craddock, Nick, Craig, David, Croarkin, Paul, Cruceanu, Cristiana, Czerski, Piotr, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, del Zompo, Maria, Depaulo, J Raymond, Djurovic, Srdjan, Edenberg, Howard, Eissa, Mariam Al, Elvsåshagen, Torbjørn, Etain, Bruno, Fanous, Ayman, Fellendorf, Frederike, Fiorentino, Alessia, Forstner, Andreas, Frye, Mark, Fullerton, Janice, Gade, Katrin, Garnham, Julie, Gershon, Elliot, Gill, Michael, Goes, Fernando, Gordon-Smith, Katherine, Grof, Paul, Guzman-Parra, Jose, Hahn, Tim, Hasler, Roland, Heilbronner, Maria, Heilbronner, Urs, Jamain, Stephane, Jimenez, Esther, Jones, Ian, Jones, Lisa, Jonsson, Lina, Kahn, Rene, Kelsoe, John, Kennedy, James, Kircher, Tilo, Kirov, George, Kittel-Schneider, Sarah, Klöhn-Saghatolislam, Farah, Knowles, James, Kranz, Thorsten, Lagerberg, Trine Vik, Landen, Mikael, Lawson, William, Leboyer, Marion, Li, Qingqin, Maj, Mario, Malaspina, Dolores, Manchia, Mirko, Mayoral, Fermin, Mcelroy, Susan, Mcinnis, Melvin, McIntosh, Andrew, Medeiros, Helena, Melle, Ingrid, Milanova, Vihra, Mitchell, Philip, Monteleone, Palmiero, Monteleone, Alessio Maria, Nöthen, Markus, Novak, Tomas, Nurnberger, John, O'Brien, Niamh, O'Connell, Kevin, O'Donovan, Claire, O'Donovan, Michael, Opel, Nils, Ortiz, Abigail, Owen, Michael, Pålsson, Erik, Pato, Carlos, Pato, Michele, Pawlak, Joanna, Pfarr, Julia-Katharina, Pisanu, Claudia, Potash, James, Rapaport, Mark, Reich-Erkelenz, Daniela, Reif, Andreas, Reininghaus, Eva, Repple, Jonathan, Richard-Lepouriel, Hélène, Rietschel, Marcella, Ringwald, Kai, Roberts, Gloria, Rouleau, Guy, Schaupp, Sabrina, Scheftner, William, Schmitt, Simon, Schofield, Peter, Schubert, K Oliver, Schulte, Eva, Schweizer, Barbara, Senner, Fanny, Severino, Giovanni, Sharp, Sally, Slaney, Claire, Smeland, Olav, Sobell, Janet, Squassina, Alessio, Stopkova, Pavla, Strauss, John, Tortorella, Alfonso, Turecki, Gustavo, Twarowska-Hauser, Joanna, Veldic, Marin, Vieta, Eduard, Vincent, John, Xu, Wei, Zai, Clement, Zandi, Peter, Di Florio, Arianna, Smoller, Jordan, Biernacka, Joanna, Mcmahon, Francis, Alda, Martin, Müller-Myhsok, Bertram, Koutsouleris, Nikolaos, Falkai, Peter, Freimer, Nelson, Andlauer, Till, Schulze, Thomas, Ophoff, Roel, Depaulo, J. Raymond, Schubert, K. Oliver, Andlauer, Till F.M., Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Etain, Bruno, Child and Adolescent Psychiatry / Psychology, Psychiatry, Kalman, J. L., Loohuis, L. M. O., Vreeker, A., Mcquillin, A., Stahl, E. A., Ruderfer, D., Grigoroiu-Serbanescu, M., Panagiotaropoulou, G., Ripke, S., Bigdeli, T. B., Stein, F., Meller, T., Meinert, S., Pelin, H., Streit, F., Papiol, S., Adams, M. J., Adolfsson, R., Adorjan, K., Agartz, I., Aminoff, S. R., Anderson-Schmidt, H., Andreassen, O. A., Ardau, R., Aubry, J. -M., Balaban, C., Bass, N., Baune, B. T., Bellivier, F., Benabarre, A., Bengesser, S., Berrettini, W. H., Boks, M. P., Bromet, E. J., Brosch, K., Budde, M., Byerley, W., Cervantes, P., Chillotti, C., Cichon, S., Clark, S. R., Comes, A. L., Corvin, A., Coryell, W., Craddock, N., Craig, D. W., Croarkin, P. E., Cruceanu, C., Czerski, P. M., Dalkner, N., Dannlowski, U., Degenhardt, F., Del Zompo, M., Depaulo, J. R., Djurovic, S., Edenberg, H. J., Al Eissa, M., Elvsashagen, T., Etain, B., Fanous, A. H., Fellendorf, F., Fiorentino, A., Forstner, A. J., Frye, M. A., Fullerton, J. M., Gade, K., Garnham, J., Gershon, E., Gill, M., Goes, F. S., Gordon-Smith, K., Grof, P., Guzman-Parra, J., Hahn, T., Hasler, R., Heilbronner, M., Heilbronner, U., Jamain, S., Jimenez, E., Jones, I., Jones, L., Jonsson, L., Kahn, R. S., Kelsoe, J. R., Kennedy, J. L., Kircher, T., Kirov, G., Kittel-Schneider, S., Klohn-Saghatolislam, F., Knowles, J. A., Kranz, T. M., Lagerberg, T. V., Landen, M., Lawson, W. B., Leboyer, M., Li, Q. S., Maj, M., Malaspina, D., Manchia, M., Mayoral, F., Mcelroy, S. L., Mcinnis, M. G., Mcintosh, A. M., Medeiros, H., Melle, I., Milanova, V., Mitchell, P. B., Monteleone, P., Monteleone, A. M., Nothen, M. M., Novak, T., Nurnberger, J. I., O'Brien, N., O'Connell, K. S., O'Donovan, C., O'Donovan, M. C., Opel, N., Ortiz, A., Owen, M. J., Palsson, E., Pato, C., Pato, M. T., Pawlak, J., Pfarr, J. -K., Pisanu, C., Potash, J. B., Rapaport, M. H., Reich-Erkelenz, D., Reif, A., Reininghaus, E., Repple, J., Richard-Lepouriel, H., Rietschel, M., Ringwald, K., Roberts, G., Rouleau, G., Schaupp, S., Scheftner, W. A., Schmitt, S., Schofield, P. R., Schubert, K. O., Schulte, E. C., Schweizer, B., Senner, F., Severino, G., Sharp, S., Slaney, C., Smeland, O. B., Sobell, J. L., Squassina, A., Stopkova, P., Strauss, J., Tortorella, A., Turecki, G., Twarowska-Hauser, J., Veldic, M., Vieta, E., Vincent, J. B., Xu, W., Zai, C. C., Zandi, P. P., Di Florio, A., Smoller, J. W., Biernacka, J. M., Mcmahon, F. J., Alda, M., Muller-Myhsok, B., Koutsouleris, N., Falkai, P., Freimer, N. B., Andlauer, T. F. M., Schulze, T. G., and Ophoff, R. A.

Subjects
Paper, Multifactorial Inheritance, medicine.medical_specialty, Autism Spectrum Disorder, Bipolar disorder, MESH: Age of Onset, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Medizin, GWAS, age at onset, polarity at onset, polygenic score, MESH: Depressive Disorder, Major, BF, Genome-wide association study, Disease, Psykiatri, SDG 3 - Good Health and Well-being, ddc:150, Polarity at onset, Internal medicine, MESH: Bipolar Disorder, Polygenic score, medicine, Humans, Academic Psychiatry, Age of Onset, Genetic association, Psychiatry, MESH: Autism Spectrum Disorder, Depressive Disorder, Major, MESH: Humans, business.industry, Age at onset, Heritability, medicine.disease, Genetic architecture, ddc, Psychiatry and Mental health, Schizophrenia, Autism spectrum disorder, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Genome-Wide Association Study, RC0321, MESH: Multifactorial Inheritance, business, Genome-Wide Association Study
Abstract

BackgroundStudying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.AimsTo examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.MethodGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.ResultsEarlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.ConclusionsAAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Published
2021

36. Analysis of shared heritability in common disorders of the brain

Author

Brainstorm Consortium, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nicholas, Kurth, Tobias, Ligthart, Lannie, Terwindt, Gisela M, Freilinger, Tobias, Ran, Caroline, Gordon, Scott D, Borck, Guntram, Adams, Hieab HH, Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E, Schürks, Markus, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G, Montgomery, Grant W, Kurki, Mitja I, Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfons, Pozo-Rosich, Patricia, Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Metspalu, Andres, Kubisch, Christian, Ferrari, Michel D, Belin, Andrea C, Van Den Maagdenberg, Arn MJM, Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nicholas, Olesen, Jes, Chasman, Daniel I, Nyholt, Dale R, Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell J, Catarino, Claudia B, Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Dennis, Ferraro, Thomas N, French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S, Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S, Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thomas, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M, Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Thomas, G Neil, Visscher, Frank, Whelan, Christopher D, Zara, Federico, Heinzen, Erin L, Marson, Anthony, Becker, Felicitas, Stroink, Hans, Zimprich, Fritz, Gasser, Thomas, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R, Sharma, Manu, Ryten, Mina, Mok, Kin Y, Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thomas, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Boraska Perica, Vesna, Thornton, Laura M, Huckins, Laura M, William Rayner, N, Lewis, Cathryn M, Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I, Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andreas, Mannik, Katrin, Baker, Jessica H, O'Toole, Julie K, Trace, Sara E, Davis, Oliver SP, Helder, Sietske G, Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N, Van Elburg, Annemarie A, Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragiskos, Tziouvas, Konstantinos, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julià, Antonio, Rabionet, Raquel, Dick, Danielle M, Ripatti, Samuli, Andreassen, Ole A, Espeseth, Thomas, Lundervold, Astri J, Steen, Vidar M, Pinto, Dalila, Scherer, Stephen W, Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lars, Padyukov, Leonid, Halmi, Katherine A, Mitchell, James, Strober, Michael, Bergen, Andrew W, Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesús, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D, Banaschewski, Tobias, Franke, Barbara, Buitelaar, Jan K, Arias Vasquez, Alejandro, Doyle, Alysa E, Reif, Andreas, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H, Dalsgaard, Soeren, Børglum, Anders D, Waldman, Irwin, Wilmot, Beth, Molly, Nikolas, Bau, Claiton HD, Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K, McGough, James J, Grevet, Eugenio H, Medland, Sarah E, Robinson, Elise, Weiss, Lauren A, Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M, Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, De-Luca, Daniel Moreno, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thomas, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Rogé, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G, Thompson, Robert C, Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Douglas, McIntosh, Andrew, Bergen, Sarah E, Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B, Reinbold, Céline S, Fullerton, Janice M, Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R, Cichon, Sven, Mühleisen, Thomas W, Degenhardt, Franziska, Schumacher, Johannes, Bauer, Michael, Mitchell, Philip B, Gershon, Elliot S, Rice, John, Potash, James B, Zandi, Peter P, Craddock, Nick, Ferrier, I Nicol, Alda, Martin, Rouleau, Guy A, Turecki, Gustavo, Ophoff, Roel, Pato, Carlos, Anjorin, Adebayo, Stahl, Eli, Leber, Markus, Czerski, Piotr M, Cruceanu, Cristiana, Jones, Ian R, Posthuma, Danielle, Andlauer, Till FM, Forstner, Andreas J, Streit, Fabian, Baune, Bernhard T, Air, Tracy, Sinnamon, Grant, Wray, Naomi R, MacIntyre, Donald J, Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M, Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H, Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S, Nauck, Matthias, Schoevers, Robert A, Beekman, Aartjan Tf, Knowles, James A, Viktorin, Alexander, Arnold, Paul, Barr, Cathy L, Bedoya-Berrio, Gabriel, Bienvenu, O Joseph, Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M, Dietrich, Andrea, Fernandez, Thomas, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L, Hartmann, Andreas, Hirschtritt, Matthew E, Hoekstra, Pieter J, Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J, Macciardi, Fabio, Madruga-Garrido, Marcos, Malaty, Irene A, Maras, Athanasios, McGrath, Lauren, Miguel, Eurípedes C, Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S, Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M, Reus, Victor, Richter, Margaret A, Riddle, Mark A, Robertson, Mary M, Roessner, Veit, Rosário, Maria, Samuels, Jack F, Sandor, Paul, Stein, Dan J, Tsetsos, Fotis, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R, Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S, McLaughlin, Nicole, Nestadt, Paul S, Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A, Cohen, David, Crespo-Facorro, Benedicto, Crowley, James, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Janis, Kučinskas, Vaidutis, Lee Chee Keong, Jimmy, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C, Nenadic, Igor, Van Os, Jim, Pantelis, Christos, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Panos, Sanders, Alan R, Schall, Ulrich, Schwab, Sibylle G, Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, James, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V, Henskens, Frans, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M, Daly, Mark, Dichgans, Martin, Faraone, Stephen V, Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S, Koeleman, Bobby, Mathews, Carol A, Price, Alkes, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W, Cotsapas, Chris, Palotie, Aarno, Smoller, Jordan W, Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M, Schott, Jonathan M, Anney, Richard, Elia, Josephine, Grigoroiu-Serbanescu, Maria, Edenberg, Howard J, Murray, Robin, Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), School of Psychology [Cardiff University], Cardiff University, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), New Jersey Institute of Technology [Newark] (NJIT), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Biotechnologie et Microbiologie Appliquée (LBMA), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Gériatrie générale et aigüe [Paris], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Columbia University [New York], Dpt of Neuroscience [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Washington [Seattle], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Children’s Hospital of Philadelphia (CHOP ), University of Kentucky (UK), School of medicine, Duke University [Durham], College of medicine, Brigham Young University (BYU), Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Department of Neurology, Emory University [Atlanta, GA], Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Health sciences center, The University of New Mexico [Albuquerque], Institute for Memory Impairments and Neurological Disorders [Irvine], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Keck School of Medicine [Los Angeles], University of Southern California (USC), University of South Florida [Tampa] (USF), University of Utah School of Medicine [Salt Lake City], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Perelman School of Medicine, University of Pennsylvania, Dublin City University [Dublin] (DCU), Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische 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(INSERM)-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), School of Medicine [Dublin], Trinity College Dublin, Department of Medicine, University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), School of Public Health [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Columbia University Medical Center (CUMC), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Saarland University [Saarbrücken], Universität Leipzig, School of Medicine [Los Angeles], Johannes Kepler Universität Linz - Johannes Kepler University Linz [Autriche] (JKU), Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], School of Medecine, Washington University in Saint Louis (WUSTL), Oslo University Hospital [Oslo], Institute for Molecular 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Anatomy and Genetics [Oxford], University of Oxford, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Christian-Albrechts-Universität zu Kiel (CAU), Institute of Clinical Molecular Biology, Kiel University, National Institute for Health and Welfare [Helsinki], Harvard T.H. Chan School of Public Health, Universitat Autònoma de Barcelona (UAB), Vall d'Hebron University Hospital [Barcelona], University of Tartu, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Human and Clinical Genetics, Universiteit Leiden-Universiteit Leiden, University of Copenhagen = Københavns Universitet (UCPH), Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology [Brisbane] (QUT), Discipline of Psychiatry [Dublin], Trinity College Dublin-Trinity College Dublin, Institute of Neurology [London], The University of Hong Kong (HKU), University of Melbourne, Cooper Medical School of Rowan University [Camden] (CMSRU), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), University of Eastern Finland, Universitätsklinikum Bonn (UKB), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, University Medical Center [Utrecht], Ohio State University [Columbus] (OSU), University of California [San Francisco] (UC San Francisco), University of California (UC), Royal College of Surgeons in Ireland (RCSI), University of Southern Denmark (SDU), United Christian Hospital [Hong Kong] (UCH), University of Cincinnati (UC), University of Cologne, Inselspital Bern, University of Wales, Jefferson University Hospitals, University of Liverpool, Medizinische Universität Wien = Medical University of Vienna, National Institutes of Health [Bethesda] (NIH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Lincoln, University of Newcastle [Callaghan, Australia] (UoN), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Virginia, University of Maryland [Baltimore County] (UMBC), University of Maryland System, Royal Holloway [University of London] (RHUL), University of Edinburgh, Universidade de Lisboa = University of Lisbon (ULISBOA), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), University of Split, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), McLean Hospital [Belmont, Ma.], Norwegian Institute of Public Health [Oslo] (NIPH), Università degli Studi di Salerno = University of Salerno (UNISA), University of Bristol [Bristol], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Utrecht University [Utrecht], Azienda Ospedaliera di Padova, Université de Liège, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Università degli Studi di Perugia = University of Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, National and Kapodistrian University of Athens (NKUA), Charles University [Prague] (CU), SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Flinders University [Adelaide, Australia], Virginia Commonwealth University (VCU), University of Oslo (UiO), University of Bergen (UiB), Weill Medical College of Cornell University [New York], University of North Dakota [Grand Forks] (UND), Oregon Research Institute (ORI), University of California [San Diego] (UC San Diego), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Hospital Universitario Mutua de Terrassa, School of Computer Science and Communication [Stockholm], Royal Institute of Technology [Stockholm] (KTH ), Jefferson (Philadelphia University + Thomas Jefferson University), University Medical Center Göttingen (UMG), Universität Heidelberg [Heidelberg] = Heidelberg University, Radboud University Medical Center [Nijmegen], Universitätsklinikum Frankfurt, Maastricht University [Maastricht], Institute of Psychological Medicine and Clinical Neurosciences, Aarhus University [Aarhus], University of Iowa [Iowa City], Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), The Hospital for sick children [Toronto] (SickKids), Hospital de Clínicas de Porto Alegre (HCPA), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University of British Columbia (UBC), IRCCS Fondazione Stella Maris [Pisa], Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade de Coimbra [Coimbra], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Our Lady's Children's Hospital Crumlin (OLCHC), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Children’s Hospital Los Angeles [Los Angeles], Yale University [New Haven], Brown University, Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], Department of Medical Epidemiology and Biostatistics (MEB), Division of Medical Genetics [Seattle], University of Illinois [Chicago] (UIC), University of Illinois System, Maine Medical Center Research Institute (MMCRI), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Toulouse Mind & Brain Institut (TMBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Johns Hopkins University School of Medicine [Baltimore], Ludwig Maximilian University [Munich] (LMU), University of Michigan System, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, University of Dundee, National University of Ireland [Galway] (NUI Galway), University Hospital Basel [Basel], Neuroscience Research Australia (NeuRA), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW), University of Chicago, Johns Hopkins University (JHU), Johns Hopkins Bloomberg School of Public Health [Baltimore], Dalhousie University [Halifax], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], State University of New York (SUNY), University Hospital of Cologne [Cologne], University of Adelaide, James Cook University (JCU), Institute for Molecular Bioscience, University of Queensland [Brisbane], Greifswald University Hospital, The University of Sydney, University Medical Center Groningen [Groningen] (UMCG), University of Calgary, University Health Network, Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Universidade de São Paulo = University of São Paulo (USP), Ospedale San Raffaele, University of Amsterdam [Amsterdam] (UvA), University of Groningen [Groningen], Yale School of Medicine [New Haven, Connecticut] (YSM), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Cape Town, Cold Spring Harbor Laboratory (CSHL), Universidad de Sevilla / University of Sevilla, University of Florida [Gainesville] (UF), University of Denver, Purdue University [West Lafayette], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Moscow Institute of Physics and Technology [Moscow] (MIPT), Sunnybrook Health Sciences Centre, Federal Institute of São Paulo (IFSP), Democritus University of Thrace (DUTH), Universiteit Gent = Ghent University (UGENT), Medical University of Warsaw - Poland, Sorbonne Université - Faculté de Médecine - Département d'Enseignement et de Recherche en Médecine Générale, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institute of Mental Health [Singapore], Universidad de Cantabria [Santander], Tel Aviv University (TAU), University College Cork (UCC), University of Rochester [USA], Statens Serum Institut [Copenhagen], Софийски университет = Sofia University, Russian Academy of Sciences [Moscow] (RAS), Latvian Biomedical Research and Study Centre [Rīga], Vilnius University [Vilnius], Nanyang Technological University [Singapour], Department of Life Sciences, Imperial College London, Jena University Hospital [Jena], Oxford University Hospitals NHS Trust, Schizophrenia Research Institute [Sydney], Faculty of Science, Medicine and Health [Wollongong], University of Wollongong [Australia], City University of Hong Kong [Hong Kong] (CUHK), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), This work was supported by grants 1R01MH10764901 and 5U01MH09443203 from the National Institute of Mental Health, as well as the Orion Farmos Research Foundation (V.A.) and the Fannie and John Hertz Foundation (H.K.F.). Consortium specific funding is detailed in the supplementary materials ('Study-specific acknowledgments')., Brainstorm Consortium, University of Kentucky, University of California [Irvine] (UCI), University of California-University of California, University of Pennsylvania [Philadelphia], Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Leipzig [Leipzig], Johannes Kepler University Linz [Linz] (JKU), University of Helsinki-University of Helsinki, University of Helsinki, University of Oxford [Oxford], University of Copenhagen = Københavns Universitet (KU), University of California [San Francisco] (UCSF), University of California, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Newcastle [Australia] (UoN), University of Virginia [Charlottesville], Universidade de Lisboa (ULISBOA), Università degli Studi di Salerno (UNISA), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Università degli Studi di Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli', Universität Heidelberg [Heidelberg], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, VU University Amsterdam, Universidade de São Paulo (USP), Yale University School of Medicine, Universidad de Sevilla, Universiteit Gent = Ghent University [Belgium] (UGENT), Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Tel Aviv University [Tel Aviv], University of Sofia, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K., Walters, Raymond K., Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J., Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A., Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H., Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-Françoi, Duron, Emmanuelle, Vardarajan, Badri N., Reitz, Christiane, Goate, Alison M., Huentelman, Matthew J., Ilyas Kamboh, M., Larson, Eric B., Rogaeva, Ekaterina, George-Hyslop, Peter St, Hakonarson, Hakon, Kukull, Walter A., Farrer, Lindsay A., Barnes, Lisa L., Beach, Thomas G., Yesim Demirci, F., Head, Elizabeth, Hulette, Christine M., Jicha, Gregory A., Kauwe, John S.K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Quinn, Joseph F., Saykin, Andrew J., Schneider, Lon S., Smith, Amanda G., Sonnen, Joshua A., Stern, Robert A., Van Deerlin, Vivianna M., Van Eldik, Linda J., Harold, Denise, Russo, Giancarlo, Rubinsztein, David C., Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C., Hampel, Harald, Owen, Michael J., Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M., Rossor, Martin, Lupton, Michelle K., Hoffmann, Per, Kornhuber, Johanne, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C., Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J., De Jager, Philip L., Geschwind, Daniel H., Riemenschneider, Matthia, Riedel-Heller, Steffi, Rotter, Jerome I., Ransmayr, Gerhard, Hyman, Bradley T., Cruchaga, Carlo, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nichola, Kurth, Tobia, Ligthart, Lannie, Terwindt, Gisela M., Freilinger, Tobia, Ran, Caroline, Gordon, Scott D., Borck, Guntram, Adams, Hieab H.H., Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E., Schürks, Marku, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja I., Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfon, Pozo-Rosich, Patricia, Hansen, Thoma, Werge, Thoma, Kaprio, Jaakko, Metspalu, Andre, Kubisch, Christian, Ferrari, Michel D., Belin, Andrea C., Van Den Maagdenberg, Arn M. J. M., Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nichola, Olesen, Je, Chasman, Daniel I., Nyholt, Dale R., Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell, Catarino, Claudia B., Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Denni, Ferraro, Thomas N., French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S., Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S., Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thoma, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M., Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Neil Thomas, G., Visscher, Frank, Whelan, Christopher D., Zara, Federico, Heinzen, Erin L., Marson, Anthony, Becker, Felicita, Stroink, Han, Zimprich, Fritz, Gasser, Thoma, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R., Sharma, Manu, Ryten, Mina, Mok, Kin Y., Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thoma, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Perica, Vesna Boraska, Thornton, Laura M., Huckins, Laura M., William Rayner, N., Lewis, Cathryn M., Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I., Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andrea, Mannik, Katrin, Baker, Jessica H., O'Toole, Julie K., Trace, Sara E., Davis, Oliver S. P., Helder, Sietske G., Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N., Van Elburg, Annemarie A., Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragisko, Tziouvas, Konstantino, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julia, Antonio, Rabionet, Raquel, Dick, Danielle M., Ripatti, Samuli, Andreassen, Ole A., Espeseth, Thoma, Lundervold, Astri J., Steen, Vidar M., Pinto, Dalila, Scherer, Stephen W., Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lar, Padyukov, Leonid, Halmi, Katherine A., Mitchell, Jame, Strober, Michael, Bergen, Andrew W., Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesú, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D., Banaschewski, Tobia, Franke, Barbara, Buitelaar, Jan K., Vasquez, Alejandro Aria, Doyle, Alysa E., Reif, Andrea, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H., Dalsgaard, Soeren, Børglum, Anders D., Waldman, Irwin, Wilmot, Beth, Molly, Nikola, Bau, Claiton H.D., Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K., McGough, James J., Grevet, Eugenio H., Medland, Sarah E., Robinson, Elise, Weiss, Lauren A., Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M., Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, Moreno-De-Luca, Daniel, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thoma, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Roge, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G., Thompson, Robert C., Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Dougla, McIntosh, Andrew, Bergen, Sarah E., Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B., Reinbold, Céline S., Fullerton, Janice M., Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R., Cichon, Sven, Mühleisen, Thomas W., Degenhardt, Franziska, Schumacher, Johanne, Bauer, Michael, Mitchell, Philip B., Gershon, Elliot S., Rice, John, Potash, James B., Zandi, Peter P., Craddock, Nick, Nicol Ferrier, I., Alda, Martin, Rouleau, Guy A., Turecki, Gustavo, Ophoff, Roel, Pato, Carlo, Anjorin, Adebayo, Stahl, Eli, Leber, Marku, Czerski, Piotr M., Cruceanu, Cristiana, Jones, Ian R., Posthuma, Danielle, Andlauer, Till F.M., Forstner, Andreas J., Streit, Fabian, Baune, Bernhard T., Air, Tracy, Sinnamon, Grant, Wray, Naomi R., MacIntyre, Donald J., Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M., Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H., Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S., Nauck, Matthia, Schoevers, Robert A., Beekman, Aartjan TF, Knowles, James A., Viktorin, Alexander, Arnold, Paul, Barr, Cathy L., Bedoya-Berrio, Gabriel, Joseph Bienvenu, O., Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M., Dietrich, Andrea, Fernandez, Thoma, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L., Hartmann, Andrea, Hirschtritt, Matthew E., Hoekstra, Pieter J., Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J., Macciardi, Fabio, Madruga-Garrido, Marco, Malaty, Irene A., Maras, Athanasio, McGrath, Lauren, Miguel, Eurípedes C., Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S., Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M., Reus, Victor, Richter, Margaret A., Riddle, Mark A., Robertson, Mary M., Roessner, Veit, Rosário, Maria, Samuels, Jack F., Sandor, Paul, Stein, Dan J., Tsetsos, Foti, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R., Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S., McLaughlin, Nicole, Nestadt, Paul S., Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A., Cohen, David, Crespo-Facorro, Benedicto, Crowley, Jame, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Jani, Kučinskas, Vaiduti, Keong, Jimmy Lee Chee, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C., Nenadic, Igor, Van Os, Jim, Pantelis, Christo, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Pano, Sanders, Alan R., Schall, Ulrich, Schwab, Sibylle G., Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, Jame, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V., Henskens, Fran, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M., Daly, Mark, Dichgans, Martin, Faraone, Stephen V., Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S., Koeleman, Bobby, Mathews, Carol A., Price, Alke, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W., Cotsapas, Chri, Palotie, Aarno, Smoller, Jordan W., Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M., Epidemiology, Radiology & Nuclear Medicine, Anttila, V, Bulik-Sullivan, B, Finucane, H, Walters, R, Bras, J, Duncan, L, Escott-Price, V, Falcone, G, Gormley, P, Malik, R, Patsopoulos, N, Ripke, S, Wei, Z, Yu, D, Lee, P, Turley, P, Grenier-Boley, B, Chouraki, V, Kamatani, Y, Berr, C, Letenneur, L, Hannequin, D, Amouyel, P, Boland, A, Deleuze, J, Duron, E, Vardarajan, B, Reitz, C, Goate, A, Huentelman, M, Ilyas Kamboh, M, Larson, E, Rogaeva, E, George-Hyslop, P, Hakonarson, H, Kukull, W, Farrer, L, Barnes, L, Beach, T, Yesim Demirci, F, Head, E, Hulette, C, Jicha, G, Kauwe, J, Kaye, J, Leverenz, J, Levey, A, Lieberman, A, Pankratz, V, Poon, W, Quinn, J, Saykin, A, Schneider, L, Smith, A, Sonnen, J, Stern, R, Van Deerlin, V, Van Eldik, L, Harold, D, Russo, G, Rubinsztein, D, Bayer, A, Tsolaki, M, Proitsi, P, Fox, N, Hampel, H, Owen, M, Mead, S, Passmore, P, Morgan, K, Nöthen, M, Rossor, M, Lupton, M, Hoffmann, P, Kornhuber, J, Lawlor, B, Mcquillin, A, Al-Chalabi, A, Bis, J, Ruiz, A, Boada, M, Seshadri, S, Beiser, A, Rice, K, Van Der Lee, S, De 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Nauck, M, Schoevers, R, Beekman, A, Knowles, J, Viktorin, A, Arnold, P, Barr, C, Bedoya-Berrio, G, Joseph Bienvenu, O, Brentani, H, Burton, C, Camarena, B, Cappi, C, Cath, D, Cavallini, M, Cusi, D, Darrow, S, Denys, D, Derks, E, Dietrich, A, Fernandez, T, Figee, M, Freimer, N, Gerber, G, Grados, M, Greenberg, E, Hanna, G, Hartmann, A, Hirschtritt, M, Hoekstra, P, Huang, A, Huyser, C, Illmann, C, Jenike, M, Kuperman, S, Leventhal, B, Lochner, C, Lyon, G, Macciardi, F, Madruga-Garrido, M, Malaty, I, Maras, A, Mcgrath, L, Miguel, E, Mir, P, Nestadt, G, Nicolini, H, Okun, M, Pakstis, A, Paschou, P, Piacentini, J, Pittenger, C, Plessen, K, Ramensky, V, Ramos, E, Reus, V, Richter, M, Riddle, M, Robertson, M, Roessner, V, Rosário, M, Samuels, J, Sandor, P, Stein, D, Tsetsos, F, Van Nieuwerburgh, F, Weatherall, S, Wendland, J, Wolanczyk, T, Worbe, Y, Zai, G, Goes, F, Mclaughlin, N, Nestadt, P, Grabe, H, Depienne, C, Konkashbaev, A, Lanzagorta, N, Valencia-Duarte, A, Bramon, E, Buccola, N, Cahn, W, Cairns, M, Chong, S, Cohen, D, Crespo-Facorro, B, Crowley, J, Davidson, M, Delisi, L, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Haan, L, Hougaard, D, Karachanak-Yankova, S, Khrunin, A, Klovins, J, Kučinskas, V, Keong, J, Limborska, S, Loughland, C, Lönnqvist, J, Maher, B, Mattheisen, M, Mcdonald, C, Murphy, K, Nenadic, I, Van Os, J, Pantelis, C, Pato, M, Petryshen, T, Quested, D, Roussos, P, Sanders, A, Schall, U, Schwab, S, Sim, K, So, H, Stögmann, E, Subramaniam, M, Toncheva, D, Waddington, J, Walters, J, Weiser, M, Cheng, W, Cloninger, R, Curtis, D, Gejman, P, Henskens, F, Mattingsdal, M, Oh, S, Scott, R, Webb, B, Breen, G, Churchhouse, C, Bulik, C, Daly, M, Dichgans, M, Faraone, S, Guerreiro, R, Holmans, P, Kendler, K, Koeleman, B, Mathews, C, Price, A, Scharf, J, Sklar, P, Williams, J, Wood, N, Cotsapas, C, Palotie, A, Smoller, J, Sullivan, P, Rosand, J, Corvin, A, Neale, B, Kauwe, John S. K., Mcquillin, Andrew, Adams, Hieab H. H., Mccormack, Mark, Bau, Claiton H. D., Mcgough, James J., Mcintosh, Andrew, Andlauer, Till F. M., Macintyre, Donald J., Mcgrath, Lauren, Mclaughlin, Nicole, Delisi, Lynn, Mcdonald, Colm, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), RIKEN Center for Integrative Medical Science, Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), University of South Florida (USF), University of Zürich [Zürich] (UZH)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Cardiff University-Medical Research Council, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Johannes Kepler University Linz [linz] (JKU), Washington University in St Louis, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Universitat Autònoma de Barcelona [Barcelona] (UAB), Hôpital Erasme (Bruxelles), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Jagiellonian University [Krakow] (UJ), Technische Universität Dresden (TUD), National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Charles University [Prague], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), University Medicine Goettingen, Università di Bologna [Bologna] (UNIBO), Forschungszentrum Jülich GmbH, UNSW Medicine [Sydney], McGill University, Universidad de Antioquia, University of Florida [Gainesville], Universiteit Gent [Ghent], Service Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], University of Wollongong, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Anttila, Verneri [0000-0002-0073-4675], Finucane, Hilary K [0000-0003-3864-9828], Walters, Raymond K [0000-0001-8422-6530], Duncan, Laramie [0000-0003-1131-661X], Escott-Price, Valentina [0000-0003-1784-5483], Falcone, Guido J [0000-0002-6407-0302], Gormley, Padhraig [0000-0002-8908-6968], Malik, Rainer [0000-0001-9212-2520], Ripke, Stephan [0000-0003-3622-835X], Wei, Zhi [0000-0001-6059-4267], Yu, Dongmei [0000-0001-7901-4365], Lee, Phil H [0000-0003-1770-3100], Breen, Gerome [0000-0003-2053-1792], Bulik, Cynthia M [0000-0001-7772-3264], Daly, Mark [0000-0002-0949-8752], Dichgans, Martin [0000-0002-0654-387X], Faraone, Stephen V [0000-0002-9217-3982], Holmans, Peter [0000-0003-0870-9412], Koeleman, Bobby [0000-0001-7749-182X], Mathews, Carol A [0000-0003-2208-7058], Sklar, Pamela [0000-0001-9715-4943], Williams, Julie [0000-0002-4069-0259], Wood, Nicholas W [0000-0002-9500-3348], Cotsapas, Chris [0000-0002-7772-5910], Smoller, Jordan W [0000-0002-0381-6334], Sullivan, Patrick [0000-0002-6619-873X], Rosand, Jonathan [0000-0002-1014-9138], Corvin, Aiden [0000-0001-6717-4089], Neale, Benjamin M [0000-0003-1513-6077], and Apollo - University of Cambridge Repository

Subjects
Etiology, [SDV]Life Sciences [q-bio], MESH: Brain Diseases, body-mass index, genetics [Mental Disorders], Disorders of the Brain, Risks factors, classification [Mental Disorders], MESH: Quantitative Trait, Heritable, MESH: Risk Factors, Risk Factors, MESH: Genetic Variation, alzheimers-disease, 610 Medicine & health, bipolar disorder, Brain Diseases, deficit hyperactivity disorder, Multidisciplinary, Mental Disorders, genetics [Brain Diseases], Brain Disease, Brain, Genetic Variation, Genome-Wide Association Study, Humans, Phenotype, Quantitative Trait, Heritable, Psychiatric Disorders, anorexia-nervosa, Mental Disorder, Psychiatric Genomics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], long-term survival, Engineering sciences. Technology, Human, General Science & Technology, population-based twin, diagnosis [Mental Disorders], MESH: Phenotype, Neurological Disorders, Quantitative Trait, MD Multidisciplinary, MESH: Mental Disorders, diagnosis [Brain Diseases], Heritable, genetic correlations, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, major depressive disorder, Risk Factor, Brain Diseases/classification, Brain Diseases/diagnosis, Brain Diseases/genetics, Mental Disorders/classification, Mental Disorders/diagnosis, Mental Disorders/genetics, classification [Brain Diseases], Perturbações do Desenvolvimento Infantil e Saúde Mental, ddc:320, MESH: Genome-Wide Association Study, genome-wide association, Brainstorm Consortium, Genetic Factors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer’s disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important “scaffolding” to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders.

Published
2018

37. Complement genes contribute sex-biased vulnerability in diverse disorders

Author

Kamitaki, Nolan, Sekar, Aswin, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Boehnke, Michael, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Mitjans, Marina, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Kimberly, Robert P, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Hougaard, David M, Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kahn, René S, Kaufman, Kenneth M, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kelly, Brian J, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Harley, John B, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K, Laurent, Claudine, Keong, Jimmy Lee Chee, Lee, S Hong, Legge, Sophie E, Langefeld, Carl D, Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M, Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Seidman, Christine E, Magnusson, Patrik K E, Maher, Brion S, Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W, McDonald, Colm, McIntosh, Andrew M, Pato, Michele T, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Pato, Carlos N, Morris, Derek W, Mors, Ole, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Ophoff, Roel A, Nicodemus, Kristin K, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Handsaker, Robert E, Graham, Robert R, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N, Steixner, Agnes A, Parkhomenko, Elena, Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pietiläinen, Olli, Criswell, Lindsey A, Pimm, Jonathan, Pocklington, Andrew J, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Reichenberg, Abraham, Reimers, Mark A, Vyse, Timothy J, Richards, Alexander L, Roffman, Joshua L, Roussos, Panos, Ruderfer, Douglas M, Salomaa, Veikko, Sanders, Alan R, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, McCarroll, Steven A, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Slominsky, Petr, Smoller, Jordan W, Ripke, Stephan, So, Hon-Cheong, Spencer, Chris C A, Stahl, Eli A, Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Neale, Benjamin M, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tooney, Paul A, Tosato, Sarah, Veijola, Juha, Corvin, Aiden, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T, Weiser, Mark, Wildenauer, Dieter B, Williams, Nigel M, Williams, Stephanie, Witt, Stephanie H, Walters, James T R, Wolen, Aaron R, Wong, Emily H M, Wormley, Brandon K, Wu, Jing Qin, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R, Stefansson, Kari, Farh, Kai-How, Visscher, Peter M, Adolfsson, Rolf, Andreassen, Ole A, Blackwood, Douglas H R, Bramon, Elvira, Buxbaum, Joseph D, Børglum, Anders D, Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Holmans, Peter A, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V, Gill, Michael, Gurling, Hugh, Hultman, Christina M, Iwata, Nakao, Jablensky, Assen V, Jönsson, Erik G, Kendler, Kenneth S, de Rivera, Heather, Lee, Phil, Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F, Li, Qingqin S, Liu, Jianjun, Malhotra, Anil K, McQuillin, Andrew, Moran, Jennifer L, Bulik-Sullivan, Brendan, Mortensen, Preben B, Mowry, Bryan J, Nöthen, Markus M, Owen, Michael J, Palotie, Aarno, Petryshen, Tracey L, Posthuma, Danielle, Rietschel, Marcella, Collier, David A, Riley, Brien P, Rujescu, Dan, Sham, Pak C, Sklar, Pamela, Clair, David St, Weinberger, Daniel R, Wendland, Jens R, Werge, Thomas, Daly, Mark J, Sullivan, Patrick F, Huang, Hailiang, O'Donovan, Michael C, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Tooley, Katherine, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Morris, David L, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Taylor, Kimberly E, Chambert, Kimberly D, Chan, Raymond C K, Chen, Ronald Y L, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Whelan, Christopher W, Cormican, Paul, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Tombleson, Philip, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Loohuis, Loes M Olde, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Adult Psychiatry, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Kamitaki, Nolan, Sekar, Aswin, Handsaker, Robert E, de Rivera, Heather, Lee, S Hong, McCarroll, Steven A, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Helsinki University Hospital Area, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Psychiatry, Center for Population, Health and Society, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Male, SLE, Sjogren's Syndrome/blood, complement cascade, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 0302 clinical medicine, MOLECULAR-BASIS, HLA Antigens, Genotype, 2.1 Biological and endogenous factors, Lupus Erythematosus, Systemic, Medicine, Aetiology, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Complement C3/analysis, SUSCEPTIBILITY VARIANTS, RISK, SJOGRENS-SYNDROME, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Complement component 4, Sex Characteristics, Multidisciplinary, Complement C4, Complement C3, HLA Antigens/genetics, Middle Aged, 3. Good health, Complement cascade, Mental Health, Sjogren's Syndrome, genetic association study, Female, ddc:500, Systemic/blood, Biotechnology, Sex characteristics, Adult, General Science & Technology, Lupus, Human leukocyte antigen, Autoimmune Disease, Lupus Erythematosus, Systemic/blood, 03 medical and health sciences, Young Adult, Systemic lupus erythematosus, C4 DEFICIENCY, SDG 3 - Good Health and Well-being, Genetics, Humans, Genetic Predisposition to Disease, Allele, Alleles, Genetic association study, Differential disease vulnerability, Lupus erythematosus, Lupus Erythematosus, business.industry, Inflammatory and immune system, Systemic, Haplotype, C4A, medicine.disease, Brain Disorders, COPY-NUMBER, 030104 developmental biology, Haplotypes, Sjögren’s syndrome, Immunology, Schizophrenia, Complement C4/analysis, AUTOANTIBODIES, 3111 Biomedicine, MHC, business, DEFICIENCY STATES, 030217 neurology & neurosurgery
Abstract

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3–6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Published
2020

38. Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults

Author

Hofer, Edith, Roshchupkin, Gennady V, Bernard, Manon, Grasby, Katrina L, Jahanshad, Neda, Painter, Jodie N, Colodro-Conde, Lucía, Bralten, Janita, Hibar, Derrek P, Lind, Penelope A, Pizzagalli, Fabrizio, Ching, Christopher R K, McMahon, Mary Agnes B, Bis, Joshua C, Shatokhina, Natalia, Zsembik, Leo C P, Agartz, Ingrid, Alhusaini, Saud, Almeida, Marcio A A, Alnæs, Dag, Amlien, Inge K, Andersson, Micael, Ard, Tyler, Armstrong, Nicola J, Gillespie, Nathan A, Ashley-Koch, Allison, Brouwer, Rachel M, Buimer, Elizabeth E L, Bülow, Robin, Bürger, Christian, Cannon, Dara M, Chakravarty, Mallar, Chen, Qiang, Cheung, Joshua W, Luciano, Michelle, Couvy-Duchesne, Baptiste, Dale, Anders M, Dalvie, Shareefa, de Araujo, Tânia K, de Zubicaray, Greig I, de Zwarte, Sonja M C, den Braber, Anouk, Doan, Nhat Trung, Dohm, Katharina, Ehrlich, Stefan, Mishra, Aniket, Engelbrecht, Hannah-Ruth, Erk, Susanne, Fan, Chun Chieh, Fedko, Iryna O, Foley, Sonya F, Ford, Judith M, Fukunaga, Masaki, Garrett, Melanie E, Ge, Tian, Giddaluru, Sudheer, Scholz, Markus, Goldman, Aaron L, Groenewold, Nynke A, Grotegerd, Dominik, Gurholt, Tiril P, Gutman, Boris A, Hansell, Narelle K, Harris, Mathew A, Harrison, Marc B, Haswell, Courtney C, Hauser, Michael, Teumer, Alexander, Herms, Stefan, Heslenfeld, Dirk J, Ho, New Fei, Hoehn, David, Hoffmann, Per, Holleran, Laurena, Hoogman, Martine, Hottenga, Jouke-Jan, Ikeda, Masashi, Janowitz, Deborah, Xia, Rui, Jansen, Iris E, Jia, Tianye, Jockwitz, Christiane, Kanai, Ryota, Karama, Sherif, Kasperaviciute, Dalia, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Klein, Marieke, Jian, Xueqiu, Knapp, Michael, Knodt, Annchen R, Krämer, Bernd, Lam, Max, Lancaster, Thomas M, Lee, Phil H, Lett, Tristram A, Lewis, Lindsay B, Lopes-Cendes, Iscia, Mosley, Thomas H, Macciardi, Fabio, Marquand, Andre F, Mathias, Samuel R, Melzer, Tracy R, Milaneschi, Yuri, Mirza-Schreiber, Nazanin, Moreira, Jose C V, Mühleisen, Thomas W, Müller-Myhsok, Bertram, Najt, Pablo, Adams, Hieab H H, Saba, Yasaman, Nakahara, Soichiro, Nho, Kwangsik, Olde Loohuis, Loes M, Orfanos, Dimitri Papadopoulos, Pearson, John F, Pitcher, Toni L, Pütz, Benno, Ragothaman, Anjanibhargavi, Rashid, Faisal M, Redlich, Ronny, Pirpamer, Lukas, Reinbold, Céline S, Repple, Jonathan, Richard, Geneviève, Riedel, Brandalyn C, Risacher, Shannon L, Rocha, Cristiane S, Mota, Nina Roth, Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J, Seiler, Stephan, Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R, Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sønderby, Ida E, Sprooten, Emma, Becker, James T, Strike, Lachlan T, Tansey, Katherine E, Thalamuthu, Anbupalam, Thomopoulos, Sophia I, Tordesillas-Gutiérrez, Diana, Turner, Jessica A, Uhlmann, Anne, Vallerga, Costanza Ludovica, van der Meer, Dennis, Carmichael, Owen, van Donkelaar, Marjolein M J, van Eijk, Liza, van Erp, Theo G M, van Haren, Neeltje E M, van Rooij, Daan, van Tol, Marie-José, Veldink, Jan H, Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Rotter, Jerome I, Wang, Yunpeng, Wardlaw, Joanna M, Wen, Wei, Westlye, Lars T, Whelan, Christopher D, Witt, Stephanie H, Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Yasuda, Clarissa L, Psaty, Bruce M, Zaremba, Dario, Zhang, Zuo, Zhu, Alyssa H, Zwiers, Marcel P, Artiges, Eric, Assareh, Amelia A, Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L, Brown, Gregory G, Lopez, Oscar L, Cichon, Sven, Curran, Joanne E, Davies, Gareth E, Degenhardt, Franziska, Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P, Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Amin, Najaf, Gowland, Penny A, Green, Robert C, Häusler, Alexander N, Heindel, Walter, Ho, Beng-Choon, Hoffmann, Wolfgang U, Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R, van der Lee, Sven J, Jang, MiHyun, Jansen, Andreas, Kolskår, Knut, Koops, Sanne, Krug, Axel, Lim, Kelvin O, Luykx, Jurjen J, Mathalon, Daniel H, Mather, Karen A, Mattay, Venkata S, Knol, Maria J, Yang, Qiong, Matthews, Sarah, Son, Jaqueline Mayoral Van, McEwen, Sarah C, Melle, Ingrid, Morris, Derek W, Mueller, Bryon A, Nauck, Matthias, Nordvik, Jan E, Nöthen, Markus M, O'Leary, Daniel S, Himali, Jayandra J, Opel, Nils, Martinot, Marie -Laure Paillère, Pike, G Bruce, Preda, Adrian, Quinlan, Erin B, Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M, Torres, Fábio R, Veltman, Dick J, Maillard, Pauline, Voyvodic, James T, Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Alvim, Marina K M, Ames, David, Anderson, Tim J, Andreassen, Ole A, Arias-Vasquez, Alejandro, Bastin, Mark E, Beiser, Alexa S, Baune, Bernhard T, Blangero, John, Boomsma, Dorret I, Brodaty, Henry, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Bustillo, Juan R, Cahn, Wiepke, Calhoun, Vince, DeCarli, Charles, Caseras, Xavier, Caspers, Svenja, Cavalleri, Gianpiero L, Cendes, Fernando, Corvin, Aiden, Crespo-Facorro, Benedicto, Dalrymple-Alford, John C, Dannlowski, Udo, de Geus, Eco J C, Deary, Ian J, Delanty, Norman, Depondt, Chantal, Desrivières, Sylvane, Donohoe, Gary, Espeseth, Thomas, Fernández, Guillén, Fisher, Simon E, Flor, Herta, Forstner, Andreas J, Francks, Clyde, Lewis, Lindsay, Franke, Barbara, Glahn, David C, Gollub, Randy L, Grabe, Hans J, Gruber, Oliver, Håberg, Asta K, Hariri, Ahmad R, Hartman, Catharina A, Hashimoto, Ryota, Heinz, Andreas, Harris, Mat, Hillegers, Manon H J, Hoekstra, Pieter J, Holmes, Avram J, Hong, L Elliot, Hopkins, William D, Hulshoff Pol, Hilleke E, Jernigan, Terry L, Jönsson, Erik G, Kahn, René S, Kennedy, Martin A, Kircher, Tilo T J, Kochunov, Peter, Kwok, John B J, Hellard, Stephanie Le, Martin, Nicholas G, Martinot, Jean -Luc, McDonald, Colm, McMahon, Katie L, Meyer-Lindenberg, Andreas, Morey, Rajendra A, Nyberg, Lars, Oosterlaan, Jaap, Ophoff, Roel A, Paus, Tomáš, Pausova, Zdenka, Penninx, Brenda W J H, Polderman, Tinca J C, Posthuma, Danielle, Rietschel, Marcella, Roffman, Joshua L, Lin, Honghuang, Veronica Witte, A., Rowland, Laura M, Sachdev, Perminder S, Sämann, Philipp G, Schumann, Gunter, Sim, Kang, Sisodiya, Sanjay M, Smoller, Jordan W, Sommer, Iris E, Pourcain, Beate St, Stein, Dan J, Beyer, Frauke, Toga, Arthur W, Trollor, Julian N, Van der Wee, Nic J A, van 't Ent, Dennis, Völzke, Henry, Walter, Henrik, Weber, Bernd, Weinberger, Daniel R, Wright, Margaret J, Zhou, Juan, Loeffler, Markus, Stein, Jason L, Thompson, Paul M, Medland, Sarah E, Kwok, John B, Trollor, Julian, Li, Shuo, Jiang, Jiyang, Vernooij, Meike W, Hofman, Albert, Uitterlinden, André G, Niessen, Wiro J, Völker, Uwe, Zare, Habil, Bruce Pike, G., Maingault, Sophie, Crivello, Fabrice, Tzourio, Christophe, Amouyel, Philippe, Mazoyer, Bernard, Neale, Michael C, Franz, Carol E, Lyons, Michael J, Ahmad, Shahzad, Panizzon, Matthew S, Logue, Mark, consortium, ENIGMA, Kremen, William S, Villringer, Arno, Satizabal, Claudia L, van Duijn, Cornelia M, Grabe, Hans, Longstreth, William T, Fornage, Myriam, Paus, Tomas, Debette, Stephanie, Ikram, M Arfan, Schmidt, Helena, Schmidt, Reinhold, Seshadri, Sudha, University of Graz, Medical University Graz, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), School of Public Health [Boston], University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), The University of Texas at San Antonio (UTSA), Murdoch University, The Hospital for sick children [Toronto] (SickKids), University of Washington [Seattle], Virginia Commonwealth University (VCU), QIMR Berghofer Medical Research Institute, University of Edinburgh, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig [Leipzig], Universität Greifswald - University of Greifswald, University of Mississippi Medical Center (UMMC), University of California [Davis] (UC Davis), University of California, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Pennington Biomedical Research Center, Louisiana State University (LSU), Los Angeles Biomedical Research Institute (LA BioMed), McGill University = Université McGill [Montréal, Canada], Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig] (IMPNSC), Max-Planck-Gesellschaft, University of New South Wales [Sydney] (UNSW), Neuroscience Research Australia (NeuRA), The University of Sydney, University of Queensland [Brisbane], The Royal Melbourne Hospital, University of Melbourne, Harvard T.H. Chan School of Public Health, Delft University of Technology (TU Delft), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Toronto, University of Calgary, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of California [San Diego] (UC San Diego), University of Oslo (UiO), Oslo University Hospital [Oslo], VA Boston Healthcare System, University of Southern California (USC), Radboud University Medical Center [Nijmegen], Radboud university [Nijmegen], Janssen Research & Development, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Prince of Wales Hospital, University Hospital Leipzig, University of Oxford [Oxford], Holland Bloorview Kids Rehabilitation Hospital [Toronto, ON, Canada], Epidemiology, Medical Informatics, Radiology & Nuclear Medicine, Neurology, Complex Trait Genetics, Biological Psychology, Cognitive Psychology, IBBA, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, Clinical Neuropsychology, Clinical Developmental Psychology, Amsterdam Neuroscience - Complex Trait Genetics, Movement Disorder (MD), Clinical Cognitive Neuropsychiatry Research Program (CCNP), General Paediatrics, ARD - Amsterdam Reproduction and Development, Karl-Franzens-Universität Graz, Universität Leipzig, University of California (UC), Radboud University [Nijmegen], University of Oxford, Psychiatry, Anatomy and neurosciences, Pediatric surgery, Human genetics, APH - Digital Health, and Karl-Franzens-Universität [Graz, Autriche]

Subjects
0301 basic medicine, Male, Genetics of the nervous system, Aging, General Physics and Astronomy, Genome-wide association study, Disease, VARIANTS, genetics [Mental Disorders], Genome-wide association studies, 0302 clinical medicine, Cognition, PARKINSONS-DISEASE, SCHIZOPHRENIA, 80 and over, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, Aged, 80 and over, education.field_of_study, Multidisciplinary, ENIGMA consortium, Mental Disorders, Brain, Neurodegenerative Diseases, Genomics, Single Nucleotide, Middle Aged, Biobank, ALZHEIMERS-DISEASE, Phenotype, VINTAGE, Neurology, Chromosome Structures, Schizophrenia, genetics [Aging], Neurological, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, ddc:500, Biotechnology, Adult, Science, geentics of the nervous system, 1.1 Normal biological development and functioning, Population, SURFACE-AREA, ORGANIZATION, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Underpinning research, THICKNESS, medicine, Genetics, Humans, Polymorphism, education, HEALTHY, METAANALYSIS, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Genetic heterogeneity, neurology, Human Genome, Neurosciences, General Chemistry, Heritability, medicine.disease, Brain Disorders, INDIVIDUALS, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Evolutionary biology, genetics [Neurodegenerative Diseases], VOLUME, genome-wide association studies, lcsh:Q, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging., Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.

Published
2020

39. The genetic architecture of the human cerebral cortex

Author

Grasby, Katrina L, Jahanshad, Neda, Shatokhina, Natalia, Mirza-Schreiber, Nazanin, Moreira, Jose C V, Mühleisen, Thomas W, Müller-Myhsok, Bertram, Najt, Pablo, Nakahara, Soichiro, Nho, Kwangsik, Olde Loohuis, Loes M, Orfanos, Dimitri Papadopoulos, Pearson, John F, Zsembik, Leo C P, Pitcher, Toni L, Pütz, Benno, Quidé, Yann, Ragothaman, Anjanibhargavi, Rashid, Faisal M, Reay, William R, Redlich, Ronny, Reinbold, Céline S, Repple, Jonathan, Richard, Geneviève, Thomopoulos, Sophia I, Riedel, Brandalyn C, Risacher, Shannon L, Rocha, Cristiane S, Mota, Nina Roth, Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J, Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R, Zhu, Alyssa H, Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sønderby, Ida E, Sprooten, Emma, Tansey, Katherine E, Teumer, Alexander, Thalamuthu, Anbupalam, Strike, Lachlan T, Tordesillas-Gutiérrez, Diana, Turner, Jessica A, Uhlmann, Anne, Vallerga, Costanza Ludovica, van der Meer, Dennis, van Donkelaar, Marjolein M J, van Eijk, Liza, van Erp, Theo G M, van Haren, Neeltje E M, van Rooij, Daan, Agartz, Ingrid, van Tol, Marie-José, Veldink, Jan H, Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Wang, Yunpeng, Wardlaw, Joanna M, Wen, Wei, Westlye, Lars T, Whelan, Christopher D, Alhusaini, Saud, Witt, Stephanie H, Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Wu, Jing Qin, Yasuda, Clarissa L, Zaremba, Dario, Zhang, Zuo, Zwiers, Marcel P, Artiges, Eric, Almeida, Marcio A A, Assareh, Amelia A, Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L, Brown, Gregory G, Cichon, Sven, Curran, Joanne E, Davies, Gareth E, Degenhardt, Franziska, Dennis, Michelle F, Alnæs, Dag, Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P, Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Gowland, Penny A, Green, Robert C, Häusler, Alexander N, Heindel, Walter, Amlien, Inge K, Ho, Beng-Choon, Hoffmann, Wolfgang U, Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R, Jang, MiHyun, Jansen, Andreas, Kimbrel, Nathan A, Kolskår, Knut, Painter, Jodie N, Andersson, Micael, Koops, Sanne, Krug, Axel, Lim, Kelvin O, Luykx, Jurjen J, Mathalon, Daniel H, Mather, Karen A, Mattay, Venkata S, Matthews, Sarah, Mayoral Van Son, Jaqueline, McEwen, Sarah C, Ard, Tyler, Melle, Ingrid, Morris, Derek W, Mueller, Bryon A, Nauck, Matthias, Nordvik, Jan E, Nöthen, Markus M, O'Leary, Daniel S, Opel, Nils, Martinot, Marie-Laure Paillère, Pike, G Bruce, Armstrong, Nicola J, Preda, Adrian, Quinlan, Erin B, Rasser, Paul E, Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M, Tooney, Paul A, Torres, Fábio R, Veltman, Dick J, Voyvodic, James T, Ashley-Koch, Allison, Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Adams, Hieab H H, Bis, Joshua C, Debette, Stephanie, Decarli, Charles, Fornage, Myriam, Gudnason, Vilmundur, Hofer, Edith, Atkins, Joshua R, Ikram, M Arfan, Launer, Lenore, Longstreth, W. T., Lopez, Oscar L, Mazoyer, Bernard, Mosley, Thomas H, Roshchupkin, Gennady V, Satizabal, Claudia L, Schmidt, Reinhold, Seshadri, Sudha, Bernard, Manon, Yang, Qiong, Initiative, Alzheimer’s Disease Neuroimaging, Consortium, CHARGE, Consortium, EPIGEN, Consortium, IMAGEN, Consortium, SYS, Initiative, Parkinson’s Progression Markers, Alvim, Marina K M, Ames, David, Anderson, Tim J, Brouwer, Rachel M, Andreassen, Ole A, Arias-Vasquez, Alejandro, Bastin, Mark E, Baune, Bernhard T, Beckham, Jean C, Blangero, John, Boomsma, Dorret I, Brodaty, Henry, Brunner, Han G, Buckner, Randy L, Buimer, Elizabeth E L, Buitelaar, Jan K, Bustillo, Juan R, Cahn, Wiepke, Cairns, Murray J, Calhoun, Vince, Carr, Vaughan J, Caseras, Xavier, Caspers, Svenja, Cavalleri, Gianpiero L, Cendes, Fernando, Bülow, Robin, Corvin, Aiden, Crespo-Facorro, Benedicto, Dalrymple-Alford, John C, Dannlowski, Udo, de Geus, Eco J C, Deary, Ian J, Delanty, Norman, Depondt, Chantal, Desrivières, Sylvane, Donohoe, Gary, Bürger, 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Masaki, Knopman, David, Hewitt, David L, Perry, David, Russell, David, Standaert, David, Winkfield, David, Green, Davis Robert C, Fontaine, Deborah, Miller, Delwyn D, Gessert, Devon, Garrett, Melanie E, Kerwin, Diana, Willeke, Diana, Drost, Dick, Papadopoulos, Dimitri, Rowe, Dominic, Simpson, Donna M, Muni, Donna, Galasko, Douglas, Scharre, Douglas W, Fillmer, Ariane, Ge, Tian, Bartha, Rob, Celmins, Dzintra, Zimmerman, Earl A, Teng, Edmond, Tolosa, Eduardo, Coleman, Edward, Zamrini, Edward, Mitsis, Effie, Finger, Elizabeth, Giddaluru, Sudheer, Oates, Elizabeth, Sosa, Elizabeth, Woo, Ellen, Rogalski, Emily, Lethbridge, Emma, Dooley, Eoin, Foster, Eric, Reiman, Eric M, Quinlan, Erin Burke, Goldman, Aaron L, Franklin, Erin, Heinzen, Erin L, Fletcher, Evan, Sprenger, Fabienne, Crivello, Fabrice, Biondo, Francesca, Parfitt, Francine, Hefti, Franz, Beyer, Frauke, Nees, Frauke, Green, Melissa J, Leonard, Gabriel, Robert, Gabriel, Thai, Gaby, Marshall, Gad A, Barker, Gareth, Conrad, Gary, Tremont, Geoffrey, Bartzokis, George, Groenewold, Nynke A, Hsiung, Ging-Yuek Robin, Malferrari, Giulia, Chiang, Gloria, Pearlson, Godfrey D, Liang, Grace, Jicha, Greg, Sorensen, Greg, Todd, Gretchen, Jimenez, Gustavo, Grotegerd, Dominik, Zare, Habil, Grabe, Hans Jörgen, Vanderswag, Helen, Schmidt, Helena, Venkov, Heli, Lemaitre, Hervé, Gurholt, Tiril P, Grossman, Hillel, Shill, Holly, Soares, Holly, Lin, Honghuang, Capote, Horacio, Bergman, Howard, Chertkow, Howard, Feldman, Howard, Fillit, Howard, Rosen, Howard J, Gutman, Boris A, Koleva, Hristina, Fernandez, Hubert, Garavan, Hugh, Shim, Hyungsub, Grachev, Igor D, Richard, Irene, Filippi, Irina, Rachinsky, Irina, Wurster, Isabel, Lind, Penelope A, Hansell, Narelle K, Mintzer, Jacobo, Ziolkowski, Jaimie, Brewer, James, Lah, James J, Leverenz, James, Becker, James T, Tetrud, James, Singleton-Garvin, Jamika, Egebjerg, Jan, Cellar, Janet S, Harris, Mathew A, Pentilla, Jani, Brosch, Jared R, Tinklenberg, Jared, Karlawish, Jason H, Meyer, Javier Villanueva, Himali, Jayandra J, Poline, Jean-Baptiste, Gunter, Jeff, Kaye, Jeffrey A, Harrison, Marc B, Dalley, Jeffrey, Burns, Jeffrey M, Petrella, Jeffrey R, Mule, Jennifer, Salazar, Jennifer, Rotter, Jerome I, Yesavage, Jerome, Cedarbaum, Jesse, Jiang, Jiyang, Haswell, Courtney C, Allard, Joanne, Lord, Joanne L, Hetelle, Joel, Kwok, John B, Brockington, John, Morris, John C, Hsiao, John, Morris, John, Olichney, John, Trojanowki, John Q, Hauser, Michael, Rogers, John, Seibyl, John, Yankey, Jon, Dubow, Jordan S, Jankovic, Joseph, Quinn, Joseph, Kass, Joseph S, Taylor, Joy L, Heidebrink, Judith L, Herms, Stefan, Trollor, Julian, Fröhner, Juliane, Anderson, Karen, Blank, Karen, Crawford, Karen, Smith, Karen Ekstam, Bell, Karen L, Williams, Karen, Kieburtz, Karl, Heslenfeld, Dirk J, Gauss, Katharina, Gloer, Katherine, Johnson, Kathleen, Tingus, Kathleen, DeMarco, Kathryn, Sink, Kaycee M, Hawkins, Keith A, Johnson, Keith A, Kantarci, Kejal, Ho, New Fei, Faber, Kelley, Harless, Kelly, Makino, Kelly M, Marek, Kenneth, Spicer, Kenneth, Shianna, Kevin, Chen, Kewei, Nam, Ki Won, Martin, Kim, Poki-Walker, Kim, Hoehn, David, Seppi, Klaus, Johnson, Kris, Fargher, Kristin, Lipowski, Kristine, Espay, Kristy, Womack, Kyle, Chahine, Lama, Flashman, Laura A, Daedelow, Laura, Hoffmann, Per, Leary, Laura, Beckett, Laurel, Honig, Lawrence S, Thal, Leon, Shaw, Leslie M, Kuller, Lew, Apostolova, Liana, Teodoro, Liberty, Rees, Linda, Pizzagalli, Fabrizio, Holleran, Laurena, Lewis, Lindsay, Hergesheimer, Lindsey, Silbert, Lisa C, Ravdin, Lisa, Taylor-Reinwald, Lisa, Uribe, Liz, Schneider, Lon S, Daiello, Lori A, Richer, Louis, Poustka, Luise, Hoogman, Martine, Pirpamer, Lukas, Mesulam, M Marcel, Ismail, M Saleem, Ranola, Madelaine, Korecka, Magdalena, Raichle, Marc, Seltzer, Marc, van der Brug, Marcel, Hottenga, Jouke-Jan, Mesulam, Marek-Marsel, Carrillo, Maria, Carroll, Maria, Knol, Maria J, Kataki, Maria, Greig-Custo, Maria T, Paillere, Marie-Laure, Albert, Marilyn, Love, Marissa Natelson, Ikeda, Masashi, Mintun, Mark A, Frasier, Mark, Logue, Mark, Minton, Mark, Loeffler, Markus, Scholz, Markus, Baca, Marne, Farlow, Martin R, Sadowski, Martin, Janowitz, Deborah, Creech, Mary L, Hynes, Mary L, Quiceno, Mary, Oakley, MaryAnn, Harris, Mat, Senjem, Matt, Bernstein, Matthew, Panizzon, Matthew S, Stern, Matthew, Becerra, Mauricio, Jansen, Iris E, Witbracht, Megan, Vernooij, Meike W, Brandabur, Melanie, Keltz, Melanie, Lamar, Melissa, Yang, Mia, Ahlijanian, Michael, Borrie, Michael, Neale, Michael C, Donohue, Michael, Jia, Tianye, Lyons, Michael J, Lin, Michael, Rapp, Michael, Smolka, Michael, Weiner, Michael W, Weiner, Michael, Figurski, Michal, Perron, Michel, Assaly, Michele, Luciano, Michelle, Jockwitz, Christiane, Rainka, Michelle, Dang, Mimi, Sheikh, Mohammed O, Ghanbari, Mohsen, Gaikwad, Mrunalini, Chowdhury, Munir, Trncic, Nadira, Amin, Najaf, Johnson, Nancy, Kanai, Ryota, Kowalksi, Nancy, Monahan, Nancy, Gillespie, Nathan A, Pacini, Nathaniel, Buckholtz, Neil, Kowall, Neil, Graff-Radford, Neill R, Fox, Nick, Pavese, Nicola, Karama, Sherif, Cairns, Nigel J, Schuff, Norbert, Foster, Norm, Relkin, Norman, Oyonumo, Ntekim E, Pomara, Nunzio, James, Olga, Ogunlana, Olu, Ching, Christopher R K, Kasperaviciute, Dalia, Carmichael, Owen, Doraiswamy, P Murali, Casalin, Paola, Barone, Paolo, Fatica, Parianne, Conrod, Patricia, Johnson, Patricia Lynn, Samuels, Patricia, Aisen, Paul, Malloy, Paul, Kaufmann, Tobias, Thompson, Paul, Ogrocki, Paula, Bezivin-Frere, Pauline, Maillard, Pauline, Fontoura, Paulo, Taylor, Peggy, Hogarth, Penelope, Gowland, Penny, Davies, Peter, Kelly, Sinead, Hardy, Peter, Snyder, Peter J, Snyder, Peter, Amouyel, Philippe, Muglia, Pierandrea, Tariot, Pierre, Lu, Po H, Varma, Pradeep, Vemuri, Prashanthi, Kikuchi, Masataka, Doody, Rachelle S, Carter, Raina, Shah, Raj C, Griffith, Randall, Yeh, Randy, Duara, Ranjan, Tarawneh, Rawan, James, Raymond, Turner, Raymond Scott, Klein, Marieke, Hernando, Raymundo, Silverstein, Rebecca, Sperling, Reisa A, Wilson, Renee, Carson, Richard E, Frank, Richard, El Khouli, Riham, Koeppe, Robert A, Santulli, Robert B, Knapp, Michael, Hauser, Robert, Umek, Robert, Radtke, Rodney, Killiany, Ronald, Petersen, Ronald, Rodriguez, Rosemarie, Miranda, Ruben, Knodt, Annchen R, Bruehl, Ruediger, Xia, Rui, Swerdlow, Russell H, Ottmann, Ruth, Millenet, Sabina, Borges-Neto, Salvador, Frank, Samuel, Black, Sandra, Weintraub, Sandra, Obradov, Sanja, Krämer, Bernd, Asthana, Sanjay, Vaishnavi, Sanjeev, Dolen, Sara, Mason, Sara S, Hohmann, Sarah, Kremen, Sarah, Miller, Sarah, Walter, Sarah, Herring, Scott, Neu, Scott, Lam, Max, Aydin, Semiha, Ahmad, Shahzad, Harlan, Sherry, Sirrel, Sherye A, Lasch, Shirley, Hu, Shu-Ching, Li, Shuo, Kittur, Smita, Chowdhury, Sohini, Lancaster, Thomas M, Pawluczyk, Sonia, Maingault, Sophie, Schneider, Stacy, Seiler, Stephan, Guthrie, Stephanie, Kielb, Stephanie, Reeder, Stephanie, Correia, Stephen, Pasternak, Stephen, McMahon, Mary Agnes B, Lee, Phil H, Salloway, Stephen, Johnson, Sterling, Williams, Steve, Chao, Steven, Arnold, Steven E, Paul, Steven, Potkin, Steven, Factor, Stewart, Isaacson, Stuart, Lett, Tristram A, Kim, Sungeun, Ainscough, Susan, Schultz, Susan K, Landau, Susan, Mendick, Susan, Rountree, Susan, Ostrowizki, Suzanne, Veillette, Suzanne, van der Lee, Sven J, Desrivieres, Sylvane, Lewis, Lindsay B, Lee, T-Y, Simuni, Tanya, Foroud, Tatiana, Foroud, Tatiana M, Wong, Terence Z, Villena, Teresa, Comery, Thomas, Obisesan, Thomas O, Lopes-Cendes, Iscia, Banaschewski, Tobias, Sherer, Todd, Montine, Tom, Paus, Tomáš, Robbins, Trevor, Bromberg, Uli, Völker, Uwe, Pavlik, Valory, Arnedo, Vanessa, Kiyasova, Vera, Bates, Vernice, Logovinsky, Veronika, Sossi, Vesna, Shibley, Victoria, Frouin, Vincent, Lee, Virginia, Poewe, Werner, Jagust, William, Brooks, William M, Macciardi, Fabio, Pavlosky, William, Potter, William, Kremen, William S, Longstreth, William T, Niessen, Wiro J, Jian, Xueqiu, Stern, Yaakov, Saba, Yasaman, Cabrera, Yuliana, Grimmer, Yvonne, Marquand, Andre F, Khachaturian, Zaven, Mari, Zoltan, Mathias, Samuel R, Melzer, Tracy R, Milaneschi, Yuri, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN Consortium, IMAGEN Consortium, SYS Consortium, Parkinson’s Progression Markers Initiative, Stochastics, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Science and Society, Cognitive Psychology, IBBA, APH - Personalized Medicine, Complex Trait Genetics, APH - Methodology, Clinical Neuropsychology, Sociology and Social Gerontology, Amsterdam Neuroscience - Complex Trait Genetics, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Neurology, Psychiatry, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Human genetics, APH - Digital Health, Psychology, Precision Medicine Institute of Psychiatry, Child and Adolescent Psychiatry / Psychology, Radiology & Nuclear Medicine, Clinical Genetics, Epidemiology, Medical Informatics, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neurodegeneratives Diseases Institute (IMN-UMR CNRS 5293), Centre National de la Recherche Scientifique (CNRS), General Paediatrics, ARD - Amsterdam Reproduction and Development, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Brain mapping, 0302 clinical medicine, Cognition, Cortex (anatomy), ComputingMilieux_MISCELLANEOUS, Cerebral Cortex, 0303 health sciences, Brain Mapping, Multidisciplinary, COMMON VARIANTS, Parkinson Disease, Organ Size, Central sulcus, Magnetic Resonance Imaging, medicine.anatomical_structure, Cerebral cortex, Neuroinformatics, EXPRESSION, endocrine system, central sulcus, SURFACE-AREA, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, medicine, Attention deficit hyperactivity disorder, Humans, General, Gene, METAANALYSIS, 030304 developmental biology, Progenitor, CORTICAL SULCI, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic variants, Genetic Variation, Attention Deficit Disorder with Hyperactivity, Genetic Loci, Genome-Wide Association Study, functional annotation, medicine.disease, Genetic architecture, 030104 developmental biology, Evolutionary biology, OBSERVER-INDEPENDENT CHARACTERIZATION, Multiple comparisons problem, ddc:320, genome-wide association, Neuroscience, 030217 neurology & neurosurgery
Abstract

Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group., The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Published
2020

40. Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia With Risk for Depression in the Danish Population

Author

Musliner, Katherine L., Mortensen, Preben B., McGrath, John J., Suppli, Nis P., Hougaard, David M., Bybjerg-Grauholm, Jonas, Baekvad-Hansen, Marie, Andreassen, Ole, Pedersen, Carsten B., Pedersen, Marianne G., Mors, Ole, Nordentoft, Merete, Borglum, Anders D., Werge, Thomas, Agerbo, Esben, Stahl, Eli A., Breen, Gerome, Forstner, Andreas J., McQuillin, Andrew, Ripke, Stephan, Trubetskoy, Vassily, Mattheisen, Manuel, Wang, Yunpeng, Coleman, Jonathan R., I, Gaspar, Helena A., de Leeuw, Christiaan A., Steinberg, Stacy, Pavlides, Jennifer M. Whitehead, Trzaskowski, Maciej, Pers, Tune H., Holmans, Peter A., Abbott, Liam, Akil, Huda, Albani, Diego, Alliey-Rodriguez, Ney, Als, Thomas D., Anjorin, Adebayo, Antilla, Verneri, Awasthi, Swapnil, Badner, Judith A., Etzekvad-Hansen, Marie, Barchas, Jack D., Bass, Nicholas, Bauer, Michael, Belliveau, Richard, Bergen, Sarah E., Pedersen, Carsten Bocker, Boen, Erlend, Boks, Marco, Boocock, James, Budde, Monika, Bunney, William, Burmeister, Margit, Byerley, William, Casas, Miguel, Cerrato, Felecia, Cervantes, Pablo, Chambert, Kimberly, Chamey, Alexander W., Chen, Danfeng, Churchhouse, Claire, Clarke, Toni-Kim, Coryell, William, Craig, David W., Cruceanu, Cristiana, Curtis, David, Czerski, Piotr M., Dale, Anders M., de Jong, Simone, Degenhardt, Franziska, Del-Favero, Jurgen, DePaulo, J. Raymond, Djurovic, Srdjan, Dobbyn, Amanda L., Dumont, Ashley, Elvsashagen, Torbjorn, Escott-Price, Valentina, Fan, Chun Chieh, Fischer, Sascha B., Flickinger, Matthew, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Fraser, Christine, Freimer, Nelson B., Frisen, Louise, Gade, Katrin, Gage, Diane, Garnham, Julie, Giambartobmei, Claudia, Pedersen, Marianne Giortz, Goldstein, Jaqueline, Gordon, Scott D., Gordon-Smith, Katherine, Green, Elaine K., Green, Melissa J., Greenwood, Tiffany A., Grove, Jakob, Guan, Weihua, Parra, Jose Guzman, Hamshere, Marian L., Hautzinger, Martin, Heilbronner, Urs, Herms, Stefan, Hipolito, Maria, Hoffmann, Per, Holland, Dominic, Huckins, Laura, Jamain, Stephan, Johnson, Jessica S., Jureus, Anders, Kandaswamy, Radhika, Karlsson, Robert, Kennedy, James L., Kittel-Schneider, Sarah, Knott, Sarah, V, Knowles, James A., Kogevinas, Manolis, Koller, Anna C., Kupka, Ralph, Lavebratt, Catharina, Lawrence, Jacob, Lawson, William B., Leber, Markus, Lee, Phil H., Levy, Shawn E., Li, Jun Z., Liu, Chunyu, Lucae, Susanne, Maaser, Anna, MacIntyre, Donald J., Mahon, Pamela B., Maier, Wolfgang, Martinsson, Lina, McCarroll, Steve, McGuffin, Peter, McInnis, Melvin G., McKay, James D., Medeiros, Helena, Medland, Sarah E., Meng, Fan, Milani, Lili, Montgomery, Grant W., Morris, Derek W., Muehleisen, Thomas W., Mullins, Niamh, Nguyen, Hoang, Nievergelt, Caroline M., Adolfsson, Annelie Nordin, Nwulia, Evaristus A., O'Donovan, Claire, Loohuis, Loes M. Olde, Ori, Anil P. S., Oruc, Lilijana, Osby, Urban, Perlis, Roy H., Perry, Amy, Pfennig, Andrea, Potash, James B., Purcell, Shaun M., Regeer, Eline J., Reif, Andreas, Reinbold, Celine S., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roussos, Panos, Ruderfer, Douglas M., Ryu, Euijung, Sanchez-Mora, Cristina, Schatzberg, Alan F., Scheftner, William A., Schork, Nicholas J., Weickert, Cynthia Shannon, Shehktman, Tatyana, Shilling, Paul D., Sigurdsson, Engilbert, Slaney, Claire, Smeland, Olav B., Sobell, Janet L., Hansen, Christine Soholm, Spijker, Anne T., St Clair, David, Steffens, Michael, Strauss, John S., Streit, Fabian, Strohmaier, Jana, Szelinger, Szabolcs, Thompson, Robert C., Thorgeirsson, Thorgeir E., Treutlein, Jens, Vedder, Helmut, Wang, Weiqing, Watson, Stanley J., Weickert, Thomas W., Witt, Stephanie H., Xi, Simon, Xu, Wei, Young, Allan H., Zandi, Peter, Zhang, Peng, Zollner, Sebastian, Agartz, Ingrid, Aida, Martin, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Berrettini, Wade H., Biemacka, Joanna M., Blackwood, Douglas H. R., Boehnke, Michael, Berglum, Anders D., Corvin, Aiden, Craddock, Nicholas, Daly, Mark J., Dannlowski, Udo, Esko, Tonu, Etain, Bruno, Frye, Mark, Fullerton, Janice M., Gershon, Elliot S., Goes, Fernando, Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Hultman, Christina M., Jones, Ian, Jones, Lisa A., Kahn, Rene S., Kirov, George, Landen, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Martin, Nicholas G., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Metspalu, Andres, Mitchell, Philip B., Morken, Gunnar, Mortensen, Preben Bo, Mueller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nimgaonkar, Vishwajit, Noethen, Markus M., O'Donovan, Michael C., Oedegaard, Ketil J., Owen, Michael, Paciga, Sara A., Pato, Carlos, Pato, Michele T., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Ribases, Marta, Rietschel, Marcella, Rouleau, Guy A., Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Serretti, Alessandro, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Ieta, Eduard, V, Vincent, John B., Nurnberger, John, I, Wray, Naomi R., Di Florio, Arianna, Edenberg, Howard J., Cichon, Sven, Ophoff, Roel A., Scott, Laura J., Andreassen, Ole A., Kelsoe, John, Sklar, Pamela, and Psychiat Genomics Consortium

Subjects
Adult, Male, medicine.medical_specialty, Multifactorial Inheritance, Bipolar Disorder, Adolescent, Denmark, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Bipolar disorder, Young adult, Association (psychology), Psychiatry, Child, Depression (differential diagnoses), Proportional Hazards Models, Depressive Disorder, Major, Proportional hazards model, business.industry, Depression, Case-control study, Age Factors, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Schizophrenia, Case-Control Studies, Linear Models, Major depressive disorder, Female, Human medicine, business, 030217 neurology & neurosurgery
Abstract

Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored.Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis.Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018.Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium.Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency).Results: Of 34 573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = -.07; SE = .02; P = .002).Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.

Published
2019

41. Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis

Author

Rees, Elliott, Carrera, Noa, Morgan, Joanne, Hambridge, Kirsty, Escott-Price, Valentina, Pocklington, Andrew J., Richards, Alexander L., Pardiñas, Antonio F., McDonald, Colm, Donohoe, Gary, Morris, Derek W., Kenny, Elaine, Kelleher, Eric, Gill, Michael, Corvin, Aiden, Kirov, George, Walters, James T.R., Holmans, Peter, Owen, Michael J., O’Donovan, Michael C., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Perceptual and Cognitive Neuroscience (PCN), Life Course Epidemiology (LCE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)

Subjects
Adult, DISORDERS, Nerve Tissue Proteins, OF-FUNCTION VARIANTS, SUSCEPTIBILITY, Receptors, N-Methyl-D-Aspartate, Article, Cohort Studies, Risk Factors, mental disorders, SETD1A, Genetics, Humans, Sequencing, GENOME-WIDE ASSOCIATION, Netherlands, Neurons, RISK, Sequence Analysis, DNA, Middle Aged, FRAMEWORK, ARC, United Kingdom, NMDAR, Cytoskeletal Proteins, INDIVIDUALS, DE-NOVO MUTATIONS, Schizophrenia, Voltage-gated sodium channels, BURDEN, Ireland
Abstract

BACKGROUND: Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. METHODS: We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios. RESULTS: While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 x 10(-4)) and NMDAR (p = 1.7 x 10(-5)) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 x 10(-4)). CONCLUSIONS: In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes.

Published
2019

42. Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Author

Huckins, Laura M, Dobbyn, Amanda, Ruderfer, Douglas M, Hoffman, Gabriel, Wang, Weiqing, Pardinas, Antonio F, Rajagopal, Veera M, Als, Thomas D, Nguyen, Hoang T, Girdhar, Kiran, Boocock, James, Roussos, Panos, Fromer, Menachem, Kramer, Robin, Domenici, Enrico, Gamazon, Eric R, Purcell, Shaun, Demontis, Ditte, Borglum, Anders D, Walters, James TR, O'Donovan, Michael C, Sullivan, Patrick, Owen, Michael J, Devlin, Bernie, Sieberts, Solveig K, Cox, Nancy J, Im, Hae Kyung, Sklar, Pamela, Stahl, Eli A, Johnson, Jessica S, Shah, Hardik R, Klein, Lambertus L, Dang, Kristen K, Logsdon, Benjamin A, Mahajan, Milind C, Mangravite, Lara M, Toyoshiba, Hiroyoshi, Gur, Raquel E, Hahn, Chang-Gyu, Schadt, Eric, Lewis, David A, Haroutunian, Vahram, Peters, Mette A, Lipska, Barbara K, Buxbaum, Joseph D, Hirai, Keisuke, Perumal, Thanneer M, Essioux, Laurent, Rajagopal, Veera Manikandan, Mattheisen, Manuel, Grove, Jakob, Werge, Thomas, Mortensen, Preben Bo, Pedersen, Carsten Bocker, Agerbo, Esben, Pedersen, Marianne Giortz, Mors, Ole, Nordentoft, Merete, Hougaard, David M, Bybjerg-Grauholm, Jonas, Baekvad-Hansen, Marie, Hansen, Christine Soholm, Ripke, Stephan, Neale, Benjamin M, Corvin, Aiden, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Jr, Belliveau Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Ikeda, Masashi, Joa, Inge, Julia, Antonio, Kahn, Rene S, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kahler, Anna K, Laurent, Claudine, Keong, Jimmy Lee Chee, Lee, S Hong, Legge, Sophie E, Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M, Lubinski, Jan, Lonnqvist, Jouko, Jr, Macek Milan, Magnusson, Patrik KE, Maher, Brion S, Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattingsdal, Morten, McCarley, Robert W, McDonald, Colm, McIntosh, Andrew M, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Muller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T, Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pietilainen, Olli, Pimm, Jonathan, Pocklington, Andrew J, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Roffman, Joshua L, Salomaa, Veikko, Sanders, Alan R, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Spencer, Chris CA, Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Soderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T, Weiser, Mark, Wildenauer, Dieter B, Williams, Nigel M, Williams, Stephanie, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily HM, Wormley, Brandon K, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R, Stefansson, Kari, Visscher, Peter M, Adolfsson, Rolf, Andreassen, Ole A, Blackwood, Douglas HR, Bramon, Elvira, Cichon, Sven, Darvasi, Ariel, Ehrenreich, Hannelore, Esko, Tonu, Gejman, Pablo V, Gill, Michael, Gurling, Hugh, Hultman, Christina M, Iwata, Nakao, Jablensky, Assen V, Jonsson, Erik G, Kendler, Kenneth S, Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F, Li, Qingqin S, Liu, Jianjun, Malhotra, Anil K, McCarroll, Steven A, McQuillin, Andrew, Moran, Jennifer L, Mortensen, Preben B, Mowry, Bryan J, Nothen, Markus M, Ophoff, Roel A, Palotie, Aarno, Pato, Carlos N, Petryshen, Tracey L, Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P, Rujescu, Dan, Sham, Pak C, St Clair, David, Weinberger, Daniel R, Wendland, Jens R, Daly, Mark J, Sullivan, Patrick F, Consortium, CommonMind, Consortium, Psychiat Genomics, Working, iPSYCH-GEMS Schizophrenia, Child and Adolescent Psychiatry / Psychology, ANS - Complex Trait Genetics, APH - Mental Health, Adult Psychiatry, Perceptual and Cognitive Neuroscience (PCN), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Stem Cell Aging Leukemia and Lymphoma (SALL), Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, CommonMind Consortium, Psychiat Genomics Consortium, iPSYCH-GEMS Schizophrenia Working, Huckins, LM, Dobbyn, A, Ruderfer, DM, Hoffman, G, Lee, SH, Im, HK, iPSYCH-GEMS Schizophrenia Working Group, The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics, Amsterdam Reproduction & Development (AR&D), Human genetics, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, and MUMC+: Hersen en Zenuw Centrum (3)

Subjects
DISORDER, Schizophrenia/genetics, iPSYCH-GEMS Schizophrenia Working Group, CHILDHOOD, Gene Expression, Genome-wide association study, VARIANTS, MOUSE, Medical and Health Sciences, ACUTE INTERMITTENT PORPHYRIA, Genome-wide association studies, 0302 clinical medicine, CommonMind Consortium, 2.1 Biological and endogenous factors, Aetiology, Prefrontal cortex, 0303 health sciences, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium, Brain, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Schizophrenia, Transcriptome, Single Nucleotide, ASSOCIATION, Transcriptome/genetics, Biological Sciences, Polymorphism, Single Nucleotide/genetics, Mental Health, Genome-Wide Association Study/methods, Medical genetics, TRAITS, Psychosis, medicine.medical_specialty, Computational biology, Quantitative trait locus, Biology, Article, 03 medical and health sciences, PSYCHOSIS, SDG 3 - Good Health and Well-being, medicine, Genetics, Polymorphism, Transcriptomics, Gene, 030304 developmental biology, Brain/physiopathology, Human Genome, medicine.disease, Brain Disorders, Gene Expression/genetics, COGNITIVE DEFICITS, Expression quantitative trait loci, Human medicine, Gene expression, Quantitative Trait Loci/genetics, 030217 neurology & neurosurgery, Imputation (genetics), Developmental Biology
Abstract

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression. Working Group The Schizophrenia Working Group of the Psychiatric Genomics Consortium Stephan Ripke37,38 Benjamin M. Neale37,38,39,40 Aiden Corvin41 James T. R. Walters6 Kai-How Farh37 Peter A. Holmans6,42 Phil Lee37,38,40 Brendan Bulik-Sullivan37,38 David A. Collier43,44 Hailiang Huang37,39 Tune H. Pers39,45,46 Ingrid Agartz47,48,49 Esben Agerbo8,32,33 Margot Albus50 Madeline Alexander51 Farooq Amin52,53 Silviu A. Bacanu54 Martin Begemann55 Richard A. Belliveau Jr38 Judit Bene56,57 Sarah E. Bergen38,58 Elizabeth Bevilacqua38 Tim B. Bigdeli54 Donald W. Black59 Richard Bruggeman60 Nancy G. Buccola61 Randy L. Buckner62,63,64 William Byerley65 Wiepke Cahn66 Guiqing Cai2,3 Dominique Campion67 Rita M. Cantor10 Vaughan J. Carr68,69 Noa Carrera6 Stanley V. Catts68,70 Kimberly D. Chambert38 Raymond C. K. Chan71 Ronald Y. L. Chen72 Eric Y. H. Chen72,73 Wei Cheng15 Eric F. C. Cheung74 Siow Ann Chong75 C. Robert Cloninger76 David Cohen77 Nadine Cohen78 Paul Cormican41 Nick Craddock6,42 James J. Crowley79 David Curtis80,81 Michael Davidson82 Kenneth L. Davis3 Franziska Degenhardt83,84 Jurgen Del Favero85 Ditte Demontis7,8,9 Dimitris Dikeos86 Timothy Dinan87 Srdjan Djurovic49,88 Gary Donohoe41,89 Elodie Drapeau3 Jubao Duan90,91 Frank Dudbridge92 Naser Durmishi93 Peter Eichhammer94 Johan Eriksson95,96,97 Valentina Escott-Price6 Laurent Essioux98 Ayman H. Fanous99,100,101,102 Martilias S. Farrell79 Josef Frank103 Lude Franke104 Robert Freedman105 Nelson B. Freimer106 Marion Friedl107 Joseph I. Friedman3 Menachem Fromer1,37,38,40 Giulio Genovese38 Lyudmila Georgieva6 Ina Giegling107,108 Paola Giusti-Rodríguez79 Stephanie Godard109 Jacqueline I. Goldstein37,39 Vera Golimbet110 Srihari Gopal111 Jacob Gratten112 Lieuwe de Haan113 Christian Hammer55 Marian L. Hamshere6 Mark Hansen114 Thomas Hansen8,30 Vahram Haroutunian3,25,23 Annette M. Hartmann107 Frans A. Henskens68,115,116 Stefan Herms83,84,117 Joel N. Hirschhorn39,46,118 Per Hoffmann83,84,117 Andrea Hofman83,84 Mads V. Hollegaard36 David M. Hougaard36 Masashi Ikeda119 Inge Joa120 Antonio Julia121 Rene S. Kahn66 Luba Kalaydjieva122,123 Sena Karachanak-Yankova124 Juha Karjalainen104 David Kavanagh6 Matthew C. Keller125 James L. Kennedy126,127,128 Andrey Khrunin129 Yunjung Kim79 Janis Klovins130 James A. Knowles131 Bettina Konte107 Vaidutis Kucinskas132 Zita Ausrele Kucinskiene132 Hana Kuzelova-Ptackova133 Anna K. Kahler58 Claudine Laurent51,134 Jimmy Lee Chee Keong75,135 S. Hong Lee112 Sophie E. Legge6 Bernard Lerer136 Miaoxin Li72,73,137 Tao Li138 Kung-Yee Liang139 Jeffrey Lieberman140 Svetlana Limborska129 Carmel M. Loughland68,141 Jan Lubinski142 Jouko Lonnqvist143 Milan Macek Jr133 Patrik K. E. Magnusson58 Brion S. Maher144 Wolfgang Maier145 Jacques Mallet146 Sara Marsal121 Manuel Mattheisen7,8,9,147 Morten Mattingsdal49,148 Robert W. McCarley149,150 Colm McDonald151 Andrew M. McIntosh152,153 Sandra Meier103 Carin J. Meijer113 Bela Melegh56,57 Ingrid Melle49,154 Raquelle I. Mesholam-Gately149,155 Andres Metspalu156 Patricia T. Michie68,157 Lili Milani156 Vihra Milanova158 Younes Mokrab43 Derek W. Morris41,89 Ole Mors8,9,159 Kieran C. Murphy160 Robin M. Murray161 Inez Myin-Germeys162 Bertram Muller-Myhsok163,164,165 Mari Nelis156 Igor Nenadic166 Deborah A. Nertney167 Gerald Nestadt168 Kristin K. Nicodemus169 Liene Nikitina-Zake130 Laura Nisenbaum170 Annelie Nordin171 Eadbhard O’Callaghan172 Colm O’Dushlaine38 F. Anthony O’Neill173 Sang-Yun Oh174 Ann Olincy126 Line Olsen8,64 Jim Van Os162,175 Christos Pantelis68,176 George N. Papadimitriou86 Sergi Papiol55 Elena Parkhomenko3 Michele T. Pato131 Tiina Paunio177,178 Milica Pejovic-Milovancevic179 Diana O. Perkins180 Olli Pietiläinen178,181 Jonathan Pimm81 Andrew J. Pocklington6 John Powell161 Alkes Price39,182 Ann E. Pulver168 Shaun M. Purcell1 Digby Quested183 Henrik B. Rasmussen30,43 Abraham Reichenberg3 Mark A. Reimers184 Alexander L. Richards6 Joshua L. Roffman62,64 Panos Roussos1,4 Douglas M. Ruderfer1,5,6 Veikko Salomaa97 Alan R. Sanders90,91 Ulrich Schall68,141 Christian R. Schubert185 Thomas G. Schulze103,186 Sibylle G. Schwab187 Edward M. Scolnick38 Rodney J. Scott68,188,189 Larry J. Seidman144,155 Jianxin Shi190 Engilbert Sigurdsson191 Teimuraz Silagadze192 Jeremy M. Silverman3,193 Kang Sim75 Petr Slominsky129 Jordan W. Smoller38,40 Hon-Cheong So72 Chris C. A. Spencer194 Eli A. Stahl1,2,3,4 Hreinn Stefansson195 Stacy Steinberg195 Elisabeth Stogmann196 Richard E. Straub197 Eric Strengman66,198 Jana Strohmaier103 T. Scott Stroup140 Mythily Subramaniam75 Jaana Suvisaari143 Dragan M. Svrakic76 Jin P. Szatkiewicz79 Erik Soderman47 Srinivas Thirumalai199 Draga Toncheva124 Sarah Tosato200 Juha Veijola201,202 John Waddington203 Dermot Walsh204 Dai Wang111 Qiang Wang138 Bradley T. Webb54 Mark Weiser82 Dieter B. Wildenauer205 Nigel M. Williams6 Stephanie Williams79 Stephanie H. Witt103 Aaron R. Wolen184 Emily H. M. Wong72 Brandon K. Wormley54 Hualin Simon Xi206 Clement C. Zai126,127 Xuebin Zheng207 Fritz Zimprich196 Naomi R. Wray112 Kari Stefansson195 Peter M. Visscher112 Rolf Adolfsson171 Ole A. Andreassen49,154 Douglas H. R. Blackwood153 Elvira Bramon208 Joseph D. Buxbaum2,3,24,25 Anders D. Børglum7,8,9,159 Sven Cichon83,84,117,209 Ariel Darvasi210 Enrico Domenici211 Hannelore Ehrenreich55 Tonu Esko39,46,118,156 Pablo V. Gejman90,91 Michael Gill41 Hugh Gurling81 Christina M. Hultman58 Nakao Iwata119 Assen V. Jablensky68,123,205,212 Erik G. Jonsson47,49 Kenneth S. Kendler213 George Kirov6 Jo Knight125,127,128 Todd Lencz214,215,216 Douglas F. Levinson51 Qingqin S. Li111 Jianjun Liu207,217 Anil K. Malhotra214,215,216 Steven A. McCarroll38,118 Andrew McQuillin81 Jennifer L. Moran38 Preben B. Mortensen8,32,33 Bryan J. Mowry112,218 Markus M. Nothen83,84 Roel A. Ophoff10,66,105 Michael J. Owen6,42 Aarno Palotie38,40,181 Carlos N. Pato131 Tracey L. Petryshen38,149,219 Danielle Posthuma220,221,222 Marcella Rietschel103 Brien P. Riley213 Dan Rujescu107,108 Pak C. Sham72,73,137 Pamela Sklar1,2,3,4,25 David St Clair223 Daniel R. Weinberger197,224 Jens R. Wendland185 Thomas Werge8,30,225 Mark J. Daly37,38,39 Patrick F. Sullivan58,79,180 Michael C. O’Donovan6,42 20Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. 21Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 22Neuropsychiatric Signaling Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 23Psychiatry, JJ Peters Virginia Medical Center, Bronx, NY, USA. 24Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA. 25Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 26Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 27CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. 28F. Hoffman-La Roche Ltd, Basel, Switzerland. 29Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. 30Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. 31Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 32National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark. 33Centre for Integrated Registerbased Research, Aarhus University, Aarhus, Denmark. 34Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. 35Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark. 36Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. 37Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. 38Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 39Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 40Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. 41Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. 42NationalCentre for Mental Health, Cardiff University, Cardiff, UK. 43Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, UK. 44Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, UK. 45Center for BiologicalSequence Analysis, Department of Systems Biology, Technical University of Denmark, Kongens Lyngby, Denmark. 46Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA. 47Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden. 48Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway. 49NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 50State Mental Hospital, Haar, Germany. 51Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. 52Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA. 53Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA. 54Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA. 55Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. 56Department of Medical Genetics, University of Pécs, Pécs, Hungary. 57Szentagothai Research Center, University of Pécs, Pécs, Hungary. 58Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 59Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA. 60University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, the Netherlands. 61School of Nursing, Louisiana State University Health Sciences Center, New Orleans, LA, USA. 62Athinoula A. Martinos Center, Massachusetts General Hospital, Boston, MA, USA. 63Center for Brain Science, Harvard University, Cambridge, MA, USA. 64Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. 65Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA. 66University Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, Utrecht, the Netherlands. 67Centre Hospitalier du Rouvray and INSERM U1079 Faculty of Medicine, Rouen, France. 68Schizophrenia Research Institute, Sydney, New South Wales, Australia. 69School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia. 70Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Queensland, Australia. 71Institute of Psychology, Chinese Academy of Science, Beijing, China. 72Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. 73State Key Laboratory for Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. 74Castle Peak Hospital, Hong Kong, China. 75Institute of Mental Health, Singapore, Singapore. 76Department of Psychiatry, Washington University, St. Louis, MO, USA. 77Department of Child and Adolescent Psychiatry, Assistance Publique Hopitaux de Paris, Pierre and Marie Curie Faculty of Medicine and Institute for Intelligent Systems and Robotics, Paris, France. 78Blue Note Biosciences, Princeton, NJ, USA. 79Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. 80Department of Psychological Medicine, Queen Mary University of London, London, UK. 81Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK. 82Sheba Medical Center, Tel Hashomer, Israel. 83Department of Genomics, Life and Brain Center, Bonn, Germany. 84Institute of Human Genetics, University of Bonn, Bonn, Germany. 85AppliedMolecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium. 86First Department of Psychiatry, University of Athens Medical School, Athens, Greece. 87Department of Psychiatry, University College Cork, Co, Cork, Ireland. 88Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. 89Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Co, Galway, Ireland. 90Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA. 91Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, IL, USA. 92Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. 93Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje, Republic of Macedonia. 94Department of Psychiatry, University of Regensburg, Regensburg, Germany. 95Department of General Practice, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland. 96Folkhälsan Research Center, Helsinki, Finland, Biomedicum Helsinki, Helsinki, Finland. 97National Institute for Health and Welfare, Helsinki, Finland. 98Translational Technologies and Bioinformatics, Pharma Research and Early Development, F. Hoffman-La Roche, Basel, Switzerland. 99Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, USA. 100Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. 101Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. 102Mental Health Service Line, Washington VA Medical Center, Washington, DC, USA. 103Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Mannheim, Germany. 104Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands. 105Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA. 106Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA. 107Department of Psychiatry, University of Halle, Halle, Germany. 108Department of Psychiatry, University of Munich, Munich, Germany. 109Departments of Psychiatry and Human and Molecular Genetics, INSERM, Institut de Myologie, Hôpital de la Pitiè-Salpêtrière, Paris, France. 110Mental Health Research Centre, Russian Academy of Medical Sciences, Moscow, Russia. 111Neuroscience Therapeutic Area, Janssen Research and Development, Raritan, NJ, USA. 112Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. 113Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands. 114Illumina, La Jolla, CA, USA. 115Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle, New South Wales, Australia. 116School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle, New South Wales, Australia. 117Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland. 118Department of Genetics, Harvard Medical School, Boston, MA, USA. 119Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan. 120Regional Centre for Clinical Researchin Psychosis, Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway. 121Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain. 122Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. 123The Perkins Institute for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. 124Department of Medical Genetics, Medical University, Sofia, Bulgaria. 125Department of Psychology, University of Colorado Boulder, Boulder, CO, USA. 126Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 127Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. 128Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. 129Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia. 130Latvian Biomedical Research and Study Centre, Riga, Latvia. 131Department of Psychiatry and Zilkha Neurogenetics Institute, Keck School of Medicine at University of Southern California, Los Angeles, CA, USA. 132Faculty of Medicine, Vilnius University, Vilnius, Lithuania. 133Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic. 134Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris, France. 135Duke-NUS Graduate Medical School, Singapore, Singapore. 136Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 137Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, China. 138Mental Health Centre and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China. 139Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA. 140Department of Psychiatry, Columbia University, New York, New York, NY, USA. 141Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, New South Wales, Australia. 142Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland. 143Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland. 144Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. 145Department of Psychiatry, University of Bonn, Bonn, Germany. 146Centre National de la Recherche Scientifique, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodénégératifs, Hôpital de la Pitiè-Salpêtrière, Paris, France. 147Department of Genomics Mathematics, University of Bonn, Bonn, Germany. 148Research Unit, Sørlandet Hospital, Kristiansand, Norway. 149Department of Psychiatry, Harvard Medical School, Boston, MA, USA. 150VA Boston Health Care System, Brockton, MA, USA. 151Department of Psychiatry, National University of Ireland Galway, Co, Galway, Ireland. 152Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. 153Division of Psychiatry, University of Edinburgh, Edinburgh, UK. 154Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 155Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA, USA. 156Estonian Genome Center, University of Tartu, Tartu, Estonia. 157School of Psychology, University of Newcastle, Newcastle, New South Wales, Australia. 158First Psychiatric Clinic, Medical University, Sofia, Bulgaria. 159Department P, Aarhus University Hospital, Risskov, Denmark. 160Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland. 161King’s College London, London, UK. 162Maastricht University Medical Centre, South Limburg Mental Health Research and TeachingNetwork, EURON, Maastricht, the Netherlands. 163Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 164Max Planck Institute of Psychiatry, Munich, Germany. 165Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 166Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. 167Department of Psychiatry, Queensland Brain Institute and Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia. 168Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 169Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. 170Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA. 171Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden. 172DETECT Early Intervention Service for Psychosis, Blackrock, Co, Dublin, Ireland. 173Centre for Public Health, Institute of Clinical Sciences, Queen’s University Belfast, Belfast, UK. 174Lawrence Berkeley National Laboratory, University of California at Berkeley, Berkeley, CA, USA. 175Institute of Psychiatry, King’s College London, London, UK. 176Melbourne Neuropsychiatry Centre, University of Melbourne & Melbourne Health, Melbourne, Victoria, Australia. 177Department of Psychiatry, University of Helsinki, Helsinki, Finland. 178Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland. 179Medical Faculty, University of Belgrade, Belgrade, Serbia. 180Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA. 181Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland. 182Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. 183Department of Psychiatry, University of Oxford, Oxford, UK. 184Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA. 185Pharma Therapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA. 186Department of Psychiatry and Psychotherapy, University of Gottingen, Göttingen, Germany. 187Psychiatry and Psychotherapy Clinic, University of Erlangen, Erlangen, Germany. 188Hunter New England Health Service, Newcastle, New South Wales, Australia. 189School of Biomedical Sciences, University of Newcastle, Newcastle, New South Wales, Australia. 190Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. 191University of Iceland, Landspitali, National University Hospital, Reykjavik, Iceland. 192Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia. 193Research and Development, Bronx Veterans Affairs Medical Center, New York, NY, USA. 194WellcomeTrust Centre for Human Genetics, Oxford, UK. 195deCODE Genetics, Reykjavik, Iceland. 196Department of Clinical Neurology, Medical University of Vienna, Wien, Austria. 197Lieber Institute for Brain Development, Baltimore, MD, USA. 198Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands. 199Berkshire Healthcare NHS Foundation Trust, Bracknell, UK. 200Section of Psychiatry, University of Verona, Verona, Italy. 201Department of Psychiatry, University of Oulu, Oulu, Finland. 202University Hospital of Oulu, Oulu, Finland. 203Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland. 204Health Research Board, Dublin, Ireland. 205School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Western Australia, Australia. 206Computational Sciences CoE, Pfizer Worldwide Research and Development, Cambridge, MA, USA. 207Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore. 208University College London, London, UK. 209Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany. 210Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel. 211NeuroscienceDiscovery and Translational Area, Pharma Research and Early Development, F. Hoffman-La Roche, Basel, Switzerland. 212Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Medical Research Foundation Building, Perth, Western Australia, Australia. 213Virginia Institute for Psychiatric and Behavioral Genetics, Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA. 214The Feinstein Institute for Medical Research, Manhasset, NY, USA. 215The Hofstra NS-LIJ School of Medicine, Hempstead, NY, USA. 216The Zucker Hillside Hospital, Glen Oaks, NY, USA. 217Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. 218Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia. 219Center for HumanGenetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. 220Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam, the Netherlands. 221Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam, the Netherlands. 222Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands. 223University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK. 224Departments of Psychiatry, Neurology, Neuroscience and Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA. 225Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Published
2019

43. Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa

Author

Walton, E, Hibar, D, Yilmaz, Z, Jahanshad, N, Cheung, J, Batury, V-L, Seitz, J, Bulik, CM, Thompson, PM, Ehrlich, Stefan, Hibar, Derrek P, Stein, Jason L, Renteria, Miguel E, Arias-Vasquez, Alejandro, Desrivieres, Sylvane, Jahanshad, Neda, Toro, Roberto, Wittfeld, Katharina, Abramovic, Lucija, Andersson, Micael, Aribisala, Benjamin S, Armstrong, Nicola J, Bernard, Manon, Bohlken, Marc M, Boks, Marco P, Bralten, Janita, Brown, Andrew A, Chakravarty, M Mallar, Chen, Qiang, Ching, Christopher RK, Cuellar-Partida, Gabriel, Den Braber, Anouk, Giddaluru, Sudheer, Goldman, Aaron L, Grimm, Oliver, Guadalupe, Tulio, Hass, Johanna, Woldehawariat, Girma, Holmes, Avram J, Hoogman, Martine, Janowitz, Deborah, Jia, Tianye, Kim, Sungeun, Klein, Marieke, Kraemer, Bernd, Lee, Phil H, Loohuis, Loes M Olde, Luciano, Michelle, Macare, Christine, Mather, Karen A, Mattheisen, Manuel, Milaneschi, Yuri, Nho, Kwangsik, Papmeyer, Martina, Ramasamy, Adaikalavan, Risacher, Shannon L, Roiz-Santianez, Roberto, Rose, Emma J, Salami, Alireza, Samann, Philipp G, Schmaal, Lianne, Schork, Andrew J, Shin, Jean, Strike, Lachlan T, Teumer, Alexander, van Donkelaar, Marjolein MJ, van Eijk, Kristel R, Walters, Raymond K, Westlye, Lars T, Whelan, Christopher D, Winkler, Anderson M, Zwiers, Marcel P, Alhusaini, Saud, Athanasiu, Lavinia, Hakobjan, Marina MH, Hartberg, Cecilie B, Haukvik, Unn K, Heister, Angelien JGAM, Hohn, David, Kasperaviciute, Dalia, Liewald, David CM, Lopez, Lorna M, Makkinje, Remco RR, Matarin, Mar, Naber, Marlies AM, Mckay, David R, Needham, Margaret, Nugent, Allison C, Putz, Benno, Shen, Li, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia SL, van Hulzen, Kimm JE, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Cichon, Sven, Corvin, Aiden, Curran, Joanne E, Czisch, Michael, de Zubicaray, Greig I, Dillman, Allissa, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fedko, Iryna O, Ferrucci, Luigi, Foroud, Tatiana M, Fox, Peter T, Fukunaga, Masaki, Gibbs, J Raphael, Goring, Harald HH, Green, Robert C, Guelfi, Sebastian, Hansell, Narelle K, Hartman, Catharina A, Hegenscheid, Katrin, Heinz, Andreas, Hernandez, Dena G, Heslenfeld, Dirk J, Hoekstra, Pieter J, Holsboer, Florian, Homuth, Georg, Hottenga, Jouke-Jan, Ikeda, Masashi, Jr, Jack Clifford R, Jenkinson, Mark, Johnson, Robert, Kanai, Ryota, Keil, Maria, Jr, Kent Jack W, Kochunov, Peter, Kwok, John B, Lawrie, Stephen M, Liu, Xinmin, Longo, Dan L, McMahon, Katie L, Meisenzahl, Eva, Melle, Ingrid, Mohnke, Sebastian, Montgomery, Grant W, Mostert, Jeanette C, Muhleisen, Thomas W, Nalls, Michael A, Nichols, Thomas E, Nilsson, Lars G, Nothen, Markus M, Ohi, Kazutaka, Olvera, Rene L, Perez-Iglesias, Rocio, Pike, G Bruce, Potkin, Steven G, Reinvang, Ivar, Reppermund, Simone, Rietschel, Marcella, Romanczuk-Seiferth, Nina, Rosen, Glenn D, Rujescu, Dan, Schnell, Knut, Schofield, Peter R, Smith, Colin, Steen, Vidar M, Sussmann, Jessika E, Thalamuthu, Anbupalam, Toga, Arthur W, Traynor, Bryan J, Troncoso, Juan, Turner, Jessica A, Hernandez, Maria C Valdes, van't Ent, Dennis, van der Brug, Marcel, van der Wee, Nic JA, van Tol, Marie-Jose, Veltman, Dick J, Wassink, Thomas H, Westman, Eric, Zielke, Ronald H, Zonderman, Alan B, Ashbrook, David G, Hager, Reinmar, Lu, Lu, McMahon, Francis J, Morris, Derek W, Williams, Robert W, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Cahn, Wiepke, Calhoun, Vince D, Cavalleri, Gianpiero L, Crespo-Facorro, Benedicto, Dale, Anders M, Davies, Gareth E, Delanty, Norman, Depondt, Chantal, Djurovic, Srdjan, Drevets, Wayne C, Espeseth, Thomas, Gollub, Randy L, Ho, Beng-Choon, Hoffmann, Wolfgang, Hosten, Norbert, Kahn, Rene S, Le Hellard, Stephanie, Meyer-Lindenberg, Andreas, Mueller-Myhsok, Bertram, Nauck, Matthias, Nyberg, Lars, Pandolfo, Massimo, Penninx, Brenda WJH, Roffman, Joshua L, Sisodiya, Sanjay M, Smoller, Jordan W, van Bokhoven, Hans, van Haren, Neeltje EM, Volzke, Henry, Walter, Henrik, Weiner, Michael W, Wen, Wei, White, Tonya, Agartz, Ingrid, Andreassen, Ole A, Blangero, John, Boomsma, Dorret I, Brouwer, Rachel M, Cannon, Dara M, Cookson, Mark R, de Geus, Eco JC, Deary, Ian J, Donohoe, Gary, Fernandez, Guillen, Fisher, Simon E, Francks, Clyde, Glahn, David C, Grabe, Hans J, Gruber, Oliver, Hardy, John, Hashimoto, Ryota, Pol, Hilleke E Hulshoff, Jonsson, Erik G, Kloszewska, Iwona, Lovestone, Simon, Mattay, Venkata S, Mecocci, Patrizia, McDonald, Colm, McIntosh, Andrew M, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Ryten, Mina, Sachdev, Perminder S, Saykin, Andrew J, Simmons, Andrew, Singleton, Andrew, Soininen, Hilkka, Wardlaw, Joanna M, Weale, Michael E, Weinberger, Daniel R, Adams, Hieab HH, Launer, Lenore J, Seiler, Stephan, Schmidt, Reinhold, Chauhan, Ganesh, Satizabal, Claudia L, Becker, James T, Yanek, Lisa R, van der Lee, Sven J, Ebling, Maritza, Fischl, Bruce, Longstreth, WT, Greve, Douglas, Schmidt, Helena, Nyquist, Paul, Vinke, Louis N, van Duijn, Cornelia M, Luting, Xue, Mazoyer, Bernard, Bis, Joshua C, Gudnason, Vilmundur, Seshadri, Sudha, Ikram, M Arfan, Martin, Nicholas G, Wright, Margaret J, Schumann, Gunter, Franke, Barbara, Thompson, Paul M, Medland, Sarah E, Duncan, Laramie, Yilmaz, Zeynep, Walters, Raymond, Goldstein, Jackie, Anttila, Verneri, Bulik-Sullivan, Brendan, Ripke, Stephan, Adan, Roger, Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole, Aschauer, Harald, Baker, Jessica, Barrett, Jeffrey, Bencko, Vladimir, Bergen, Andrew, Berrettini, Wade, Birgegard, Andreas, Boni, Claudette, Perica, Vesna Boraska, Brandt, Harry, Burghardt, Roland, Carlberg, Laura, Cassina, Matteo, Cichon, Carolyn Cesta Sven, Clementi, Maurizio, Cohen-Woods, Sarah, Coleman, Joni, Cone, Roger, Courtet, Philippe, Crawford, Steven, Crow, Scott, Crowley, Jim, Danner, Unna, Davis, Oliver, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece, Dick, Danielle, Dikeos, Dimitris, Dina, Christian, Ding, Bo, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Egberts, Karin, Escaramis, Georgia, Esko, Tonu, Estivill, Xavier, Favaro, Angela, Fernandez-Aranda, Fernando, Fichter, Manfred, Finan, Chris, Fischer, Krista, Floyd, James, Focker, Manuel, Foretova, Lenka, Forzan, Monica, Fox, Caroline, Franklin, Christopher, Gallinger, Valerie Gaborieau Steven, Gambaro, Giovanni, Gaspar, Helena, Giegling, Ina, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos, Monica, Guillaume, Sebastien, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine, Harrison, Rebecca, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske, Hendriks, Judith, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hilliard, Christopher, Huckins, Laura, Hudson, James, Huemer, Julia, Imgart, Hartmut, Inoko, Hidetoshi, Jamain, Sigrid Jall Stephane, Janout, Vladimir, Jimenez-Murcia, Susana, Johnson, Craig, Jordan, Jenny, Julia, Antonio, Jureus, Anders, Kalsi, Gursharan, Kaplan, Allan, Kaprio, Jaakko, Karhunen, Leila, Karwautz, Andreas, Kas, Martien, Kaye, Walter, Kennedy, Martin, Kennedy, James, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klareskog, Lars, Klump, Kelly, Knudsen, Gun Peggy, Koeleman, Bobby, Koubek, Doris, La Via, Maria, Landen, Mikael, Leboyer, Marion, Levitan, Robert, Li, Dong, Lichtenstein, Paul, Lilenfeld, Lisa, Lissowska, Jolanta, Lundervold, Astri, Magistretti, Pierre, Maj, Mario, Mannik, Katrin, Marsal, Sara, Kaminska, Debora, Martin, Nicholas, Mattingsdal, Morten, McDevitt, Sara, McGuffin, Peter, Merl, Elisabeth, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, James, Mitchell, Karen, Monteleone, Palmiero, Monteleone, Alessio Maria, Montgomery, Grant, Mortensen, Preben, Munn-Chernoff, Melissa, Mueller, Timo, Nacmias, Benedetta, Navratilova, Marie, Nilsson, Ida, Norring, Claes, Ntalla, Ioanna, Ophoff, Roel, O'Toole, Julie, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Pinto, Richard Parker Dalila, Rabionet, Raquel, Raevuori, Anu, Rajewski, Andrzej, Ramoz, Nicolas, Rayner, N William, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rybakowski, Filip, Santonastaso, Paolo, Scherag, Andre, Scherer, Stephen, Schmidt, Ulrike, Schork, Nicholas, Schosser, Alexandra, Scott, Laura, Seitz, Jochen, Slachtova, Lenka, Sladek, Robert, Slagboom, P Eline, Slof-Op't Landt, Margarita, Slopien, Agnieszka, Smith, Tosha, Soranzo, Nicole, Sorbi, Sandro, Southam, Lorraine, Steen, Vidar, Strengman, Eric, Strober, Michael, Szatkiewicz, Jin, Szeszenia-Dabrowska, Neonila, Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tschop, Matthias, Tsitsika, Artemis, Tziouvas, Konstantinos, van Elburg, Annemarie, van Furth, Eric, Wade, Tracey, Wagner, Gudrun, Watson, Hunna, Wichmann, H-Erich, Widen, Elisabeth, Woodside, D Blake, Yanovski, Jack, Yao, Shuyang, Zerwas, Stephanie, Zipfel, Stephan, Thornton, Laura, Hinney, Anke, Breen, Gerome, Bulik, Cynthia M, PGC-ED, Grp, ENIGMA Genetics Working, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Kas lab, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, and APH - Mental Health

Subjects
0301 basic medicine, Anorexia Nervosa, Eating Disorders, REWARD CIRCUITRY, Genome-wide association study, ADOLESCENT, PGC-ED, Bioinformatics, Linkage Disequilibrium, 0302 clinical medicine, Anorexia nervosa, Brain structure, Genetic correlation, SCHIZOPHRENIA, ENIGMA Genetics Working Group, 2.1 Biological and endogenous factors, Psychology, Aetiology, Cervell, RISK, ABNORMALITIES, Anorèxia nerviosa, Brain, FUNCTIONAL CONNECTIVITY, Organ Size, Single Nucleotide, Serious Mental Illness, Magnetic Resonance Imaging, 3. Good health, Anorexia, Mental Health, Neurology, Anorexia nervosa (differential diagnoses), Brain size, MENDELIAN RANDOMIZATION, Biomedical Imaging, Cognitive Sciences, RESPONSE-INHIBITION, Neuroscience (miscellaneous), Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mendelian randomization, Journal Article, Genetics, Humans, Genetic Testing, GENOME-WIDE ASSOCIATION, Polymorphism, POLYMORPHISMS, Genetic association, Neurology & Neurosurgery, Prevention, Human Genome, Neurosciences, Mendelian Randomization Analysis, Genetic architecture, Brain Disorders, 030104 developmental biology, Genetic marker, Case-Control Studies, 030217 neurology & neurosurgery, Genètica, Genome-Wide Association Study
Abstract

Molecular neurobiology 56(7), 5146-5156 (2019). doi:10.1007/s12035-018-1439-4, Published by Humana Press, Totowa, NJ

Published
2019

44. Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept

Author

Franke, Barbara, Stein, Jason L, McIntosh, Andrew M, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Lee, Phil, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Gopal, Srihari, McMahon, Francis J, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan L, Meyer-Lindenberg, Andreas, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Hougaard, David M, Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kähler, Anna K, Kahn, René S, Mattheisen, Manuel, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kelly, Brian J, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Andreassen, Ole A, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Laurent, Claudine, Lee, S Hong, Keong, Jimmy Lee Chee, Legge, Sophie E, Lerer, Bernard, Gruber, Oliver, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Lönnqvist, Jouko, Loughland, Carmel M, Lubinski, Jan, Macek, Milan, Magnusson, Patrik K E, Sachdev, Perminder S, Maher, Brion S, Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattingsdal, Morten, McCarley, Robert W, McDonald, Colm, Meier, Sandra, Roiz-Santiañez, Roberto, Meijer, Carin J, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W, Saykin, Andrew J, Mors, Ole, Müller-Myhsok, Bertram, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Ripke, Stephan, Ehrlich, Stefan, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Mather, Karen A, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T, Paunio, Tiina, Perkins, Diana O, Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J, Turner, Jessica A, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Roffman, Joshua L, Schwarz, Emanuel, Roussos, Panos, Ruderfer, Douglas M, Salomaa, Veikko, Sanders, Alan R, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Scolnick, Edward M, Scott, Rodney J, Thalamuthu, Anbupalam, Seidman, Larry J, Shi, Jianxin, Silverman, Jeremy M, Sim, Kang, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Söderman, Erik, Spencer, Chris C A, Stahl, Eli A, Shugart, Yin Yao, Stogmann, Elisabeth, Straub, Richard E, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Thirumalai, Srinivas, Ho, Yvonne Yw, Toncheva, Draga, Tooney, Paul A, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T, Weiser, Mark, Wildenauer, Dieter B, Martin, Nicholas G, Williams, Nigel M, Williams, Stephanie, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily H M, Wormley, Brandon K, Wu, Jing Qin, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Wright, Margaret J, Zimprich, Fritz, Wray, Naomi R, Visscher, Peter M, Adolfsson, Rolf, Blackwood, Douglas H R, Børglum, Anders D, Bramon, Elvira, Buxbaum, Joseph D, Cichon, Sven, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V, Gill, Michael, Gurling, Hugh, Hultman, Christina M, Iwata, Nakao, Jablensky, Assen V, Anttila, Verneri, Consortium, ENIGMA, Jönsson, Erik G, Kendler, Kenneth S, Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F, Li, Qingqin S, Liu, Jianjun, Malhotra, Anil K, McCarroll, Steven A, O'Donovan, Michael C, McQuillin, Andrew, Moran, Jennifer L, Mortensen, Preben B, Mowry, Bryan J, Nöthen, Markus M, Ophoff, Roel A, Owen, Michael J, Palotie, Aarno, Pato, Carlos N, Petryshen, Tracey L, Thompson, Paul M, Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P, Rujescu, Dan, Sham, Pak C, Sklar, Pamela, Clair, David St, Weinberger, Daniel R, Wendland, Jens R, Werge, Thomas, Neale, Benjamin M, Daly, Mark J, Sullivan, Patrick F, Hibar, Derrek P, Renteria, Miguel E, Arias-Vasquez, Alejandro, Desrivières, Sylvane, Jahanshad, Neda, Toro, Roberto, Medland, Sarah E, Wittfeld, Katharina, Abramovic, Lucija, Andersson, Micael, Aribisala, Benjamin S, Armstrong, Nicola J, Bernard, Manon, Bohlken, Marc M, Boks, Marco P, Bralten, Janita, Brown, Andrew A, Chakravarty, M Mallar, Chen, Qiang, Ching, Christopher R K, Cuellar-Partida, Gabriel, den Braber, Anouk, Giddaluru, Sudheer, Goldman, Aaron L, Grimm, Oliver, Guadalupe, Tulio, Hass, Johanna, Woldehawariat, Girma, Holmes, Avram J, Hoogman, Martine, Janowitz, Deborah, Jia, Tianye, Kim, Sungeun, Klein, Marieke, Kraemer, Bernd, Loohuis, Loes M Olde, Luciano, Michelle, Macare, Christine, Milaneschi, Yuri, Nho, Kwangsik, Papmeyer, Martina, Ramasamy, Adaikalavan, Risacher, Shannon L, Corvin, Aiden, Rose, Emma J, Salami, Alireza, Sämann, Philipp G, Schmaal, Lianne, Schork, Andrew J, Shin, Jean, Strike, Lachlan T, Teumer, Alexander, van Donkelaar, Marjolein M J, van Eijk, Kristel R, Walters, James T R, Walters, Raymond K, Westlye, Lars T, Whelan, Christopher D, Winkler, Anderson M, Zwiers, Marcel P, Alhusaini, Saud, Athanasiu, Lavinia, Hakobjan, Marina M H, Hartberg, Cecilie B, Farh, Kai-How, Haukvik, Unn, Heister, Angelien J G A M, Höhn, David, Kasperaviciute, Dalia, Liewald, David C M, Lopez, Lorna M, Makkinje, Remco R R, Matarin, Mar, Naber, Marlies A M, McKay, David R, Holmans, Peter A, Needham, Margaret, Nugent, Allison C, Pütz, Benno, Royle, Natalie A, Shen, Li, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia S L, van Hulzen, Kimm J E, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Bulik-Sullivan, Brendan, Curran, Joanne E, Czisch, Michael, de Zubicaray, Greig I, Dillman, Allissa, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fedko, Iryna O, Ferrucci, Luigi, Collier, David A, Foroud, Tatiana M, Fox, Peter T, Fukunaga, Masaki, Gibbs, Raphael, Göring, Harald H H, Green, Robert C, Guelfi, Sebastian, Hansell, Narelle K, Hartman, Catharina A, Hegenscheid, Katrin, Huang, Hailiang, Heinz, Andreas, Hernandez, Dena G, Heslenfeld, Dirk J, Hoekstra, Pieter J, Holsboer, Florian, Homuth, Georg, Hottenga, Jouke-Jan, Jack, Clifford R, Jenkinson, Mark, Pers, Tune H, Johnson, Robert, Kanai, Ryota, Keil, Maria, Kent, Jack W, Kochunov, Peter, Kwok, John B, Lawrie, Stephen M, Liu, Xinmin, Longo, Dan L, McMahon, Katie L, Agartz, Ingrid, Meisenzahl, Eva, Mohnke, Sebastian, Montgomery, Grant W, Mostert, Jeanette C, Mühleisen, Thomas W, Nalls, Michael A, Nichols, Thomas E, Nilsson, Lars G, Agerbo, Esben, Ohi, Kazutaka, Olvera, Rene L, Perez-Iglesias, Rocio, Pike, G Bruce, Potkin, Steven G, Reinvang, Ivar, Reppermund, Simone, Romanczuk-Seiferth, Nina, Rosen, Glenn D, Albus, Margot, Schnell, Knut, Schofield, Peter R, Smith, Colin, Steen, Vidar M, Sussmann, Jessika E, Toga, Arthur W, Traynor, Bryan, Troncoso, Juan, Alexander, Madeline, Hernández, Maria C Valdés, van 't Ent, Dennis, van der Brug, Marcel, van der Wee, Nic J A, van Tol, Marie-Jose, Veltman, Dick J, Wassink, Thomas H, Westman, Eric, Zielke, Ronald H, Amin, Farooq, Zonderman, Alan, Ashbrook, David G, Hager, Reinmar, Lu, Lu, Williams, Robert W, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Bacanu, Silviu A, Cahn, Wiepke, Calhoun, Vince D, Cavalleri, Gianpiero L, Crespo-Facorro, Benedicto, Dale, Anders M, Davies, Gareth E, Delanty, Norman, Depondt, Chantal, Djurovic, Srdjan, Drevets, Wayne C, Begemann, Martin, Espeseth, Thomas, Gollub, Randy L, Ho, Beng-Choon, Hoffmann, Wolfgang, Hosten, Norbert, LeHellard, Stephanie, Nauck, Matthias, Belliveau, Richard A, Nyberg, Lars, Pandolfo, Massimo, Penninx, Brenda W J H, Sisodiya, Sanjay M, van Bokhoven, Hans, van Haren, Neeltje E M, Völzke, Henry, Walter, Henrik, Bene, Judit, Weiner, Michael W, Wen, Wei, White, Tonya, Blangero, John, Boomsma, Dorret I, Brouwer, Rachel M, Cannon, Dara M, Cookson, Mark R, Bergen, Sarah E, de Geus, Eco J C, Deary, Ian J, Donohoe, Gary, Fernández, Guillén, Fisher, Simon E, Francks, Clyde, Glahn, David C, Grabe, Hans J, Hardy, John, Bevilacqua, Elizabeth, Hashimoto, Ryota, Hulshoff Pol, Hilleke E, Kloszewska, Iwona, Lovestone, Simon, Mattay, Venkata S, Mecocci, Patrizia, Bigdeli, Tim B, Paus, Tomas, Pausova, Zdenka, Ryten, Mina, Simmons, Andy, Singleton, Andrew, Soininen, Hilkka, Wardlaw, Joanna M, Weale, Michael E, Black, Donald W, Adams, Hieab H H, Launer, Lenore J, Seiler, Stephan, Schmidt, Reinhold, Chauhan, Ganesh, Satizabal, Claudia L, Becker, James T, Yanek, Lisa, van der Lee, Sven J, Bruggeman, Richard, Ebling, Maritza, Fischl, Bruce, Longstreth, W. T., Greve, Douglas, Schmidt, Helena, Nyquist, Paul, Vinke, Louis N, van Duijn, Cornelia M, Luting, Xue, Mazoyer, Bernard, Buccola, Nancy G, Bis, Joshua C, Gudnason, Vilmundur, Seshadri, Sudha, Ikram, M Arfan, Schumann, Gunter, Byerley, William F, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Chan, Raymond C K, Chen, Eric Y H, Chen, Ronald Y L, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Neale, Michael C, Del Favero, Jurgen, DeLisi, Lynn E, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Franke, Barbara, Stein, Jason L, Ripke, Stephan, Anttila, Verneri, Hong Lee, S, Ikram, M Arfan, Schizophrenia Working Group of the Psychiatric Genomics Consortium, ENIGMA Consortium, Radboud University Medical Center [Nijmegen], University of Southern California (USC), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], University of Warwick [Coventry], University of Oxford [Oxford], Virginia Commonwealth University (VCU), University of Edinburgh, National Institutes of Health [Bethesda] (NIH), Chinese PLA General Hospital, University of Missouri [Columbia], University of Missouri System, Cardiff University, Aarhus University [Aarhus], Stanford University [Stanford], Max-Planck-Institut, University of Iowa [Iowa City], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Schizophrenia Research Institute [Sydney], Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Mathematics [CUHK], The Chinese University of Hong Kong [Hong Kong], The University of Hong Kong (HKU), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Castle Peak Hospital [Hong Kong], Institute of Mental Health [Singapore], Service de psychiatrie des enfants et adultes [CHU Pitié-Salpêtrière ], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Queen Mary University of London (QMUL), Open University of Israël, University of Antwerp (UA), Harvard Medical School [Boston] (HMS), University of Athens Medical School [Athens], University College Cork (UCC), University of Oslo (UiO), London School of Hygiene and Tropical Medicine (LSHTM), Universität Regensburg (UR), Biomedicum Helsinki, Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], Universität Heidelberg [Heidelberg], University Medical Center Groningen [Groningen] (UMCG), Haverford College, Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], CHU Limoges, University of Queensland [Brisbane], James J. Peters VA Medical Center [New York], Martin-Luther-University Halle-Wittenberg, University of Newcastle [Australia] (UoN), University of Basel (Unibas), Division of Medical Genetics [Seattle], University of Washington [Seattle], Statens Serum Institut [Copenhagen], Tohoku University [Sendai], University of Stavanger, Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), University of Sofia, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Universität Stuttgart [Stuttgart], Russian Academy of Sciences [Moscow] (RAS), Latvian Biomedical Research and Study Centre [Rīga], Vilnius University [Vilnius], University Hospital Motol [Prague], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hadassah Hebrew University Medical Center [Jerusalem], Karolinska Institutet [Stockholm], University of Bonn, Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Vall d'Hebron University Hospital [Barcelona], Department of Life Sciences, Imperial College London, Deutscher Wetterdienst [Offenbach] (DWD), Eli Lilly and Company Limited [Windlesham], Trinity College Dublin, Royal College of Surgeons in Ireland (RCSI), Université de Lausanne (UNIL), University of Tartu, Johns Hopkins University School of Medicine [Baltimore], Stockholm University, Queen's University [Belfast] (QUB), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Universidade de São Paulo (USP), Department of Mathematics [Nanticoke], Luzerne County Community College, National Institute for Health and Welfare [Helsinki], King‘s College London, University of Chicago, Fraunhofer Heinrich Hertz Institute [Berlin] (HHI), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), National Cancer Institute [Bethesda] (NCI-NIH), The Wellcome Trust Centre for Human Genetics [Oxford], Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, The Natural History Museum [London] (NHM), University of Calgary, Department of Medical Epidemiology and Biostatistics (MEB), The University of Western Australia (UWA), Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Montreal Neurological Institute and Hospital, McGill University, Universidade do Algarve (UAlg), Beijing Normal University, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Dpt of Psychiatry [New Haven], Yale University School of Medicine, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Bijvoet Center of Biomolecular Research, Utrecht University [Utrecht], School of Psychology, University of Queensland, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Department of Mathematics, University of Colorado, University of Colorado [Boulder], VU University Amsterdam, Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Health and Human Services, McConnell Brain Imaging Centre (MNI), McGill University-McGill University, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Computer Science and Artificial Intelligence Laboratory [Cambridge] (CSAIL), Massachusetts Institute of Technology (MIT), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Del-Favero, Jurgen, Enigma Consortium, School of Medicine / Clinical Medicine, University of Oxford, University of Missouri [Columbia] (Mizzou), Stanford University, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Heidelberg [Heidelberg] = Heidelberg University, University of Newcastle [Callaghan, Australia] (UoN), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Софийски университет = Sofia University, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universität Bonn = University of Bonn, Université de Lausanne = University of Lausanne (UNIL), Universidade de São Paulo = University of São Paulo (USP), Fraunhofer Institute for Telecommunications - Heinrich Hertz Institute (Fraunhofer HHI), Fraunhofer (Fraunhofer-Gesellschaft), Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Beijing Normal University (BNU), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), Centre épigénétique et destin cellulaire (EDC), Bijvoet Center of Biomolecular Research [Utrecht], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Vrije Universiteit Amsterdam [Amsterdam] (VU), McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Biological Psychology, EMGO+ - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Other departments, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Adult Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), and MUMC+: Hersen en Zenuw Centrum (3)

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), genetic association, Genome-wide association study, brain imaging, VARIANTS, Genome-wide association studies, Linkage Disequilibrium, 0302 clinical medicine, pathology [Brain], 2.1 Biological and endogenous factors, Psychology, GWAS, genetics [Schizophrenia], genetics, genetics [Genetic Predisposition to Disease], Aetiology, Non-U.S. Gov't, PERSPECTIVE, humans, Schizophrenia Working Group of the Psychiatric Genomics Consortium, neuroimaging, General Neuroscience, Research Support, Non-U.S. Gov't, Brain, Single Nucleotide, Organ Size, Endophenotypes, Genetic Predisposition to Disease, Humans, Magnetic Resonance Imaging, Neuroimaging, Polymorphism, Single Nucleotide, Schizophrenia, Genome-Wide Association Study, Neuroscience (all), Serious Mental Illness, ENIGMA Consortium, 3. Good health, endophenotype, Mental Health, Meta-analysis, Neurological, genetics [Polymorphism, Single Nucleotide], Cognitive Sciences, MRI, Neuroinformatics, DISORDERS, heredity, Schizophrenia (object-oriented programming), brain, Non-P.H.S, Brain Structure and Function, RELATIVES, PHENOTYPES, Research Support, N.I.H, 03 medical and health sciences, Magnetic resonance imaging, ENDOPHENOTYPE, Research Support, N.I.H., Extramural, ddc:570, Journal Article, Polymorphism, GENOME-WIDE ASSOCIATION, pathology [Schizophrenia], METAANALYSIS, genetic predisposition to disease, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, genome-wide association study, [SCCO.NEUR]Cognitive science/Neuroscience, Human Genome, Neurosciences, Extramural, Genetic architecture, Brain Disorders, meta-analysis, schizophrenia, INDIVIDUALS, 030104 developmental biology, Genetic marker, Endophenotype, DISCOVERY, Genetic markers, U.S. Gov't, Human medicine, Neuroscience, genetic predisposition, 030217 neurology & neurosurgery, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
Abstract

Article, Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders., final draft, peerReviewed

Published
2016

45. Analysis of shared heritability in common disorders of the brain

Author

Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K., Walters, Raymond K., Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J., Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A., Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H., Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-Francois, Duron, Emmanuelle, Vardarajan, Badri N., Reitz, Christiane, Goate, Alison M., Huentelman, Matthew J., Kamboh, M. Ilyas, Larson, Eric B., Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A., Farrer, Lindsay A., Barnes, Lisa L., Beach, Thomas G., Demirci, F. Yesim, Head, Elizabeth, Hulette, Christine M., Jicha, Gregory A., Kauwe, John S. K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Lesch, Klaus-Peter, van Os, Jim, Corvin, Aiden, Neale, Benjamin M., Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), and MUMC+: Hersen en Zenuw Centrum (3)

Subjects
MAJOR DEPRESSIVE DISORDER, Brain Diseases/classification, ANOREXIA-NERVOSA, DEFICIT HYPERACTIVITY DISORDER, LONG-TERM SURVIVAL, Genetic Variation, BIPOLAR DISORDER, POPULATION-BASED TWIN, BODY-MASS INDEX, ALZHEIMERS-DISEASE, Quantitative Trait, Heritable, Phenotype, Risk Factors, Mental Disorders/classification, Humans, GENOME-WIDE ASSOCIATION, GENETIC CORRELATIONS, Genome-Wide Association Study
Abstract

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Published
2018

46. Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 controls via the ENIGMA consortium

Author

van Erp, Theo GM., Walton, Esther, Hibar, Derrek P., Schmaal, Lianne, Jiang, Wenhao, Glahn, David C., Pearlson, Godfrey D., Yao, Nailin, Fukunaga, Masaki, Hashimoto, Ryota, Okada, Naohiro, Yamamori, Hidenaga, Bustillo, Juan R., Clark, Vincent P., Agartz, Ingrid, Mueller, Bryon A., Cahn, Wiepke, de Zwarte, Sonja MC., Hulshoff Pol, Hilleke E., Kahn, René S., Ophoff, Roel A., van Haren, Neeltje EM., Andreassen, Ole A., Dale, Anders M., Doan, Nhat Trung, Gurholt, Tiril P., Hartberg, Cecilie B., Haukvik, Unn K., Jørgensen, Kjetil N., Lagerberg, Trine V., Melle, Ingrid, Westlye, Lars T., Gruber, Oliver, Kraemer, Bernd, Richter, Anja, Zilles, David, Calhoun, Vince D., Crespo-Facorro, Benedicto, Roiz-Santiañez, Roberto, Tordesillas-Gutiérrez, Diana, Loughland, Carmel, Carr, Vaughan J., Catts, Stanley, Cropley, Vanessa L., Fullerton, Janice M., Green, Melissa J., Henskens, Frans, Jablensky, Assen, Lenroot, Rhoshel K., Mowry, Bryan J., Michie, Patricia T., Pantelis, Christos, Quidé, Yann, Schall, Ulrich, Scott, Rodney J., Cairns, Murray J., Seal, Marc, Tooney, Paul A., Rasser, Paul E., Cooper, Gavin, Weickert, Cynthia Shannon, Weickert, Thomas W., Morris, Derek W., Hong, Elliot, Kochunov, Peter, Beard, Lauren M., Gur, Raquel E., Gur, Ruben C., Satterthwaite, Theodore D., Wolf, Daniel H., Belger, Aysenil, Brown, Gregory G., Ford, Judith M., Macciardi, Fabio, Mathalon, Daniel H., O’Leary, Daniel S., Potkin, Steven G., Preda, Adrian, Voyvodic, James, Lim, Kelvin O., McEwen, Sarah, Yang, Fude, Tan, Yunlong, Tan, Shuping, Wang, Zhiren, Fan, Fengmei, Chen, Jingxu, Xiang, Hong, Tang, Shiyou, Guo, Hua, Wan, Ping, Wei, Dong, Bockholt, Henry J., Ehrlich, Stefan, Wolthusen, Rick PF., King, Margaret D., Shoemaker, Jody M., Sponheim, Scott R., De Haan, Lieuwe, Koenders, Laura, Machielsen, Marise W., van Amelsvoort, Therese, Veltman, Dick J., Assogna, Francesca, Banaj, Nerisa, de Rossi, Pietro, Iorio, Mariangela, Piras, Fabrizio, Spalletta, Gianfranco, McKenna, Peter J., Pomarol-Clotet, Edith, Salvador, Raymond, Corvin, Aiden, Donohoe, Gary, Kelly, Sinead, Whelan, Christopher D., Dickie, Erin W., Rotenberg, David, Voineskos, Aristotle, Ciufolini, Simone, Radua, Joaquim, Dazzan, Paola, Murray, Robin, Marques, Tiago Reis, Simmons, Andrew, Borgwardt, Stefan, Egloff, Laura, Harrisberger, Fabienne, Riecher-Rössler, Anita, Smieskova, Renata, Alpert, Kathryn I., Wang, Lei, Jönsson, Erik G., Koops, Sanne, Sommer, Iris EC., Bertolino, Alessandro, Bonvino, Aurora, Di Giorgio, Annabella, Neilson, Emma, Mayer, Andrew R., Stephen, Julia M., Kwon, Jun Soo, Yun, Je-Yeon, Cannon, Dara M., McDonald, Colm, Lebedeva, Irina, Tomyshev, Alexander S., Akhadov, Tolibjohn, Kaleda, Vasily, Fatouros-Bergman, Helena, Flyckt, Lena, Busatto, Geraldo F., Rosa, Pedro GP., Serpa, Mauricio H., Zanetti, Marcus V., Hoschl, Cyril, Skoch, Antonin, Spaniel, Filip, Tomecek, David, Hagenaars, Saskia P., McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., Knöchel, Christian, Oertel-Knöchel, Viola, Stäblein, Michael, Howells, Fleur M., Stein, Dan J., Temmingh, Henk, Uhlmann, Anne, Lopez-Jaramillo, Carlos, Dima, Danai, McMahon, Agnes, Faskowitz, Joshua I., Gutman, Boris A., Jahanshad, Neda, Thompson, Paul M., and Turner, Jessica A.

Subjects
Data Aggregation, Schizophrenia, Brain, Humans, Cooperative Behavior, Social Behavior, Article
Abstract

BACKGROUND. The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta Analysis) Schizophrenia Working Group. METHOD. The study included data from 4474 individuals with schizophrenia (mean age=32.3, range: 11–78; 66% male) and 5098 healthy volunteers (mean age=32.8, range: 10–87; 53% male), assessed with standardized methods, at 39 centers worldwide. RESULTS. Compared to healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen’s d=−0.530/−0.516) and smaller surface area (left/right hemisphere: d=−0.251/−0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, the effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were 2 to 3 times larger in antipsychotic medicated relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness, and positive correlations with age at onset. CONCLUSIONS. The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

Published
2018

47. MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls

Author

Cosgrove, D, Harold, D, Mothersill, O, Anney, Richard, Hill, Martin, Bray, Nicholas, Blokland, G, Petryshen, T, Donnelly, Peter, Bates, Lesley, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Hopkins, Lucinda, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, PaulWeston, Widaa, SaraWidaa, Whittaker, Pamela, Richards, Alexander, Mantripragada, Kiran, Owen, Michael, O'Donovan, Michael, Gill, M, Corvin, A, Morris, D W, Donohoe, G, Broad Institute of MIT and Harvard, and Petryshen, Tracey

Subjects
0301 basic medicine, Adult, Male, Multifactorial Inheritance, Memory, Episodic, BF, Bioinformatics, Spatial memory, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, 0302 clinical medicine, Cognition, Memory, Task Performance and Analysis, medicine, Humans, Effects of sleep deprivation on cognitive performance, Episodic memory, Biological Psychiatry, Intelligence quotient, Working memory, Memoria, Functional Neuroimaging, Brain, Middle Aged, medicine.disease, R1, Magnetic Resonance Imaging, Psychiatry and Mental health, MicroRNAs, 030104 developmental biology, Memory, Short-Term, Schizophrenia, Case-Control Studies, Original Article, Female, Schizophrenic Psychology, Psychology, Facial Recognition, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, have been associated with poorer cognitive performance. As microRNA-137 is known to regulate the expression of ~1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognitive performance. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. We then tested, in a sample of 808 patients and 192 controls, whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory (n=108) and face processing tasks (n=83). Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance on intelligence quotient, working memory and episodic memory. These effects were observed most clearly at a polygenic threshold of P=0.05, although significant results were observed at all three thresholds analyzed. This association was found independently for the gene set as a whole, excluding the schizophrenia-associated MIR137 SNP itself. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P=10−5) was significantly associated with increased activation of the right inferior occipital gyrus. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate to its broader downstream genetic effects.

Published
2016

48. Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia

Author

Ripke, Stephan, O'Dushlaine, Colm, Chambert, Kimberly, Moran, Jennifer L, Kähler, Anna K, Akterin, Susanne, Bergen, Sarah, Collins, Ann L, Crowley, James J, Fromer, Menachem, Kim, Yunjung, Lee, Sang Hong, Magnusson, Patrik KE, Sanchez, Nick, Stahl, Eli A, Williams, Stephanie, Wray, Naomi R, Xia, Kai, Bettella, Francesco, Børglum, Anders D, Bulik-Sullivan, Brendan K, Cormican, Paul, Craddock, Nick, de Leeuw, Christiaan, Durmishi, Naser, Gill, Michael, Golimbet, Vera, Hamshere, Marian L, Holmans, Peter, Hougaard, David M, Kendler, Kenneth S, Lin, Kuang, Morris, Derek W, Mors, Ole, Mortensen, Preben B, Neale, Benjamin M, O'Neill, Francis A, Owen, Michael J, Milovancevic, MilicaPejovic, Posthuma, Danielle, Powell, John, Richards, Alexander L, Riley, Brien P, Ruderfer, Douglas, Rujescu, Dan, Sigurdsson, Engilbert, Silagadze, Teimuraz, Smit, August B, Stefansson, Hreinn, Steinberg, Stacy, Suvisaari, Jaana, Tosato, Sarah, Verhage, Matthijs, Walters, James T, Bramon, Elvira, Corvin, Aiden P, O'Donovan, Michael C, Stefansson, Kari, Scolnick, Edward, Purcell, Shaun, McCarroll, Steve, Sklar, Pamela, Hultman, Christina M, and Sullivan, Patrick F

Subjects
Male, Sweden, Polymorphism, Single Nucleotide, Article, schizophrenia, meta-analysis, Case-Control Studies, mental disorders, genome-wide association, Humans, genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Published
2013

49. Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

Author

Power, Robert A, Nagoshi, Craig, DeFries, John C, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, and Whittaker, Pamela

Subjects
Adult, Male, Intelligence, Population, Genome-wide association study, Single-nucleotide polymorphism, Biology, Runs of Homozygosity, Polymorphism, Single Nucleotide, Article, Consanguinity, 03 medical and health sciences, Cognition, 0302 clinical medicine, Genetics, Humans, Child, education, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Genome, Human, Homozygote, Assortative mating, Minor allele frequency, Case-Control Studies, Female, Inbreeding, 030217 neurology & neurosurgery
Abstract

The consequence of reduced cognitive ability from inbreeding has long been investigated, mainly restricted to cousin-cousin marriages. Molecular genetic techniques now allow us to test the relationship between increased ancestral inbreeding and cognitive ability in a population of traditionally unrelated individuals. In a representative UK sample of 2329 individuals, we used genome-wide SNP data to estimate the percentage of the genome covered by runs of homozygous SNPs (ROH). This was tested for association with general cognitive ability, as well as measures of verbal and non-verbal ability. Further, association was tested between these traits and specific ROH. Burden of ROH was not associated with cognitive ability after correction for multiple testing, although burden of ROH was nominally associated with increased non-verbal cognitive ability (P=0.03). Moreover, although no individual ROH was significantly associated with cognitive ability, there was a significant bias towards increased cognitive ability in carriers of ROH (P=0.002). A potential explanation for these results is increased positive assortative mating in spouses with higher cognitive ability, although we found no evidence in support of this hypothesis in a separate sample. Reduced minor allele frequency across the genome was associated with higher cognitive ability, which could contribute to an apparent increase in ROH. This may reflect minor alleles being more likely to be deleterious.

Published
2013

50. No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

Author

Johnson, Emma C., Bjelland, Douglas W., Howrigan, Daniel P., Abdellaoui, Abdel, Breen, Gerome, Borglum, Anders, Cichon, Sven, Degenhardt, Franziska, Forstner, Andreas J., Frank, Josef, Genovese, Giulio, Heilmann-Heimbach, Stefanie, Herms, Stefan, Hoffman, Per, Maier, Wolfgang, Mattheisen, Manuel, Morris, Derek, Mowry, Bryan, Müller-Mhysok, Betram, Neale, Benjamin, Nenadic, Igor, Nöthen, Markus M., O’Dushlaine, Colm, Rietschel, Marcella, Ruderfer, Douglas M., Rujescu, Dan, Schulze, Thomas G., Simonson, Matthew A., Stahl, Eli, Strohmaier, Jana, Witt, Stephanie H., Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T R, Farh, Kai How, Holmans, Peter A., Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberly D., Chan, Raymond C K, Chen, Ronald Y L, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Robert Cloninger, C., Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kahn, René S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Chee Keong, Jimmy Lee, Hong Lee, S., Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Magnusson, Patrik K E, Maher, Brion S., Mallet, Jacques, Marsal, Sara, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, Anthony O'Neill, F., Oh, Sang Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon Cheong, Spencer, Chris C A, Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Scott Stroup, T., Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Wolen, Aaron R., Wong, Emily H M, Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H R, Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jönsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Riley, Brien P., Sham, Pak C., Sklar, Pamela, Clair, David S., Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., O'Donovan, Michael C., Sullivan, Patrick F., Keller, Matthew C., Biological Psychology, Johnson, Emma C, Bjelland, Douglas W, Howrigan, Daniel P, Abdellaoui, Abdel, Lee, S Hong, Keller, Matthew C, and Schizophrenia Working Group of the Psychiatric Genomics Consortium

Subjects
0301 basic medicine, Male, Cancer Research, Heredity, Ecology, Evolution, Behavior and Systematics, Molecular Biology, Genetics, Genetics (clinical), Social Sciences, Genome-wide association study, Disease, 030105 genetics & heredity, Runs of Homozygosity, Homozygosity, Consanguinity, Sociology, Polymorphism (computer science), Consortia, Medicine and Health Sciences, Genetics(clinical), Inbreeding, Ecology, Depression, Homozygote, Genomics, 3. Good health, Schizophrenia, Research Design, Physical Sciences, Female, Statistics (Mathematics), Research Article, lcsh:QH426-470, Evolution, Replication Studies, inbreeding, Single-nucleotide polymorphism, Biology, Genome Complexity, Research and Analysis Methods, Polymorphism, Single Nucleotide, 03 medical and health sciences, SDG 17 - Partnerships for the Goals, Behavior and Systematics, SDG 3 - Good Health and Well-being, Mental Health and Psychiatry, medicine, Confidence Intervals, Humans, replication study, Mood Disorders, Genome, Human, Biology and Life Sciences, Computational Biology, medicine.disease, schizophrenia, lcsh:Genetics, 030104 developmental biology, homozygosity, Mathematics, Genome-Wide Association Study
Abstract

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest., Author Summary It is well known that mating between relatives increases the risk that a child will have a rare recessive genetic disease, but there has also been increasing interest and inconsistent findings on whether inbreeding is a risk factor for common, complex psychiatric disorders such as schizophrenia. The best powered study to date investigating this theory predicted that the odds of developing schizophrenia increase by approximately 17% for every additional percent of the genome that shows evidence of inbreeding. In this replication, we used genome-wide single nucleotide polymorphism data from 18,562 schizophrenia cases and 21,268 controls to quantify the degree to which they were inbred and to test the hypothesis that schizophrenia cases show higher mean levels of inbreeding. Contrary to the original study, we did not find evidence for distant inbreeding to play a role in schizophrenia risk. There are various confounding factors that could explain the discrepancy in results from the original study and our replication, and this should serve as a cautionary note–careful attention should be paid to issues like ascertainment when using the data from genome-wide case-control association studies for secondary analyses for which the data may not have originally been intended.

Published
2016

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