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1. Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Author

Georgiadis, Foivos, Larivière, Sara, Glahn, David, Hong, L, Kochunov, Peter, Mowry, Bryan, Loughland, Carmel, Pantelis, Christos, Henskens, Frans, Green, Melissa, Cairns, Murray, Michie, Patricia, Rasser, Paul, Catts, Stanley, Tooney, Paul, Scott, Rodney, Schall, Ulrich, Carr, Vaughan, Quidé, Yann, Krug, Axel, Stein, Frederike, Nenadić, Igor, Brosch, Katharina, Kircher, Tilo, Gur, Raquel, Gur, Ruben, Satterthwaite, Theodore, Karuk, Andriana, Pomarol-Clotet, Edith, Radua, Joaquim, Fuentes-Claramonte, Paola, Salvador, Raymond, Spalletta, Gianfranco, Voineskos, Aristotle, Sim, Kang, Crespo-Facorro, Benedicto, Tordesillas Gutiérrez, Diana, Ehrlich, Stefan, Crossley, Nicolas, Grotegerd, Dominik, Repple, Jonathan, Lencer, Rebekka, Dannlowski, Udo, Calhoun, Vince, Rootes-Murdy, Kelly, Demro, Caroline, Ramsay, Ian, Sponheim, Scott, Schmidt, Andre, Borgwardt, Stefan, Tomyshev, Alexander, Lebedeva, Irina, Höschl, Cyril, Spaniel, Filip, Preda, Adrian, Nguyen, Dana, Uhlmann, Anne, Stein, Dan, Howells, Fleur, Temmingh, Henk, Diaz Zuluaga, Ana, López Jaramillo, Carlos, Iasevoli, Felice, Ji, Ellen, Homan, Stephanie, Omlor, Wolfgang, Homan, Philipp, Kaiser, Stefan, Seifritz, Erich, Misic, Bratislav, Valk, Sofie, Thompson, Paul, Van Erp, Theodorus, Turner, Jessica, Bernhardt, Boris, and Kirschner, Matthias

Subjects
Humans, Schizophrenia, Connectome, Adult, Female, Male, Magnetic Resonance Imaging, Cerebral Cortex, Nerve Net, Brain, Middle Aged, Neural Pathways, Young Adult
Abstract

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenias alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Published
2024

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. 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 J., Artiges, Eric, Atkins, Joshua R., Bauer, Jochen, Benedetti, Francesco, Boomsma, Dorret I., Brodaty, Henry, Brosch, Katharina, Buckner, Randy L., Cairns, Murray J., Calhoun, Vince, Caspers, Svenja, Cichon, Sven, Corvin, Aiden P., Crespo-Facorro, Benedicto, Dannlowski, Udo, David, Friederike S., de Geus, Eco J.C., de Zubicaray, Greig I., Desrivières, Sylvane, Doherty, Joanne L., Donohoe, Gary, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fisher, Simon E., Forstner, Andreas J., Fortaner-Uyà, Lidia, Frouin, Vincent, Fukunaga, Masaki, Ge, Tian, Glahn, David C., Goltermann, Janik, Grabe, Hans J., Green, Melissa J., Groenewold, Nynke A., Grotegerd, Dominik, Grøntvedt, Gøril Rolfseng, Hahn, Tim, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Henskens, Frans A., Holmes, Avram J., Håberg, Asta K., Haavik, Jan, Jacquemont, Sebastien, Jansen, Andreas, Jockwitz, Christiane, Jönsson, Erik G., Kikuchi, Masataka, Kircher, Tilo, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David E., Liu, Jingyu, Loughnan, Robert, Mather, Karen A., McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meinert, Susanne, Moreau, Clara A., Morris, Derek W., Mowry, Bryan J., Mühleisen, Thomas W., Nenadić, Igor, Nöthen, Markus M., Nyberg, Lars, Ophoff, Roel A., Owen, Michael J., Pantelis, Christos, Paolini, Marco, Paus, Tomas, Pausova, Zdenka, Persson, Karin, Quidé, Yann, Marques, Tiago Reis, Sachdev, Perminder S., Sando, Sigrid B., Schall, Ulrich, Scott, Rodney J., Selbæk, Geir, Shumskaya, Elena, Silva, Ana I., Sisodiya, Sanjay M., Stein, Frederike, Stein, Dan J., Straube, Benjamin, Streit, Fabian, Strike, Lachlan T., Teumer, Alexander, Teutenberg, Lea, Thalamuthu, Anbupalam, Tooney, Paul A., Tordesillas-Gutierrez, Diana, Trollor, Julian N., van ’t Ent, Dennis, van den Bree, Marianne B.M., van Haren, Neeltje E.M., Vázquez-Bourgon, Javier, Völzke, Henry, Wen, Wei, Wittfeld, Katharina, Ching, Christopher R.K., Westlye, Lars T., Thompson, Paul M., Bearden, Carrie E., Selmer, Kaja K., Alnæs, Dag, Andreassen, Ole A., and Sønderby, Ida E.

Published
2024
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6. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Marshall, Christian R., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wang, Zhouzhi, Scherer, Stephen W., Howrigan, Daniel P, Ripke, Stephan, Bulik-Sullivan, Brendan, Farh, Kai-How, Fromer, Menachem, Goldstein, Jacqueline I., Huang, Hailiang, Lee, Phil, Daly, Mark J., Neale, Benjamin M., Belliveau, Richard A., Jr., Bergen, Sarah E., Bevilacqua, Elizabeth, Chambert, Kimberley D., O'Dushlaine, Colm, Scolnick, Edward M., Smoller, Jordan W., Moran, Jennifer L., Palotie, Aarno, Petryshen, Tracey L., Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Fuentes Fajarado, Karin V., Maile, Michelle S., Holmans, Peter A., Carrera, Noa, Craddock, Nick, Escott-Price, Valentina, Georgieva, Lyudmila, Hamshere, Marian L., Kavanagh, David, Legge, Sophie E., Pocklington, Andrew J., Richards, Alexander L., Ruderfer, Douglas M., Williams, Nigel M., Kirov, George, Owen, Michael J., Pinto, Dalila, Cai, Guiqing, Davis, Kenneth L., Drapeau, Elodie, Friedman, Joseph I, Haroutunian, Vahram, Parkhomenko, Elena, Reichenberg, Abraham, Silverman, Jeremy M., Buxbaum, Joseph D., Domenici, Enrico, Agartz, Ingrid, Djurovic, Srdjan, Mattingsdal, Morten, Melle, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Söderman, Erik, Albus, Margot, Alexander, Madeline, Laurent, Claudine, Levinson, Douglas F., Amin, Farooq, Atkins, Joshua, Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Wu, Jing Qin, Bacanu, Silviu A., Bigdeli, Tim B., Reimers, Mark A., Webb, Bradley T., Wolen, Aaron R., Wormley, Brandon K., Kendler, Kenneth S., Riley, Brien P., Kähler, Anna K., Magnusson, Patrik K.E., Hultman, Christina M., Bertalan, Marcelo, Hansen, Thomas, Olsen, Line, Rasmussen, Henrik B., Werge, Thomas, Mattheisen, Manuel, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Roffman, Joshua L., Byerley, William, Cahn, Wiepke, Kahn, René S, Strengman, Eric, Ophoff, Roel A., Carr, Vaughan J., Catts, Stanley V., Henskens, Frans A., Loughland, Carmel M., Michie, Patricia T., Pantelis, Christos, Schall, Ulrich, Jablensky, Assen V., Kelly, Brian J., Campion, Dominique, Cantor, Rita M., Cheng, Wei, Cloninger, C. Robert, Svrakic, Dragan M, Cohen, David, Cormican, Paul, Donohoe, Gary, Morris, Derek W., Corvin, Aiden, Gill, Michael, Crespo-Facorro, Benedicto, Crowley, James J., Farrell, Martilias S., Giusti-Rodríguez, Paola, Kim, Yunjung, Szatkiewicz, Jin P., Williams, Stephanie, Curtis, David, Pimm, Jonathan, Gurling, Hugh, McQuillin, Andrew, Davidson, Michael, Weiser, Mark, Degenhardt, Franziska, Forstner, Andreas J., Herms, Stefan, Hoffmann, Per, Hofman, Andrea, Cichon, Sven, Nöthen, Markus M., Del Favero, Jurgen, DeLisi, Lynn E., McCarley, Robert W., Levy, Deborah L., Mesholam-Gately, Raquelle I., Seidman, Larry J., Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Duan, Jubao, Sanders, Alan R., Gejman, Pablo V., Gershon, Elliot S., Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Salomaa, Veikko, Essioux, Laurent, Fanous, Ayman H., Knowles, James A., Pato, Michele T., Pato, Carlos N., Frank, Josef, Meier, Sandra, Schulze, Thomas G., Strohmaier, Jana, Witt, Stephanie H., Rietschel, Marcella, Franke, Lude, Karjalainen, Juha, Freedman, Robert, Olincy, Ann, Freimer, Nelson B., Purcell, Shaun M., Roussos, Panos, Stahl, Eli A., Sklar, Pamela, Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Godard, Stephanie, Hirschhorn, Joel N., Pers, Tune H., Price, Alkes, Esko, Tõnu, Gratten, Jacob, Lee, S. Hong, Visscher, Peter M., Wray, Naomi R., Mowry, Bryan J., de Haan, Lieuwe, Meijer, Carin J., Hansen, Mark, Ikeda, Masashi, Iwata, Nakao, Joa, Inge, Kalaydjieva, Luba, Keller, Matthew C., Kennedy, James L., Zai, Clement C., Knight, Jo, Lerer, Bernard, Liang, Kung-Yee, Lieberman, Jeffrey, Stroup, T. Scott, Lönnqvist, Jouko, Suvisaari, Jaana, Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, McDonald, Colm, McIntosh, Andrew M., Blackwood, Douglas H.R., Metspalu, Andres, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Collier, David A., Müller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Powell, John, Myin-Germeys, Inez, Van Os, Jim, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Pulver, Ann E., Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, Adolfsson, Rolf, O'Callaghan, Eadbhard, Oh, Sang-Yun, O'Neill, F. Anthony, Paunio, Tiina, Pietiläinen, Olli, Perkins, Diana O., Quested, Digby, Savitz, Adam, Li, Qingqin S., Schwab, Sibylle G., Shi, Jianxin, Spencer, Chris C.A., Thirumalai, Srinivas, Veijola, Juha, Waddington, John, Walsh, Dermot, Wildenauer, Dieter B., Bramon, Elvira, Darvasi, Ariel, Posthuma, Danielle, St. Clair, David, Shanta, Omar, Klein, Marieke, Park, Peter J., Weinberger, Daniel, Moran, John V., Gage, Fred H., Vaccarino, Flora M., Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Bizzotto, Sara, Coulter, Michael, Dias, Caroline, D'Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lodato, Michael, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Abyzov, Alexej, Bae, Taejeong, Jang, Yeongjun, Wang, Yifan, Gage, Fred, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Pattni, Reenal, Amero, Aitor Serres, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Moruno, Manuel Solis, Perez, Raquel Garcia, Povolotskaya, Inna, Soriano, Eduardo, Averbuj, Dan, Ball, Laurel, Breuss, Martin, Yang, Xiaoxu, Chung, Changuk, Emery, Sarah B., Flasch, Diane A., Kidd, Jeffrey M., Kopera, Huira C., Kwan, Kenneth Y., Mills, Ryan E., Moldovan, John B., Sun, Chen, Zhao, Xuefang, Zhou, Weichen, Frisbie, Trenton J., Cherskov, Adriana, Fasching, Liana, Jourdon, Alexandre, Pochareddy, Sirisha, Scuderi, Soraya, Sestan, Nenad, Maury, Eduardo A., Sherman, Maxwell A., Genovese, Giulio, Gilgenast, Thomas G., Kamath, Tushar, Burris, S.J., Rajarajan, Prashanth, Flaherty, Erin, Akbarian, Schahram, Chess, Andrew, McCarroll, Steven A., Loh, Po-Ru, Phillips-Cremins, Jennifer E., Brennand, Kristen J., Macosko, Evan Z., Walters, James T.R., O’Donovan, Michael, Sullivan, Patrick, Sebat, Jonathan, Lee, Eunjung A., and Walsh, Christopher A.

Published
2023
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7. Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA

Author

Radua, Joaquim, Vieta, Eduard, Shinohara, Russell, Kochunov, Peter, Quidé, Yann, Green, Melissa J, Weickert, Cynthia S, Weickert, Thomas, Bruggemann, Jason, Kircher, Tilo, Nenadić, Igor, Cairns, Murray J, Seal, Marc, Schall, Ulrich, Henskens, Frans, Fullerton, Janice M, Mowry, Bryan, Pantelis, Christos, Lenroot, Rhoshel, Cropley, Vanessa, Loughland, Carmel, Scott, Rodney, Wolf, Daniel, Satterthwaite, Theodore D, Tan, Yunlong, Sim, Kang, Piras, Fabrizio, Spalletta, Gianfranco, Banaj, Nerisa, Pomarol-Clotet, Edith, Solanes, Aleix, Albajes-Eizagirre, Anton, Canales-Rodríguez, Erick J, Sarro, Salvador, Di Giorgio, Annabella, Bertolino, Alessandro, Stäblein, Michael, Oertel, Viola, Knöchel, Christian, Borgwardt, Stefan, du Plessis, Stefan, Yun, Je-Yeon, Kwon, Jun Soo, Dannlowski, Udo, Hahn, Tim, Grotegerd, Dominik, Alloza, Clara, Arango, Celso, Janssen, Joost, Díaz-Caneja, Covadonga, Jiang, Wenhao, Calhoun, Vince, Ehrlich, Stefan, Yang, Kun, Cascella, Nicola G, Takayanagi, Yoichiro, Sawa, Akira, Tomyshev, Alexander, Lebedeva, Irina, Kaleda, Vasily, Kirschner, Matthias, Hoschl, Cyril, Tomecek, David, Skoch, Antonin, van Amelsvoort, Therese, Bakker, Geor, James, Anthony, Preda, Adrian, Weideman, Andrea, Stein, Dan J, Howells, Fleur, Uhlmann, Anne, Temmingh, Henk, López-Jaramillo, Carlos, Díaz-Zuluaga, Ana, Fortea, Lydia, Martinez-Heras, Eloy, Solana, Elisabeth, Llufriu, Sara, Jahanshad, Neda, Thompson, Paul, Turner, Jessica, van Erp, Theo, collaborators, ENIGMA Consortium, Glahn, David, Pearlson, Godfrey, Hong, Elliot, Krug, Axel, Carr, Vaughan, Tooney, Paul, Cooper, Gavin, Rasser, Paul, Michie, Patricia, Catts, Stanley, Gur, Raquel, Gur, Ruben, Yang, Fude, Fan, Fengmei, Chen, Jingxu, and Guo, Hua

Subjects
Brain Disorders, Biomedical Imaging, Mental Health, Schizophrenia, Neurosciences, Mental health, Adult, Algorithms, Cerebral Cortex, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Meta-Analysis as Topic, Middle Aged, Neuroimaging, Young Adult, Brain, Cortical thickness, Gray matter, Mega-analysis, Volume, ENIGMA Consortium collaborators, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Published
2020

8. Transcriptomic abnormalities in peripheral blood in bipolar disorder, and discrimination of the major psychoses

Author

Hess, Jonathan L, Tylee, Daniel S, Barve, Rahul, de Jong, Simone, Ophoff, Roel A, Kumarasinghe, Nishantha, Tooney, Paul, Schall, Ulrich, Gardiner, Erin, Beveridge, Natalie Jane, Scott, Rodney J, Yasawardene, Surangi, Perera, Antionette, Mendis, Jayan, Carr, Vaughan, Kelly, Brian, Cairns, Murray, Unit, the Neurobehavioural Genetics, Tsuang, Ming T, and Glatt, Stephen J

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Serious Mental Illness, Mental Health, Brain Disorders, Bipolar Disorder, Schizophrenia, Genetics, Mental health, Gene Expression Profiling, Humans, Psychotic Disorders, Transcriptome, Bipolar disorder, Biomarker, Peripheral blood, Neurobehavioural Genetics Unit, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences
Abstract

We performed a transcriptome-wide meta-analysis and gene co-expression network analysis to identify genes and gene networks dysregulated in the peripheral blood of bipolar disorder (BD) cases relative to unaffected comparison subjects, and determined the specificity of the transcriptomic signatures of BD and schizophrenia (SZ). Nineteen genes and 4 gene modules were significantly differentially expressed in BD cases. Thirteen gene modules were shown to be differentially expressed in a combined case-group of BD and SZ subjects called "major psychosis", including genes biologically linked to apoptosis, reactive oxygen, chromatin remodeling, and immune signaling. No modules were differentially expressed between BD and SZ cases. Machine-learning classifiers trained to separate diagnostic classes based solely on gene expression profiles could distinguish BD cases from unaffected comparison subjects with an area under the curve (AUC) of 0.724, as well as BD cases from SZ cases with AUC = 0.677 in withheld test samples. We introduced a novel and straightforward method called "polytranscript risk scoring" that could distinguish BD cases from unaffected subjects (AUC = 0.672) and SZ cases (AUC = 0.607) significantly better than expected by chance. Taken together, our results highlighted gene expression alterations common to BD and SZ that involve biological processes of inflammation, oxidative stress, apoptosis, and chromatin regulation, and highlight disorder-specific changes in gene expression that discriminate the major psychoses.

Published
2020

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

Author

Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey S., Lam, Max, Watanabe, Kyoko, Frei, Oleksandr, Ge, Tian, Harwood, Janet C., Koopmans, Frank, Magnusson, Sigurdur, Richards, Alexander L., Sidorenko, Julia, Wu, Yang, Zeng, Jian, Grove, Jakob, Kim, Minsoo, Li, Zhiqiang, Voloudakis, Georgios, Zhang, Wen, Adams, Mark, Agartz, Ingrid, Atkinson, Elizabeth G., Agerbo, Esben, Al Eissa, Mariam, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z., Alptekin, Köksal, Als, Thomas D., Amin, Farooq, Arolt, Volker, Arrojo, Manuel, Athanasiu, Lavinia, Azevedo, Maria Helena, Bacanu, Silviu A., Bass, Nicholas J., Begemann, Martin, Belliveau, Richard A., Bene, Judit, Benyamin, Beben, Bergen, Sarah E., Blasi, Giuseppe, Bobes, Julio, Bonassi, Stefano, Braun, Alice, Bressan, Rodrigo Affonseca, Bromet, Evelyn J., Bruggeman, Richard, Buckley, Peter F., Buckner, Randy L., Bybjerg-Grauholm, Jonas, Cahn, Wiepke, Cairns, Murray J., Calkins, Monica E., Carr, Vaughan J., Castle, David, Catts, Stanley V., Chambert, Kimberley D., Chan, Raymond C. K., Chaumette, Boris, Cheng, Wei, Cheung, Eric F. C., Chong, Siow Ann, Cohen, David, Consoli, Angèle, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Davidson, Michael, Davis, Kenneth L., de Haan, Lieuwe, Degenhardt, Franziska, DeLisi, Lynn E., Demontis, Ditte, Dickerson, Faith, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanás, Lourdes, Faraone, Stephen V., Fiorentino, Alessia, Forstner, Andreas, Frank, Josef, Freimer, Nelson B., Fromer, Menachem, Frustaci, Alessandra, Gadelha, Ary, Genovese, Giulio, Gershon, Elliot S., Giannitelli, Marianna, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., González Peñas, Javier, González-Pinto, Ana, Gopal, Srihari, Gratten, Jacob, Green, Michael F., Greenwood, Tiffany A., Guillin, Olivier, Gülöksüz, Sinan, Gur, Raquel E., Gur, Ruben C., Gutiérrez, Blanca, Hahn, Eric, Hakonarson, Hakon, Haroutunian, Vahram, Hartmann, Annette M., Harvey, Carol, Hayward, Caroline, Henskens, Frans A., Herms, Stefan, Hoffmann, Per, Howrigan, Daniel P., Ikeda, Masashi, Iyegbe, Conrad, Joa, Inge, Julià, Antonio, Kähler, Anna K., Kam-Thong, Tony, Kamatani, Yoichiro, Karachanak-Yankova, Sena, Kebir, Oussama, Keller, Matthew C., Kelly, Brian J., Khrunin, Andrey, Kim, Sung-Wan, Klovins, Janis, Kondratiev, Nikolay, Konte, Bettina, Kraft, Julia, Kubo, Michiaki, Kučinskas, Vaidutis, Kučinskiene, Zita Ausrele, Kusumawardhani, Agung, Kuzelova-Ptackova, Hana, Landi, Stefano, Lazzeroni, Laura C., Lee, Phil H., Legge, Sophie E., Lehrer, Douglas S., Lencer, Rebecca, Lerer, Bernard, Li, Miaoxin, Lieberman, Jeffrey, Light, Gregory A., Limborska, Svetlana, Liu, Chih-Min, Lönnqvist, Jouko, Loughland, Carmel M., Lubinski, Jan, Luykx, Jurjen J., Lynham, Amy, Macek, Jr, Milan, Mackinnon, Andrew, Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Malaspina, Dolores, Mallet, Jacques, Marder, Stephen R., Marsal, Sara, Martin, Alicia R., Martorell, Lourdes, Mattheisen, Manuel, McCarley, Robert W., McDonald, Colm, McGrath, John J., Medeiros, Helena, Meier, Sandra, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mitjans, Marina, Molden, Espen, Molina, Esther, Molto, María Dolores, Mondelli, Valeria, Moreno, Carmen, Morley, Christopher P., Muntané, Gerard, Murphy, Kieran C., Myin-Germeys, Inez, Nenadić, Igor, Nestadt, Gerald, Nikitina-Zake, Liene, Noto, Cristiano, Nuechterlein, Keith H., O’Brien, Niamh Louise, O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Ota, Vanessa Kiyomi, Pantelis, Christos, Papadimitriou, George N., Parellada, Mara, Paunio, Tiina, Pellegrino, Renata, Periyasamy, Sathish, Perkins, Diana O., Pfuhlmann, Bruno, Pietiläinen, Olli, Pimm, Jonathan, Porteous, David, Powell, John, Quattrone, Diego, Quested, Digby, Radant, Allen D., Rampino, Antonio, Rapaport, Mark H., Rautanen, Anna, Reichenberg, Abraham, Roe, Cheryl, Roffman, Joshua L., Roth, Julian, Rothermundt, Matthias, Rutten, Bart P. F., Saker-Delye, Safaa, Salomaa, Veikko, Sanjuan, Julio, Santoro, Marcos Leite, Savitz, Adam, Schall, Ulrich, Scott, Rodney J., Seidman, Larry J., Sharp, Sally Isabel, Shi, Jianxin, Siever, Larry J., Sigurdsson, Engilbert, Sim, Kang, Skarabis, Nora, Slominsky, Petr, So, Hon-Cheong, Sobell, Janet L., Söderman, Erik, Stain, Helen J., Steen, Nils Eiel, Steixner-Kumar, Agnes A., Stögmann, Elisabeth, Stone, William S., Straub, Richard E., Streit, Fabian, Strengman, Eric, Stroup, T. Scott, Subramaniam, Mythily, Sugar, Catherine A., Suvisaari, Jaana, Svrakic, Dragan M., Swerdlow, Neal R., Szatkiewicz, Jin P., Ta, Thi Minh Tam, Takahashi, Atsushi, Terao, Chikashi, Thibaut, Florence, Toncheva, Draga, Tooney, Paul A., Torretta, Silvia, Tosato, Sarah, Tura, Gian Battista, Turetsky, Bruce I., Üçok, Alp, Vaaler, Arne, van Amelsvoort, Therese, van Winkel, Ruud, Veijola, Juha, Waddington, John, Walter, Henrik, Waterreus, Anna, Webb, Bradley T., Weiser, Mark, Williams, Nigel M., Witt, Stephanie H., Wormley, Brandon K., Wu, Jing Qin, Xu, Zhida, Yolken, Robert, Zai, Clement C., Zhou, Wei, Zhu, Feng, Zimprich, Fritz, Atbaşoğlu, Eşref Cem, Ayub, Muhammad, Benner, Christian, Bertolino, Alessandro, Black, Donald W., Bray, Nicholas J., Breen, Gerome, Buccola, Nancy G., Byerley, William F., Chen, Wei J., Cloninger, C. Robert, Crespo-Facorro, Benedicto, Donohoe, Gary, Freedman, Robert, Galletly, Cherrie, Gandal, Michael J., Gennarelli, Massimo, Hougaard, David M., Hwu, Hai-Gwo, Jablensky, Assen V., McCarroll, Steven A., Moran, Jennifer L., Mors, Ole, Mortensen, Preben B., Müller-Myhsok, Bertram, Neil, Amanda L., Nordentoft, Merete, Pato, Michele T., Petryshen, Tracey L., Pirinen, Matti, Pulver, Ann E., Schulze, Thomas G., Silverman, Jeremy M., Smoller, Jordan W., Stahl, Eli A., Tsuang, Debby W., Vilella, Elisabet, Wang, Shi-Heng, Xu, Shuhua, Adolfsson, Rolf, Arango, Celso, Baune, Bernhard T., Belangero, Sintia Iole, Børglum, Anders D., Braff, David, Bramon, Elvira, Buxbaum, Joseph D., Campion, Dominique, Cervilla, Jorge A., Cichon, Sven, Collier, David A., Corvin, Aiden, Curtis, David, Forti, Marta Di, Domenici, Enrico, Ehrenreich, Hannelore, Escott-Price, Valentina, Esko, Tõnu, Fanous, Ayman H., Gareeva, Anna, Gawlik, Micha, Gejman, Pablo V., Gill, Michael, Glatt, Stephen J., Golimbet, Vera, Hong, Kyung Sue, Hultman, Christina M., Hyman, Steven E., Iwata, Nakao, Jönsson, Erik G., Kahn, René S., Kennedy, James L., Khusnutdinova, Elza, Kirov, George, Knowles, James A., Krebs, Marie-Odile, Laurent-Levinson, Claudine, Lee, Jimmy, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., Malhotra, Dheeraj, McIntosh, Andrew, McQuillin, Andrew, Menezes, Paulo R., Morgan, Vera A., Morris, Derek W., Mowry, Bryan J., Murray, Robin M., Nimgaonkar, Vishwajit, Nöthen, Markus M., Ophoff, Roel A., Paciga, Sara A., Palotie, Aarno, Pato, Carlos N., Qin, Shengying, Rietschel, Marcella, Riley, Brien P., Rivera, Margarita, Rujescu, Dan, Saka, Meram C., Sanders, Alan R., Schwab, Sibylle G., Serretti, Alessandro, Sham, Pak C., Shi, Yongyong, St Clair, David, Stefánsson, Hreinn, Stefansson, Kari, Tsuang, Ming T., van Os, Jim, Vawter, Marquis P., Weinberger, Daniel R., Werge, Thomas, Wildenauer, Dieter B., Yu, Xin, Yue, Weihua, Holmans, Peter A., Pocklington, Andrew J., Roussos, Panos, Vassos, Evangelos, Verhage, Matthijs, Visscher, Peter M., Yang, Jian, Posthuma, Danielle, Andreassen, Ole A., Kendler, Kenneth S., Owen, Michael J., Wray, Naomi R., Daly, Mark J., Huang, Hailiang, Neale, Benjamin M., Sullivan, Patrick F., Ripke, Stephan, Walters, James T. R., and O’Donovan, Michael C.

Published
2022
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10. Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (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 A, 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, Shannon Weickert, Cynthia, 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, and Koenders, Laura

Subjects
Karolinska Schizophrenia Project, Brain, Frontal Lobe, Prefrontal Cortex, Temporal Lobe, Humans, Magnetic Resonance Imaging, Severity of Illness Index, Linear Models, Case-Control Studies, Schizophrenia, Age of Onset, Adolescent, Adult, Aged, Middle Aged, Child, Female, Male, Young Adult, Neuroimaging, Cortical, Imaging, Meta-analysis, Surface area, Thickness, Serious Mental Illness, Biomedical Imaging, Mental Health, Clinical Research, Neurosciences, Brain Disorders, Mental health, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundThe 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.MethodsThe study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.ResultsCompared with 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: Cohen's 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, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication 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.ConclusionsThe 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

12. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, Niamh, Forstner, Andreas J., O’Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R. I., Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Børte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bækvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøcker Pedersen, Carsten, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Giørtz Pedersen, Marianne, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lucae, Susanne, Lundberg, Martin, MacIntyre, Donald J., Magnusson, Sigurdur H., Maier, Wolfgang, Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, Mattheisen, Manuel, McCarroll, Steven A., McGregor, Nathaniel W., McGuffin, Peter, McKay, James D., Medeiros, Helena, Medland, Sarah E., Millischer, Vincent, Montgomery, Grant W., Moran, Jennifer L., Morris, Derek W., Mühleisen, Thomas W., O’Brien, Niamh, O’Donovan, Claire, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Potash, James B., Quested, Digby, Raj, Towfique, Rapaport, Mark H., DePaulo, J. Raymond, Regeer, Eline J., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sánchez-Mora, Cristina, Schulte, Eva C., Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sigurdsson, Engilbert, Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Smith, Daniel J., Sobell, Janet L., Søholm Hansen, Christine, Soler Artigas, Maria, Spijker, Anne T., Stein, Dan J., Strauss, John S., Świątkowska, Beata, Terao, Chikashi, Thorgeirsson, Thorgeir E., Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Xi, Simon, Xu, Wei, Yang, Jessica Mei Kay, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Børglum, Anders D., Breen, Gerome, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dannlowski, Udo, Dikeos, Dimitris, Esko, Tõnu, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Goes, Fernando S., Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hougaard, David M., Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen V., Jones, Ian, Jones, Lisa A., Kahn, René S., Kelsoe, John R., Kirov, George, Landén, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Martin, Nicholas G., Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Milani, Lili, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Nordentoft, Merete, Nöthen, Markus M., O’Donovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Owen, Michael J., Paciga, Sara A., Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Perlis, Roy H., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Ripke, Stephan, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Streit, Fabian, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Werge, Thomas, Wray, Naomi R., Zwart, John-Anker, Biernacka, Joanna M., Nurnberger, John I., Cichon, Sven, Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., and Andreassen, Ole A.

Published
2021
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13. 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 J., Artiges, Eric, Atkins, Joshua R., Bauer, Jochen, Benedetti, Francesco, Boomsma, Dorret I., Brodaty, Henry, Brosch, Katharina, Buckner, Randy L., Cairns, Murray J., Calhoun, Vince, Caspers, Svenja, Cichon, Sven, Corvin, Aiden P., Crespo-Facorro, Benedicto, Dannlowski, Udo, David, Friederike S., de Geus, Eco J.C., de Zubicaray, Greig I., Desrivières, Sylvane, Doherty, Joanne L., Donohoe, Gary, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fisher, Simon E., Forstner, Andreas J., Fortaner-Uyà, Lidia, Frouin, Vincent, Fukunaga, Masaki, Ge, Tian, Glahn, David C., Goltermann, Janik, Grabe, Hans J., Green, Melissa J., Groenewold, Nynke A., Grotegerd, Dominik, Grøntvedt, Gøril Rolfseng, Hahn, Tim, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Henskens, Frans A., Holmes, Avram J., Håberg, Asta K., Haavik, Jan, Jacquemont, Sebastien, Jansen, Andreas, Jockwitz, Christiane, Jönsson, Erik G., Kikuchi, Masataka, Kircher, Tilo, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David E., Liu, Jingyu, Loughnan, Robert, Mather, Karen A., McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meinert, Susanne, Moreau, Clara A., Morris, Derek W., Mowry, Bryan J., Mühleisen, Thomas W., Nenadić, Igor, Nöthen, Markus M., Nyberg, Lars, Ophoff, Roel A., Owen, Michael J., Pantelis, Christos, Paolini, Marco, Paus, Tomas, Pausova, Zdenka, Persson, Karin, Quidé, Yann, Marques, Tiago Reis, Sachdev, Perminder S., Sando, Sigrid B., Schall, Ulrich, Scott, Rodney J., Selbæk, Geir, Shumskaya, Elena, Silva, Ana I., Sisodiya, Sanjay M., Stein, Frederike, Stein, Dan J., Straube, Benjamin, Streit, Fabian, Strike, Lachlan T., Teumer, Alexander, Teutenberg, Lea, Thalamuthu, Anbupalam, Tooney, Paul A., Tordesillas-Gutierrez, Diana, Trollor, Julian N., van ’t Ent, Dennis, van den Bree, Marianne B.M., van Haren, Neeltje E.M., Vázquez-Bourgon, Javier, Völzke, Henry, Wen, Wei, Wittfeld, Katharina, Ching, Christopher R.K., Westlye, Lars T., Thompson, Paul M., Bearden, Carrie E., Selmer, Kaja K., Alnæs, Dag, Andreassen, Ole A., Sønderby, Ida E., Boen, Rune, Kaufmann, Tobias, van der Meer, Dennis, Frei, Oleksandr, Agartz, Ingrid, Ames, David, Andersson, Micael, Armstrong, Nicola J., Artiges, Eric, Atkins, Joshua R., Bauer, Jochen, Benedetti, Francesco, Boomsma, Dorret I., Brodaty, Henry, Brosch, Katharina, Buckner, Randy L., Cairns, Murray J., Calhoun, Vince, Caspers, Svenja, Cichon, Sven, Corvin, Aiden P., Crespo-Facorro, Benedicto, Dannlowski, Udo, David, Friederike S., de Geus, Eco J.C., de Zubicaray, Greig I., Desrivières, Sylvane, Doherty, Joanne L., Donohoe, Gary, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fisher, Simon E., Forstner, Andreas J., Fortaner-Uyà, Lidia, Frouin, Vincent, Fukunaga, Masaki, Ge, Tian, Glahn, David C., Goltermann, Janik, Grabe, Hans J., Green, Melissa J., Groenewold, Nynke A., Grotegerd, Dominik, Grøntvedt, Gøril Rolfseng, Hahn, Tim, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Henskens, Frans A., Holmes, Avram J., Håberg, Asta K., Haavik, Jan, Jacquemont, Sebastien, Jansen, Andreas, Jockwitz, Christiane, Jönsson, Erik G., Kikuchi, Masataka, Kircher, Tilo, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David E., Liu, Jingyu, Loughnan, Robert, Mather, Karen A., McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meinert, Susanne, Moreau, Clara A., Morris, Derek W., Mowry, Bryan J., Mühleisen, Thomas W., Nenadić, Igor, Nöthen, Markus M., Nyberg, Lars, Ophoff, Roel A., Owen, Michael J., Pantelis, Christos, Paolini, Marco, Paus, Tomas, Pausova, Zdenka, Persson, Karin, Quidé, Yann, Marques, Tiago Reis, Sachdev, Perminder S., Sando, Sigrid B., Schall, Ulrich, Scott, Rodney J., Selbæk, Geir, Shumskaya, Elena, Silva, Ana I., Sisodiya, Sanjay M., Stein, Frederike, Stein, Dan J., Straube, Benjamin, Streit, Fabian, Strike, Lachlan T., Teumer, Alexander, Teutenberg, Lea, Thalamuthu, Anbupalam, Tooney, Paul A., Tordesillas-Gutierrez, Diana, Trollor, Julian N., van ’t Ent, Dennis, van den Bree, Marianne B.M., van Haren, Neeltje E.M., Vázquez-Bourgon, Javier, Völzke, Henry, Wen, Wei, Wittfeld, Katharina, Ching, Christopher R.K., Westlye, Lars T., Thompson, Paul M., Bearden, Carrie E., Selmer, Kaja K., Alnæs, Dag, Andreassen, Ole A., and Sønderby, Ida E.

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 individual’s 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

14. Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Author

Georgiadis, Foivos; https://orcid.org/0000-0001-8784-9653, Larivière, Sara, Glahn, David, Hong, L Elliot, Kochunov, Peter, Mowry, Bryan; https://orcid.org/0000-0002-4115-5645, Loughland, Carmel, Pantelis, Christos; https://orcid.org/0000-0002-9565-0238, Henskens, Frans A; https://orcid.org/0000-0003-2358-5630, Green, Melissa J; https://orcid.org/0000-0002-9361-4874, Cairns, Murray J; https://orcid.org/0000-0003-2490-2538, Michie, Patricia T; https://orcid.org/0000-0002-4169-8519, Rasser, Paul E, Catts, Stanley, Tooney, Paul; https://orcid.org/0000-0003-3745-4367, Scott, Rodney J; https://orcid.org/0000-0001-7724-3404, Schall, Ulrich, Carr, Vaughan; https://orcid.org/0000-0002-8907-5804, Quidé, Yann; https://orcid.org/0000-0002-8569-7139, Krug, Axel; https://orcid.org/0000-0002-0564-2497, Stein, Frederike, Nenadić, Igor; https://orcid.org/0000-0002-0749-7473, Brosch, Katharina; https://orcid.org/0000-0002-0526-8095, Ji, Ellen; https://orcid.org/0000-0003-1527-8868, Homan, Stephanie; https://orcid.org/0000-0003-1449-7508, Omlor, Wolfgang, Homan, Philipp; https://orcid.org/0000-0001-9034-148X, Seifritz, Erich; https://orcid.org/0000-0002-7311-4426, ENIGMA Schizophrenia Consortium, Kirschner, Matthias; https://orcid.org/0000-0002-9486-1439, et al, Georgiadis, Foivos; https://orcid.org/0000-0001-8784-9653, Larivière, Sara, Glahn, David, Hong, L Elliot, Kochunov, Peter, Mowry, Bryan; https://orcid.org/0000-0002-4115-5645, Loughland, Carmel, Pantelis, Christos; https://orcid.org/0000-0002-9565-0238, Henskens, Frans A; https://orcid.org/0000-0003-2358-5630, Green, Melissa J; https://orcid.org/0000-0002-9361-4874, Cairns, Murray J; https://orcid.org/0000-0003-2490-2538, Michie, Patricia T; https://orcid.org/0000-0002-4169-8519, Rasser, Paul E, Catts, Stanley, Tooney, Paul; https://orcid.org/0000-0003-3745-4367, Scott, Rodney J; https://orcid.org/0000-0001-7724-3404, Schall, Ulrich, Carr, Vaughan; https://orcid.org/0000-0002-8907-5804, Quidé, Yann; https://orcid.org/0000-0002-8569-7139, Krug, Axel; https://orcid.org/0000-0002-0564-2497, Stein, Frederike, Nenadić, Igor; https://orcid.org/0000-0002-0749-7473, Brosch, Katharina; https://orcid.org/0000-0002-0526-8095, Ji, Ellen; https://orcid.org/0000-0003-1527-8868, Homan, Stephanie; https://orcid.org/0000-0003-1449-7508, Omlor, Wolfgang, Homan, Philipp; https://orcid.org/0000-0001-9034-148X, Seifritz, Erich; https://orcid.org/0000-0002-7311-4426, ENIGMA Schizophrenia Consortium, Kirschner, Matthias; https://orcid.org/0000-0002-9486-1439, and et al

Abstract

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network ar

Published
2024

15. Fine-mapping genomic loci refines bipolar disorder risk genes

Author

Koromina, Maria, Ravi, Ashvin, Panagiotaropoulou, Georgia, Schilder, Brian M., Humphrey, Jack, Braun, Alice, Bidgeli, Tim, Chatzinakos, Chris, Coombes, Brandon, Kim, Jaeyoung, Liu, Xiaoxi, Terao, Chikashi, O'Connell, Kevin S., Adams, Mark, Adolfsson, Rolf, Alda, Martin, Alfredsson, Lars, Andlauer, Till, Andreassen, Ole A., Antoniou, Anastasia, Baune, Bernhard T., Bengesser, Susanne, Biernacka, Joanna, Boehnke, Michael, Bosch, Rosa, Cairns, Murray, Carr, Vaughan J., Casas Brugué, Miquel, Catts, Stanley, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Dafnas, Konstantinos, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Di Florio, Arianna, Dikeos, Dimitris, Fellendorf, Frederike Tabea, Ferentinos, Panagiotis, Forstner, Andreas Josef, Forty, Liz, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gizer, Ian R., Gordon-Smith, Katherine, Green, Melissa J., Grigoroiu-Serbanescu, Maria, Guzman-Parra, José, Hahn, Tim, Henskens, Frans, Hillert, Jan, Jablensky, Assen V., Jones, Lisa, Jones, Ian, Jonsson, Lina, Kelsoe, John R., Kircher, Tilo, Kirov, George, Kittel-Schneider, Sarah, Kogevinas, Manolis, Landén, Mikael, Leboyer, Marion, Lenger, Melanie, Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, MacIntyre, Donald, Martin, Nicholas G., Maratou, Eirini, Mathews, Carol A., Mayoral, Fermı́n, McElroy, Susan L., McGregor, Nathaniel W., McIntosh, Andrew M., McQuillin, Andrew, Michie, Patricia, Milanova, Vihra, Mitchell, Philip B., Moutsatsou, Paraskevi, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Nenadić, Igor, Nöthen, Markus Maria, O'Donovan, Claire, O'Donovan, Michael, Ophoff, Roel André, Owen, Michael J., Pantelis, Christos, Pato, Carlos, Pato, Michele T., Patrinos, George P., Pawlak, Joanna M., Perlis, Roy H., Porichi, Evgenia, Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Schall, Ulrich, Schulze, Thomas Gerd, Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Soler Artigas, Marı́a, Stein, Dan J., Streit, Fabian, Toma, Claudio, Tooney, Paul, Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas, Witt, Stephanie H., Hong, Kyung Sue, Ikeda, Masashi, Iwata, Nakao, Świątkowska, Beata, Won, Hong-Hee, Edenberg, Howard J., Ripke, Stephan, Raj, Towfique, Coleman, Jonathan R. I., Mullins, Niamh, Koromina, Maria, Ravi, Ashvin, Panagiotaropoulou, Georgia, Schilder, Brian M., Humphrey, Jack, Braun, Alice, Bidgeli, Tim, Chatzinakos, Chris, Coombes, Brandon, Kim, Jaeyoung, Liu, Xiaoxi, Terao, Chikashi, O'Connell, Kevin S., Adams, Mark, Adolfsson, Rolf, Alda, Martin, Alfredsson, Lars, Andlauer, Till, Andreassen, Ole A., Antoniou, Anastasia, Baune, Bernhard T., Bengesser, Susanne, Biernacka, Joanna, Boehnke, Michael, Bosch, Rosa, Cairns, Murray, Carr, Vaughan J., Casas Brugué, Miquel, Catts, Stanley, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Dafnas, Konstantinos, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Di Florio, Arianna, Dikeos, Dimitris, Fellendorf, Frederike Tabea, Ferentinos, Panagiotis, Forstner, Andreas Josef, Forty, Liz, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gizer, Ian R., Gordon-Smith, Katherine, Green, Melissa J., Grigoroiu-Serbanescu, Maria, Guzman-Parra, José, Hahn, Tim, Henskens, Frans, Hillert, Jan, Jablensky, Assen V., Jones, Lisa, Jones, Ian, Jonsson, Lina, Kelsoe, John R., Kircher, Tilo, Kirov, George, Kittel-Schneider, Sarah, Kogevinas, Manolis, Landén, Mikael, Leboyer, Marion, Lenger, Melanie, Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, MacIntyre, Donald, Martin, Nicholas G., Maratou, Eirini, Mathews, Carol A., Mayoral, Fermı́n, McElroy, Susan L., McGregor, Nathaniel W., McIntosh, Andrew M., McQuillin, Andrew, Michie, Patricia, Milanova, Vihra, Mitchell, Philip B., Moutsatsou, Paraskevi, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Nenadić, Igor, Nöthen, Markus Maria, O'Donovan, Claire, O'Donovan, Michael, Ophoff, Roel André, Owen, Michael J., Pantelis, Christos, Pato, Carlos, Pato, Michele T., Patrinos, George P., Pawlak, Joanna M., Perlis, Roy H., Porichi, Evgenia, Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Schall, Ulrich, Schulze, Thomas Gerd, Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Soler Artigas, Marı́a, Stein, Dan J., Streit, Fabian, Toma, Claudio, Tooney, Paul, Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas, Witt, Stephanie H., Hong, Kyung Sue, Ikeda, Masashi, Iwata, Nakao, Świątkowska, Beata, Won, Hong-Hee, Edenberg, Howard J., Ripke, Stephan, Raj, Towfique, Coleman, Jonathan R. I., and Mullins, Niamh

Abstract

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Published
2024

16. Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA

Author

Glahn, David, Pearlson, Godfrey, Hong, Elliot, Krug, Axel, Carr, Vaughan, Tooney, Paul, Cooper, Gavin, Rasser, Paul, Michie, Patricia, Catts, Stanley, Gur, Raquel, Gur, Ruben, Yang, Fude, Fan, Fengmei, Chen, Jingxu, Guo, Hua, Tan, Shuping, Wang, Zhiren, Xiang, Hong, Piras, Federica, Assogna, Francesca, Salvador, Raymond, McKenna, Peter, Bonvino, Aurora, King, Margaret, Kaiser, Stefan, Nguyen, Dana, Pineda-Zapata, Julian, Radua, Joaquim, Vieta, Eduard, Shinohara, Russell, Kochunov, Peter, Quidé, Yann, Green, Melissa J., Weickert, Cynthia S., Weickert, Thomas, Bruggemann, Jason, Kircher, Tilo, Nenadić, Igor, Cairns, Murray J., Seal, Marc, Schall, Ulrich, Henskens, Frans, Fullerton, Janice M., Mowry, Bryan, Pantelis, Christos, Lenroot, Rhoshel, Cropley, Vanessa, Loughland, Carmel, Scott, Rodney, Wolf, Daniel, Satterthwaite, Theodore D., Tan, Yunlong, Sim, Kang, Piras, Fabrizio, Spalletta, Gianfranco, Banaj, Nerisa, Pomarol-Clotet, Edith, Solanes, Aleix, Albajes-Eizagirre, Anton, Canales-Rodríguez, Erick J., Sarro, Salvador, Di Giorgio, Annabella, Bertolino, Alessandro, Stäblein, Michael, Oertel, Viola, Knöchel, Christian, Borgwardt, Stefan, du Plessis, Stefan, Yun, Je-Yeon, Kwon, Jun Soo, Dannlowski, Udo, Hahn, Tim, Grotegerd, Dominik, Alloza, Clara, Arango, Celso, Janssen, Joost, Díaz-Caneja, Covadonga, Jiang, Wenhao, Calhoun, Vince, Ehrlich, Stefan, Yang, Kun, Cascella, Nicola G., Takayanagi, Yoichiro, Sawa, Akira, Tomyshev, Alexander, Lebedeva, Irina, Kaleda, Vasily, Kirschner, Matthias, Hoschl, Cyril, Tomecek, David, Skoch, Antonin, van Amelsvoort, Therese, Bakker, Geor, James, Anthony, Preda, Adrian, Weideman, Andrea, Stein, Dan J., Howells, Fleur, Uhlmann, Anne, Temmingh, Henk, López-Jaramillo, Carlos, Díaz-Zuluaga, Ana, Fortea, Lydia, Martinez-Heras, Eloy, Solana, Elisabeth, Llufriu, Sara, Jahanshad, Neda, Thompson, Paul, Turner, Jessica, and van Erp, Theo

Published
2020
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17. Transcriptomic abnormalities in peripheral blood in bipolar disorder, and discrimination of the major psychoses

Author

Hess, Jonathan L., Tylee, Daniel S., Barve, Rahul, de Jong, Simone, Ophoff, Roel A., Kumarasinghe, Nishantha, Tooney, Paul, Schall, Ulrich, Gardiner, Erin, Beveridge, Natalie Jane, Scott, Rodney J., Yasawardene, Surangi, Perera, Antionette, Mendis, Jayan, Carr, Vaughan, Kelly, Brian, Cairns, Murray, Tsuang, Ming T., and Glatt, Stephen J.

Published
2020
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18. Fine-mapping genomic loci refines bipolar disorder risk genes

Author

Koromina, Maria, primary, Ravi, Ashvin, additional, Panagiotaropoulou, Georgia, additional, Schilder, Brian M., additional, Humphrey, Jack, additional, Braun, Alice, additional, Bidgeli, Tim, additional, Chatzinakos, Chris, additional, Coombes, Brandon, additional, Kim, Jaeyoung, additional, Liu, Xiaoxi, additional, Terao, Chikashi, additional, O'Connell, Kevin S., additional, Adams, Mark, additional, Adolfsson, Rolf, additional, Alda, Martin, additional, Alfredsson, Lars, additional, Andlauer, Till F.M., additional, Andreassen, Ole A., additional, Antoniou, Anastasia, additional, Baune, Bernhard T., additional, Bengesser, Susanne, additional, Biernacka, Joanna, additional, Boehnke, Michael, additional, Bosch, Rosa, additional, Cairns, Murray, additional, Carr, Vaughan J., additional, Casas, Miquel, additional, Catts, Stanley, additional, Cichon, Sven, additional, Corvin, Aiden, additional, Craddock, Nicholas, additional, Dafnas, Konstantinos, additional, Dalkner, Nina, additional, Dannlowski, Udo, additional, Degenhardt, Franziska, additional, Di Florio, Arianna, additional, Dikeos, Dimitris, additional, Fellendorf, Frederike Tabea, additional, Ferentinos, Panagiotis, additional, Forstner, Andreas J., additional, Forty, Liz, additional, Frye, Mark, additional, Fullerton, Janice M., additional, Gawlik, Micha, additional, Gizer, Ian R., additional, Gordon-Smith, Katherine, additional, Green, Melissa J., additional, Grigoroiu-Serbanescu, Maria, additional, Guzman-Parra, Josep, additional, Hahn, Tim, additional, Henskens, Frans, additional, Hillert, Jan, additional, Jablensky, Assen V., additional, Jones, Lisa, additional, Jones, Ian, additional, Jonsson, Lina, additional, Kelsoe, John R., additional, Kircher, Tilo, additional, Kirov, George, additional, Kittel-Schneider, Sarah, additional, Kogevinas, Manolis, additional, Landen, Mikael, additional, Leboyer, Marion, additional, Lenger, Melanie, additional, Lissowska, Jolanta, additional, Lochner, Christine, additional, Loughland, Carmel, additional, MacIntyre, Donald, additional, Martin, Nicholas G., additional, Maratou, Eirini, additional, Mathews, Carol A., additional, Mayoral, Fermin, additional, McElroy, Susan L., additional, McGregor, Nathaniel W., additional, McIntosh, Andrew, additional, McQuillin, Andrew, additional, Michie, Patricia, additional, Mitchell, Philip B., additional, Moutsatsou, Paraskevi, additional, Mowry, Bryan, additional, Mueller-Myhsok, Bertram, additional, Myers, Richard, additional, Nenadic, Igor, additional, Noethen, Markus M., additional, O'Donovan, Michael, additional, O'Donovan, Claire, additional, Ophoff, Roel A., additional, Owen, Michael J., additional, Pantelis, Chris, additional, Pato, Carlos, additional, Pato, Michele T., additional, Patrinos, George P., additional, Pawlak, Joanna M., additional, Perlis, Roy H., additional, Porichi, Evgenia, additional, Posthuma, Danielle, additional, Ramos-Quiroga, Josep Antoni, additional, Reif, Andreas, additional, Reininghaus, Eva Z., additional, Ribases, Marta, additional, Rietschel, Marcella, additional, Schall, Ulrich, additional, Schulze, Thomas G., additional, Scott, Laura, additional, Scott, Rodney J., additional, Serretti, Alessandro, additional, Shannon Weickert, Cynthia, additional, Smoller, Jordan W., additional, Soler Artigas, Maria Soler, additional, Stein, Dan J., additional, Streit, Fabian, additional, Toma, Claudio, additional, Tooney, Paul, additional, Vieta, Eduard, additional, Vincent, John B., additional, Waldman, Irwin D., additional, Weickert, Thomas, additional, Witt, Stephanie H., additional, Swiatkowska, Beata, additional, Hong, Kyung Sue Sue, additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Won, Hong-Hee, additional, Edenberg, Howard J., additional, Ripke, Stephan, additional, Raj, Towfique, additional, Coleman, Jonathan R. I., additional, and Mullins, Niamh, additional

Published
2024
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20. Transcriptome-wide mega-analyses reveal joint dysregulation of immunologic genes and transcription regulators in brain and blood in schizophrenia

Author

Hess, Jonathan L, Tylee, Daniel S, Barve, Rahul, de Jong, Simone, Ophoff, Roel A, Kumarasinghe, Nishantha, Tooney, Paul, Schall, Ulrich, Gardiner, Erin, Beveridge, Natalie Jane, Scott, Rodney J, Yasawardene, Surangi, Perera, Antionette, Mendis, Jayan, Carr, Vaughan, Kelly, Brian, Cairns, Murray, Unit, the Neurobehavioural Genetics, Tsuang, Ming T, and Glatt, Stephen J

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Clinical Research, Schizophrenia, Brain Disorders, Neurosciences, Mental Health, Genetics, Serious Mental Illness, Biotechnology, Mental health, Biomarkers, Gene Expression Profiling, Humans, Machine Learning, Microarray Analysis, Models, Statistical, Prefrontal Cortex, Psychotic Disorders, Transcriptome, Gene expression, Brain, Blood, Innate immunity, Support vector machine, Random forests, Neurobehavioural Genetics Unit, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences
Abstract

The application of microarray technology in schizophrenia research was heralded as paradigm-shifting, as it allowed for high-throughput assessment of cell and tissue function. This technology was widely adopted, initially in studies of postmortem brain tissue, and later in studies of peripheral blood. The collective body of schizophrenia microarray literature contains apparent inconsistencies between studies, with failures to replicate top hits, in part due to small sample sizes, cohort-specific effects, differences in array types, and other confounders. In an attempt to summarize existing studies of schizophrenia cases and non-related comparison subjects, we performed two mega-analyses of a combined set of microarray data from postmortem prefrontal cortices (n=315) and from ex-vivo blood tissues (n=578). We adjusted regression models per gene to remove non-significant covariates, providing best-estimates of transcripts dysregulated in schizophrenia. We also examined dysregulation of functionally related gene sets and gene co-expression modules, and assessed enrichment of cell types and genetic risk factors. The identities of the most significantly dysregulated genes were largely distinct for each tissue, but the findings indicated common emergent biological functions (e.g. immunity) and regulatory factors (e.g., predicted targets of transcription factors and miRNA species across tissues). Our network-based analyses converged upon similar patterns of heightened innate immune gene expression in both brain and blood in schizophrenia. We also constructed generalizable machine-learning classifiers using the blood-based microarray data. Our study provides an informative atlas for future pathophysiologic and biomarker studies of schizophrenia.

Published
2016

21. Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

Author

Mehta, Divya, Tropf, Felix C, Gratten, Jacob, Bakshi, Andrew, Zhu, Zhihong, Bacanu, Silviu-Alin, Hemani, Gibran, Magnusson, Patrik KE, Barban, Nicola, Esko, Tõnu, Metspalu, Andres, Snieder, Harold, Mowry, Bryan J, Kendler, Kenneth S, Yang, Jian, Visscher, Peter M, McGrath, John J, Mills, Melinda C, Wray, Naomi R, Lee, S Hong, Andreassen, Ole A, Bramon, Elvira, Bruggeman, Richard, Buxbaum, Joseph D, Cairns, Murray J, Cantor, Rita M, Cloninger, C Robert, Cohen, David, Crespo-Facorro, Benedicto, Darvasi, Ariel, DeLisi, Lynn E, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Escott-Price, Valentina, Freimer, Nelson B, Georgieva, Lyudmila, de Haan, Lieuwe, Henskens, Frans A, Joa, Inge, Julià, Antonio, Khrunin, Andrey, Lerer, Bernard, Limborska, Svetlana, Loughland, Carmel M, Macek, Milan, Marsal, Sara, McCarley, Robert W, McIntosh, Andrew M, McQuillin, Andrew, Melegh, Bela, Michie, Patricia T, Morris, Derek W, Murphy, Kieran C, Myin-Germeys, Inez, Olincy, Ann, Van Os, Jim, Pantelis, Christos, Posthuma, Danielle, Quested, Digby, Schall, Ulrich, Scott, Rodney J, Seidman, Larry J, Toncheva, Draga, Tooney, Paul A, Waddington, John, Weinberger, Daniel R, Weiser, Mark, and Wu, Jing Qin

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Human Genome, Prevention, Brain Disorders, Serious Mental Illness, Mental Health, Schizophrenia, Clinical Research, Mental health, Adult, Alleles, Birth Order, Cohort Studies, Denmark, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Maternal Age, Phenotype, Pregnancy, Risk, Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, and TwinsUK, Other Medical and Health Sciences, Psychology, Cognitive Sciences, Clinical sciences, Clinical and health psychology
Abstract

ImportanceA recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age.ObjectiveTo determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets.Design, setting, and participantsThis investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study.Main outcomes and measuresWe tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age.ResultsWe observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014.Conclusions and relevanceThis study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

Published
2016

24. Upregulation of the Renin–Angiotensin System Is Associated with Patient Survival and the Tumour Microenvironment in Glioblastoma.

Author

Lozinski, Mathew, Lumbers, Eugenie R., Bowden, Nikola A., Martin, Jennifer H., Fay, Michael F., Pringle, Kirsty G., and Tooney, Paul A.

Subjects
TUMOR microenvironment, RENIN-angiotensin system, OVERALL survival, GLIOBLASTOMA multiforme, RAS oncogenes, DOSE-response relationship (Radiation), CARDIOVASCULAR system
Abstract

Glioblastoma is a highly aggressive disease with poor survival outcomes. An emerging body of literature links the role of the renin–angiotensin system (RAS), well-known for its function in the cardiovascular system, to the progression of cancers. We studied the expression of RAS-related genes (ATP6AP2, AGTR1, AGTR2, ACE, AGT, and REN) in The Cancer Genome Atlas (TCGA) glioblastoma cohort, their relationship to patient survival, and association with tumour microenvironment pathways. The expression of RAS genes was then examined in 12 patient-derived glioblastoma cell lines treated with chemoradiation. In cases of glioblastoma within the TCGA, ATP6AP2, AGTR1, ACE, and AGT had consistent expressions across samples, while AGTR2 and REN were lowly expressed. High expression of AGTR1 was independently associated with lower progression-free survival (PFS) (p = 0.01) and had a non-significant trend for overall survival (OS) after multivariate analysis (p = 0.095). The combined expression of RAS receptors (ATP6AP2, AGTR1, and AGTR2) was positively associated with gene pathways involved in hypoxia, microvasculature, stem cell plasticity, and the molecular characterisation of glioblastoma subtypes. In patient-derived glioblastoma cell lines, ATP6AP2 and AGTR1 were upregulated after chemoradiotherapy and correlated with an increase in HIF1A expression. This data suggests the RAS is correlated with changes in the tumour microenvironment and associated with glioblastoma survival outcomes. [ABSTRACT FROM AUTHOR]

Published
2024
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26. Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium

Author

Farde, Lars, Flyckt, Lena, Engberg, Göran, Erhardt, Sophie, Fatouros-Bergman, Helena, Cervenka, Simon, Schwieler, Lilly, Piehl, Fredrik, Agartz, Ingrid, Collste, Karin, Victorsson, Pauliina, Malmqvist, Anna, Hedberg, Mikael, Orhan, Funda, van Erp, Theo G.M., 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., Mueller, Bryon A., Cahn, Wiepke, de Zwarte, Sonja M.C., Hulshoff Pol, Hilleke E., Kahn, René S., Ophoff, Roel A., van Haren, Neeltje E.M., 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 A., 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, Shannon Weickert, Cynthia, 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 P.F., 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 N., Ciufolini, Simone, Radua, Joaquim, Dazzan, Paola, Murray, Robin, Reis Marques, Tiago, 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 E.C., 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, Busatto, Geraldo F., Rosa, Pedro G.P., 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 S., Uhlmann, Anne, Lopez-Jaramillo, Carlos, Dima, Danai, McMahon, Agnes, Faskowitz, Joshua I., Gutman, Boris A., Jahanshad, Neda, Thompson, Paul M., and Turner, Jessica A.

Published
2018
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28. Genetic variants for head size share genes and pathways with cancer

Author

Amouyel, Philippe, Arfanakis, Konstantinos, Aribisala, Benjamin S., Bastin, Mark E., Chauhan, Ganesh, Chen, Christopher, Cheng, Ching-Yu, de Jager, Philip L., Deary, Ian J., Fleischman, Debra A., Gottesman, Rebecca F., Gudnason, Vilmundur, Hilal, Saima, Hofer, Edith, Janowitz, Deborah, Jukema, J. Wouter, Liewald, David C.M., Lopez, Lorna M., Lopez, Oscar, Luciano, Michelle, Martinez, Oliver, Niessen, Wiro J., Nyquist, Paul, Rotter, Jerome I., Rundek, Tatjana, Sacco, Ralph L., Schmidt, Helena, Tiemeier, Henning, Trompet, Stella, van der Grond, Jeroen, Völzke, Henry, Wardlaw, Joanna M., Yanek, Lisa, Yang, Jingyun, Agartz, Ingrid, Alhusaini, Saud, Almasy, Laura, Ames, David, Amunts, Katrin, Andreassen, Ole A., Armstrong, Nicola, Bernard, Manon, Blangero, John, Blanken, Laura M.E., Boks, Marco P., Boomsma, Dorret I., Brickman, Adam M., Brodaty, Henry, Buckner, Randy L., Buitelaar, Jan K., Cannon, Dara M., Carr, Vaughan J., Catts, Stanley V., Chakravarty, M. Mallar, Chen, Qiang, Ching, Christopher R.K., Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E., Davies, Gareth E., de Geus, Eco J.C., de Zubicaray, Greig I., den Braber, Anouk, Desrivières, Sylvane, Dillman, Allissa, Djurovic, Srdjan, Drevets, Wayne C., Duggirala, Ravi, Ehrlich, Stefan, Erk, Susanne, Espeseth, Thomas, Fedko, Iryna O., Fernández, Guillén, Fisher, Simon E., Foroud, Tatiana M., Ge, Tian, Giddaluru, Sudheer, Glahn, David C., Goldman, Aaron L., Green, Robert C., Greven, Corina U., Grimm, Oliver, Hansell, Narelle K., Hartman, Catharina A., Hashimoto, Ryota, Heinz, Andreas, Henskens, Frans, Hibar, Derrek P., Ho, Beng-Choon, Hoekstra, Pieter J., Holmes, Avram J., Hoogman, Martine, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E., Jablensky, Assen, Jenkinson, Mark, Jia, Tianye, Jöckel, Karl-Heinz, Jönsson, Erik G., Kim, Sungeun, Klein, Marieke, Kochunov, Peter, Kwok, John B., Lawrie, Stephen M., Le Hellard, Stephanie, Lemaître, Hervé, Loughland, Carmel, Marquand, Andre F., Martin, Nicholas G., Martinot, Jean-Luc, Matarin, Mar, Mathalon, Daniel H., Mather, Karen A., Mattay, Venkata S., McDonald, Colm, McMahon, Francis J., McMahon, Katie L., E, Rebekah, McWhirter, Mecocci, Patrizia, Melle, Ingrid, Meyer-Lindenberg, Andreas, Michie, Patricia T., Milaneschi, Yuri, Morris, Derek W., Mowry, Bryan, Nho, Kwangsik, Nichols, Thomas E., Nöthen, Markus N., Olvera, Rene L., Oosterlaan, Jaap, Ophoff, Roel A., Pandolfo, Massimo, Pantelis, Christos, Pappa, Irene, Penninx, Brenda, Pike, G. Bruce, Rasser, Paul E., Rentería, Miguel E., Reppermund, Simone, Rietschel, Marcella, Risacher, Shannon L., Romanczuk-Seiferth, Nina, Rose, Emma Jane, Sachdev, Perminder S., Sämann, Philipp G., Saykin, Andrew J., Schall, Ulrich, Schofield, Peter R., Schramm, Sara, Schumann, Gunter, Scott, Rodney, Shen, Li, Sisodiya, Sanjay M., Soininen, Hilkka, Sprooten, Emma, Srikanth, Velandai, Steen, Vidar M., Strike, Lachlan T., Thalamuthu, Anbupalam, Toga, Arthur W., Tooney, Paul, Tordesillas-Gutiérrez, Diana, Turner, Jessica A., Valdés Hernández, Maria del C., van der Meer, Dennis, Van der Wee, Nic J.A., Van Haren, Neeltje E.M., van 't Ent, Dennis, Veltman, Dick J., Walter, Henrik, Weinberger, Daniel R., Weiner, Michael W., Wen, Wei, Westlye, Lars T., Westman, Eric, Winkler, Anderson M., Woldehawariat, Girma, Wright, Margaret J., Wu, Jingqin, Knol, Maria J., Poot, Raymond A., Evans, Tavia E., Satizabal, Claudia L., Mishra, Aniket, Sargurupremraj, Muralidharan, van der Auwera, Sandra, Duperron, Marie-Gabrielle, Jian, Xueqiu, Hostettler, Isabel C., van Dam-Nolen, Dianne H.K., Lamballais, Sander, Pawlak, Mikolaj A., Lewis, Cora E., Carrion-Castillo, Amaia, van Erp, Theo G.M., Reinbold, Céline S., Shin, Jean, Scholz, Markus, Håberg, Asta K., Kämpe, Anders, Li, Gloria H.Y., Avinun, Reut, Atkins, Joshua R., Hsu, Fang-Chi, Amod, Alyssa R., Lam, Max, Tsuchida, Ami, Teunissen, Mariël W.A., Aygün, Nil, Patel, Yash, Liang, Dan, Beiser, Alexa S., Beyer, Frauke, Bis, Joshua C., Bos, Daniel, Bryan, R. Nick, Bülow, Robin, Caspers, Svenja, Catheline, Gwenaëlle, Cecil, Charlotte A.M., Dalvie, Shareefa, Dartigues, Jean-François, DeCarli, Charles, Enlund-Cerullo, Maria, Ford, Judith M., Franke, Barbara, Freedman, Barry I., Friedrich, Nele, Green, Melissa J., Haworth, Simon, Helmer, Catherine, Hoffmann, Per, Homuth, Georg, Ikram, M. Kamran, Jack, Clifford R., Jr., Jahanshad, Neda, Jockwitz, Christiane, Kamatani, Yoichiro, Knodt, Annchen R., Li, Shuo, Lim, Keane, Longstreth, W.T., Macciardi, Fabio, Mäkitie, Outi, Mazoyer, Bernard, Medland, Sarah E., Miyamoto, Susumu, Moebus, Susanne, Mosley, Thomas H., Muetzel, Ryan, Mühleisen, Thomas W., Nagata, Manabu, Nakahara, Soichiro, Palmer, Nicholette D., Pausova, Zdenka, Preda, Adrian, Quidé, Yann, Reay, William R., Roshchupkin, Gennady V., Schmidt, Reinhold, Schreiner, Pamela J., Setoh, Kazuya, Shapland, Chin Yang, Sidney, Stephen, St Pourcain, Beate, Stein, Jason L., Tabara, Yasuharu, Teumer, Alexander, Uhlmann, Anne, van der Lugt, Aad, Vernooij, Meike W., Werring, David J., Windham, B. Gwen, Witte, A. Veronica, Wittfeld, Katharina, Yang, Qiong, Yoshida, Kazumichi, Brunner, Han G., Le Grand, Quentin, Sim, Kang, Stein, Dan J., Bowden, Donald W., Cairns, Murray J., Hariri, Ahmad R., Cheung, Ching-Lung, Andersson, Sture, Villringer, Arno, Paus, Tomas, Cichon, Sven, Calhoun, Vince D., Crivello, Fabrice, Launer, Lenore J., White, Tonya, Koudstaal, Peter J., Houlden, Henry, Fornage, Myriam, Matsuda, Fumihiko, Grabe, Hans J., Ikram, M. Arfan, Debette, Stéphanie, Thompson, Paul M., Seshadri, Sudha, and Adams, Hieab H.H.

Published
2024
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29. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Maury, Eduardo A., primary, Sherman, Maxwell A., additional, Genovese, Giulio, additional, Gilgenast, Thomas G., additional, Kamath, Tushar, additional, Burris, S.J., additional, Rajarajan, Prashanth, additional, Flaherty, Erin, additional, Akbarian, Schahram, additional, Chess, Andrew, additional, McCarroll, Steven A., additional, Loh, Po-Ru, additional, Phillips-Cremins, Jennifer E., additional, Brennand, Kristen J., additional, Macosko, Evan Z., additional, Walters, James T.R., additional, O’Donovan, Michael, additional, Sullivan, Patrick, additional, Sebat, Jonathan, additional, Lee, Eunjung A., additional, Walsh, Christopher A., additional, Marshall, Christian R., additional, Merico, Daniele, additional, Thiruvahindrapuram, Bhooma, additional, Wang, Zhouzhi, additional, Scherer, Stephen W., additional, Howrigan, Daniel P, additional, Ripke, Stephan, additional, Bulik-Sullivan, Brendan, additional, Farh, Kai-How, additional, Fromer, Menachem, additional, Goldstein, Jacqueline I., additional, Huang, Hailiang, additional, Lee, Phil, additional, Daly, Mark J., additional, Neale, Benjamin M., additional, Belliveau, Richard A., additional, Bergen, Sarah E., additional, Bevilacqua, Elizabeth, additional, Chambert, Kimberley D., additional, O'Dushlaine, Colm, additional, Scolnick, Edward M., additional, Smoller, Jordan W., additional, Moran, Jennifer L., additional, Palotie, Aarno, additional, Petryshen, Tracey L., additional, Wu, Wenting, additional, Greer, Douglas S., additional, Antaki, Danny, additional, Shetty, Aniket, additional, Gujral, Madhusudan, additional, Brandler, William M., additional, Malhotra, Dheeraj, additional, Fuentes Fajarado, Karin V., additional, Maile, Michelle S., additional, Holmans, Peter A., additional, Carrera, Noa, additional, Craddock, Nick, additional, Escott-Price, Valentina, additional, Georgieva, Lyudmila, additional, Hamshere, Marian L., additional, Kavanagh, David, additional, Legge, Sophie E., additional, Pocklington, Andrew J., additional, Richards, Alexander L., additional, Ruderfer, Douglas M., additional, Williams, Nigel M., additional, Kirov, George, additional, Owen, Michael J., additional, Pinto, Dalila, additional, Cai, Guiqing, additional, Davis, Kenneth L., additional, Drapeau, Elodie, additional, Friedman, Joseph I, additional, Haroutunian, Vahram, additional, Parkhomenko, Elena, additional, Reichenberg, Abraham, additional, Silverman, Jeremy M., additional, Buxbaum, Joseph D., additional, Domenici, Enrico, additional, Agartz, Ingrid, additional, Djurovic, Srdjan, additional, Mattingsdal, Morten, additional, Melle, Ingrid, additional, Andreassen, Ole A., additional, Jönsson, Erik G., additional, Söderman, Erik, additional, Albus, Margot, additional, Alexander, Madeline, additional, Laurent, Claudine, additional, Levinson, Douglas F., additional, Amin, Farooq, additional, Atkins, Joshua, additional, Cairns, Murray J., additional, Scott, Rodney J., additional, Tooney, Paul A., additional, Wu, Jing Qin, additional, Bacanu, Silviu A., additional, Bigdeli, Tim B., additional, Reimers, Mark A., additional, Webb, Bradley T., additional, Wolen, Aaron R., additional, Wormley, Brandon K., additional, Kendler, Kenneth S., additional, Riley, Brien P., additional, Kähler, Anna K., additional, Magnusson, Patrik K.E., additional, Hultman, Christina M., additional, Bertalan, Marcelo, additional, Hansen, Thomas, additional, Olsen, Line, additional, Rasmussen, Henrik B., additional, Werge, Thomas, additional, Mattheisen, Manuel, additional, Black, Donald W., additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buckner, Randy L., additional, Roffman, Joshua L., additional, Byerley, William, additional, Cahn, Wiepke, additional, Kahn, René S, additional, Strengman, Eric, additional, Ophoff, Roel A., additional, Carr, Vaughan J., additional, Catts, Stanley V., additional, Henskens, Frans A., additional, Loughland, Carmel M., additional, Michie, Patricia T., additional, Pantelis, Christos, additional, Schall, Ulrich, additional, Jablensky, Assen V., additional, Kelly, Brian J., additional, Campion, Dominique, additional, Cantor, Rita M., additional, Cheng, Wei, additional, Cloninger, C. Robert, additional, Svrakic, Dragan M, additional, Cohen, David, additional, Cormican, Paul, additional, Donohoe, Gary, additional, Morris, Derek W., additional, Corvin, Aiden, additional, Gill, Michael, additional, Crespo-Facorro, Benedicto, additional, Crowley, James J., additional, Farrell, Martilias S., additional, Giusti-Rodríguez, Paola, additional, Kim, Yunjung, additional, Szatkiewicz, Jin P., additional, Williams, Stephanie, additional, Curtis, David, additional, Pimm, Jonathan, additional, Gurling, Hugh, additional, McQuillin, Andrew, additional, Davidson, Michael, additional, Weiser, Mark, additional, Degenhardt, Franziska, additional, Forstner, Andreas J., additional, Herms, Stefan, additional, Hoffmann, Per, additional, Hofman, Andrea, additional, Cichon, Sven, additional, Nöthen, Markus M., additional, Del Favero, Jurgen, additional, DeLisi, Lynn E., additional, McCarley, Robert W., additional, Levy, Deborah L., additional, Mesholam-Gately, Raquelle I., additional, Seidman, Larry J., additional, Dikeos, Dimitris, additional, Papadimitriou, George N., additional, Dinan, Timothy, additional, Duan, Jubao, additional, Sanders, Alan R., additional, Gejman, Pablo V., additional, Gershon, Elliot S., additional, Dudbridge, Frank, additional, Eichhammer, Peter, additional, Eriksson, Johan, additional, Salomaa, Veikko, additional, Essioux, Laurent, additional, Fanous, Ayman H., additional, Knowles, James A., additional, Pato, Michele T., additional, Pato, Carlos N., additional, Frank, Josef, additional, Meier, Sandra, additional, Schulze, Thomas G., additional, Strohmaier, Jana, additional, Witt, Stephanie H., additional, Rietschel, Marcella, additional, Franke, Lude, additional, Karjalainen, Juha, additional, Freedman, Robert, additional, Olincy, Ann, additional, Freimer, Nelson B., additional, Purcell, Shaun M., additional, Roussos, Panos, additional, Stahl, Eli A., additional, Sklar, Pamela, additional, Giegling, Ina, additional, Hartmann, Annette M., additional, Konte, Bettina, additional, Rujescu, Dan, additional, Godard, Stephanie, additional, Hirschhorn, Joel N., additional, Pers, Tune H., additional, Price, Alkes, additional, Esko, Tõnu, additional, Gratten, Jacob, additional, Lee, S. Hong, additional, Visscher, Peter M., additional, Wray, Naomi R., additional, Mowry, Bryan J., additional, de Haan, Lieuwe, additional, Meijer, Carin J., additional, Hansen, Mark, additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Joa, Inge, additional, Kalaydjieva, Luba, additional, Keller, Matthew C., additional, Kennedy, James L., additional, Zai, Clement C., additional, Knight, Jo, additional, Lerer, Bernard, additional, Liang, Kung-Yee, additional, Lieberman, Jeffrey, additional, Stroup, T. Scott, additional, Lönnqvist, Jouko, additional, Suvisaari, Jaana, additional, Maher, Brion S., additional, Maier, Wolfgang, additional, Mallet, Jacques, additional, McDonald, Colm, additional, McIntosh, Andrew M., additional, Blackwood, Douglas H.R., additional, Metspalu, Andres, additional, Milani, Lili, additional, Milanova, Vihra, additional, Mokrab, Younes, additional, Collier, David A., additional, Müller-Myhsok, Bertram, additional, Murphy, Kieran C., additional, Murray, Robin M., additional, Powell, John, additional, Myin-Germeys, Inez, additional, Van Os, Jim, additional, Nenadic, Igor, additional, Nertney, Deborah A., additional, Nestadt, Gerald, additional, Pulver, Ann E., additional, Nicodemus, Kristin K., additional, Nisenbaum, Laura, additional, Nordin, Annelie, additional, Adolfsson, Rolf, additional, O'Callaghan, Eadbhard, additional, Oh, Sang-Yun, additional, O'Neill, F. Anthony, additional, Paunio, Tiina, additional, Pietiläinen, Olli, additional, Perkins, Diana O., additional, Quested, Digby, additional, Savitz, Adam, additional, Li, Qingqin S., additional, Schwab, Sibylle G., additional, Shi, Jianxin, additional, Spencer, Chris C.A., additional, Thirumalai, Srinivas, additional, Veijola, Juha, additional, Waddington, John, additional, Walsh, Dermot, additional, Wildenauer, Dieter B., additional, Bramon, Elvira, additional, Darvasi, Ariel, additional, Posthuma, Danielle, additional, St. Clair, David, additional, Shanta, Omar, additional, Klein, Marieke, additional, Park, Peter J., additional, Weinberger, Daniel, additional, Moran, John V., additional, Gage, Fred H., additional, Vaccarino, Flora M., additional, Gleeson, Joseph, additional, Mathern, Gary, additional, Courchesne, Eric, additional, Roy, Subhojit, additional, Bizzotto, Sara, additional, Coulter, Michael, additional, Dias, Caroline, additional, D'Gama, Alissa, additional, Ganz, Javier, additional, Hill, Robert, additional, Huang, August Yue, additional, Khoshkhoo, Sattar, additional, Kim, Sonia, additional, Lodato, Michael, additional, Miller, Michael, additional, Borges-Monroy, Rebeca, additional, Rodin, Rachel, additional, Zhou, Zinan, additional, Bohrson, Craig, additional, Chu, Chong, additional, Cortes-Ciriano, Isidro, additional, Dou, Yanmei, additional, Galor, Alon, additional, Gulhan, Doga, additional, Kwon, Minseok, additional, Luquette, Joe, additional, Viswanadham, Vinay, additional, Jones, Attila, additional, Rosenbluh, Chaggai, additional, Cho, Sean, additional, Langmead, Ben, additional, Thorpe, Jeremy, additional, Erwin, Jennifer, additional, Jaffe, Andrew, additional, McConnell, Michael, additional, Narurkar, Rujuta, additional, Paquola, Apua, additional, Shin, Jooheon, additional, Straub, Richard, additional, Abyzov, Alexej, additional, Bae, Taejeong, additional, Jang, Yeongjun, additional, Wang, Yifan, additional, Gage, Fred, additional, Linker, Sara, additional, Reed, Patrick, additional, Wang, Meiyan, additional, Urban, Alexander, additional, Zhou, Bo, additional, Zhu, Xiaowei, additional, Pattni, Reenal, additional, Amero, Aitor Serres, additional, Juan, David, additional, Lobon, Irene, additional, Marques-Bonet, Tomas, additional, Moruno, Manuel Solis, additional, Perez, Raquel Garcia, additional, Povolotskaya, Inna, additional, Soriano, Eduardo, additional, Averbuj, Dan, additional, Ball, Laurel, additional, Breuss, Martin, additional, Yang, Xiaoxu, additional, Chung, Changuk, additional, Emery, Sarah B., additional, Flasch, Diane A., additional, Kidd, Jeffrey M., additional, Kopera, Huira C., additional, Kwan, Kenneth Y., additional, Mills, Ryan E., additional, Moldovan, John B., additional, Sun, Chen, additional, Zhao, Xuefang, additional, Zhou, Weichen, additional, Frisbie, Trenton J., additional, Cherskov, Adriana, additional, Fasching, Liana, additional, Jourdon, Alexandre, additional, Pochareddy, Sirisha, additional, Scuderi, Soraya, additional, and Sestan, Nenad, additional

Published
2023
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34. Comparison between [ 68 Ga]Ga-PSMA-617 and [ 18 F]FET PET as Imaging Biomarkers in Adult Recurrent Glioblastoma.

Author

Brighi, Caterina, Puttick, Simon, Woods, Amanda, Keall, Paul, Tooney, Paul A., Waddington, David E. J., Sproule, Vicki, Rose, Stephen, and Fay, Michael

Subjects
POSITRON emission tomography, MAGNETIC resonance imaging, GLIOBLASTOMA multiforme
Abstract

The aim of this prospective clinical study was to evaluate the potential of the prostate specific membrane antigen (PSMA) targeting ligand, [68Ga]-PSMA–Glu–NH–CO–NH–Lys-2-naphthyl-L-Ala-cyclohexane-DOTA ([68Ga]Ga-PSMA-617) as a positron emission tomography (PET) imaging biomarker in recurrent glioblastoma patients. Patients underwent [68Ga]Ga-PSMA-617 and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET scans on two separate days. [68Ga]Ga-PSMA-617 tumour selectivity was assessed by comparing tumour volume delineation and by assessing the intra-patient correlation between tumour uptake on [68Ga]Ga-PSMA-617 and [18F]FET PET images. [68Ga]Ga-PSMA-617 tumour specificity was evaluated by comparing its tumour-to-brain ratio (TBR) with [18F]FET TBR and its tumour volume with the magnetic resonance imaging (MRI) contrast-enhancing (CE) tumour volume. Ten patients were recruited in this study. [68Ga]Ga-PSMA-617-avid tumour volume was larger than the [18F]FET tumour volume (p = 0.063). There was a positive intra-patient correlation (median Pearson r = 0.51; p < 0.0001) between [68Ga]Ga-PSMA-617 and [18F]FET in the tumour volume. [68Ga]Ga-PSMA-617 had significantly higher TBR (p = 0.002) than [18F]FET. The [68Ga]Ga-PSMA-617-avid tumour volume was larger than the CE tumour volume (p = 0.0039). Overall, accumulation of [68Ga]-Ga-PSMA-617 beyond [18F]FET-avid tumour regions suggests the presence of neoangiogenesis in tumour regions that are not overly metabolically active yet. Higher tumour specificity suggests that [68Ga]-Ga-PSMA-617 could be a better imaging biomarker for recurrent tumour delineation and secondary treatment planning than [18F]FET and CE MRI. [ABSTRACT FROM AUTHOR]

Published
2023
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35. Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Author

Georgiadis, Foivos, primary, Larivière, Sara, additional, Glahn, David, additional, Hong, L. Elliot, additional, Kochunov, Peter, additional, Mowry, Bryan, additional, Loughland, Carmel, additional, Pantelis, Christos, additional, Henskens, Frans A., additional, Green, Melissa J., additional, Cairns, Murray J., additional, Michie, Patricia T, additional, Rasser, Paul E., additional, Tooney, Paul, additional, Scott, Rodney J., additional, Catts, Stanley, additional, Schall, Ulrich, additional, Carr, Vaughan, additional, Quidé, Yann, additional, Krug, Axel, additional, Stein, Frederike, additional, Nenadić, Igor, additional, Brosch, Katharina, additional, Kircher, Tilo, additional, Gur, Raquel, additional, Gur, Ruben, additional, Satterthwaite, Theodore D., additional, Karuk, Andriana, additional, Clotet, Edith Pomarol-, additional, Radua, Joaquim, additional, Fuentes-Claramonte, Paola, additional, Salvador, Raymond, additional, Spalletta, Gianfranco, additional, Voineskos, Aristotle, additional, Sim, Kang, additional, Crespo-Facorro, Benedicto, additional, Gutiérrez, Diana Tordesillas, additional, Ehrlich, Stefan, additional, Crossley, Nicolas, additional, Grotegerd, Dominik, additional, Repple, Jonathan, additional, Lencer, Rebekka, additional, Dannlowski, Udo, additional, Calhoun, Vince, additional, Demro, Caroline, additional, Ramsay, Ian S., additional, Sponheim, Scott R., additional, Schmidt, Andre, additional, Borgwardt, Stefan, additional, Tomyshev, Alexander S., additional, Lebedeva, Irina, additional, Hoschl, Cyril, additional, Spaniel, Filip, additional, Preda, Adrian, additional, Nguyen, Dana, additional, Uhlmann, Anne, additional, Stein, Dan J, additional, Howells, Fleur M, additional, Temmingh, Henk S., additional, Diaz Zuluaga, Ana M., additional, Jaramillo, Carlos López, additional, Iasevoli, Felice, additional, Ji, Ellen, additional, Homan, Stephanie, additional, Omlor, Wolfgang, additional, Homan, Philipp, additional, Kaiser, Stefan, additional, Seifritz, Erich, additional, Misic, Bratislav, additional, Valk, Sofie L., additional, Thompson, Paul, additional, van Erp, Theo G.M., additional, Turner, Jessica, additional, Bernhardt, Boris, additional, and Kirschner, Matthias, additional

Published
2023
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38. CX3CR1 is dysregulated in blood and brain from schizophrenia patients

Author

Bergon, Aurélie, Belzeaux, Raoul, Comte, Magali, Pelletier, Florence, Hervé, Mylène, Gardiner, Erin J., Beveridge, Natalie J., Liu, Bing, Carr, Vaughan, Scott, Rodney J., Kelly, Brian, Cairns, Murray J., Kumarasinghe, Nishantha, Schall, Ulrich, Blin, Olivier, Boucraut, José, Tooney, Paul A., Fakra, Eric, and Ibrahim, El Chérif

Published
2015
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43. 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

45. 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., Willcocks, Isabella R., Holmans, Peter A., Dennison, Charlotte A., Lynham, Amy J., Legge, Sophie E., Baune, Bernhard T., Bigdeli, Tim B., Cairns, Murray J., Corvin, Aiden, Fanous, Ayman H., Frank, Josef, Kelly, Brian, McQuillin, Andrew, Melle, Ingrid, Mortensen, Preben B., Mowry, Bryan J., Pato, Carlos N., Periyasamy, Sathish, Rietschel, Marcella, Rujescu, Dan, Simonsen, Carmen, St Clair, David, Tooney, Paul, Wu, Jing Qin, Andreassen, Ole A., Kowalec, Kaarina, Sullivan, Patrick F., Murray, Robin M., Owen, Michael J., MacCabe, James H., O’Donovan, Michael C., Walters, James T. R., Ripke, Stephan, Neale, Benjamin M., Farh, Kai-How, 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, Homman, Lina, Belliveau, Richard A ., Pardiñas, Antonio F., Smart, Sophie E., Willcocks, Isabella R., Holmans, Peter A., Dennison, Charlotte A., Lynham, Amy J., Legge, Sophie E., Baune, Bernhard T., Bigdeli, Tim B., Cairns, Murray J., Corvin, Aiden, Fanous, Ayman H., Frank, Josef, Kelly, Brian, McQuillin, Andrew, Melle, Ingrid, Mortensen, Preben B., Mowry, Bryan J., Pato, Carlos N., Periyasamy, Sathish, Rietschel, Marcella, Rujescu, Dan, Simonsen, Carmen, St Clair, David, Tooney, Paul, Wu, Jing Qin, Andreassen, Ole A., Kowalec, Kaarina, Sullivan, Patrick F., Murray, Robin M., Owen, Michael J., MacCabe, James H., O’Donovan, Michael C., Walters, James T. R., Ripke, Stephan, Neale, Benjamin M., Farh, Kai-How, 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, Homman, Lina, and Belliveau, Richard A .

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, Funding/Support: 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/L0, STRATA

Published
2022
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46. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author

Blokland, Gabriëlla A.M., Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, 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, 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, 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-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., Herms, Stefan, 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, 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, Kähler, Anna K., Laurent, Claudine, Lee Chee Keong, Jimmy, Lee, S. Hong, 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., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, 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, 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, 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., Riley, Brien P., Esko, Tõnu, Jönsson, Erik G., Palotie, Aarno, Ehrenreich, Hannelore, Steixner-Kumar, Agnes, Sham, Pak C., Iwata, Nakao, Weinberger, Daniel R., Gejman, Pablo V., Sanders, Alan R., Buxbaum, Joseph D., Rujescu, Dan, Bramon, Elvira, Pato, Michele T., Lee, Jimmy, Molden, Espen, Ophoff, Roel A., McQuillin, Andrew, Bass, Nicholas, Adolfsson, Rolf, Malhotra, Anil K., Stahl, Eli A., Breen, Gerome, Forstner, Andreas J., Trubetskoy, Vassily, Wang, Yunpeng, Coleman, Jonathan R.I., Gaspar, Héléna A., de Leeuw, Christiaan A., Steinberg, Stacy, Whitehead Pavlides, Jennifer M., Trzaskowski, Maciej, Byrne, Enda M., Richards, Alexander L., Abbott, Liam, Akil, Huda, Albani, Diego, Alliey-Rodriguez, Ney, Als, Thomas D., Bauer, Michael, Craig, David W., Gordon, Scott D., Green, Melissa J., Johnson, Jessica S., Li, Jun Z., Medland, Sarah E., Nguyen, Hoang, Rice, John P., Thompson, Robert C., Martin, Nicholas G., Schofield, Peter R., Adams, Mark J., Colodro-Conde, Lucía, Derks, Eske M., Gill, Michael, Howard, David M., Lind, Penelope A., Mehta, Divya, Nyholt, Dale R., Smith, Daniel J., Visscher, Peter M., other, and, Blokland, Gabriëlla A.M., Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, 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, 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, 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-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., Herms, Stefan, 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, 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, Kähler, Anna K., Laurent, Claudine, Lee Chee Keong, Jimmy, Lee, S. Hong, 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., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, 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, 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, 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., Riley, Brien P., Esko, Tõnu, Jönsson, Erik G., Palotie, Aarno, Ehrenreich, Hannelore, Steixner-Kumar, Agnes, Sham, Pak C., Iwata, Nakao, Weinberger, Daniel R., Gejman, Pablo V., Sanders, Alan R., Buxbaum, Joseph D., Rujescu, Dan, Bramon, Elvira, Pato, Michele T., Lee, Jimmy, Molden, Espen, Ophoff, Roel A., McQuillin, Andrew, Bass, Nicholas, Adolfsson, Rolf, Malhotra, Anil K., Stahl, Eli A., Breen, Gerome, Forstner, Andreas J., Trubetskoy, Vassily, Wang, Yunpeng, Coleman, Jonathan R.I., Gaspar, Héléna A., de Leeuw, Christiaan A., Steinberg, Stacy, Whitehead Pavlides, Jennifer M., Trzaskowski, Maciej, Byrne, Enda M., Richards, Alexander L., Abbott, Liam, Akil, Huda, Albani, Diego, Alliey-Rodriguez, Ney, Als, Thomas D., Bauer, Michael, Craig, David W., Gordon, Scott D., Green, Melissa J., Johnson, Jessica S., Li, Jun Z., Medland, Sarah E., Nguyen, Hoang, Rice, John P., Thompson, Robert C., Martin, Nicholas G., Schofield, Peter R., Adams, Mark J., Colodro-Conde, Lucía, Derks, Eske M., Gill, Michael, Howard, David M., Lind, Penelope A., Mehta, Divya, Nyholt, Dale R., Smith, Daniel J., Visscher, Peter M., and other, and

Abstract

Background: Sex 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. Methods: We 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. Results: Across 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). Conclusions: In 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 effe

Published
2022

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

Author

Blokland, Gabriëlla A. M., Grove, Jakob, Chen, Chia-Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, 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, Anette 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., 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., Baune, Bernhard T., Air, Tracy, Preisig, Martin, Uher, Rudolf, Levinson, Douglas F., Weissman, Myrna M., Potash, James B., Shi, Jianxin, Knowles, James A., Perlis, Roy H., Lucae, Susanne, Boomsma, Dorret I, Penninx, Brenda W. J. H., Hottenga, Jouke-Jan, de Geus, Eco J. C., Willemsen, Gonneke, Milaneschi, Yuri, Tiemeier, Henning, Grabe, Hans J., Teumer, Alexander, Van der Auwera, Sandra, Völker, Uwe, Hamilton, Steven P., Magnusson, Patrik K. E., Viktorin, Alexander, Mehta, Divya, Mullins, Niamh, Adams, Mark J., Breen, Gerome, McIntosh, Andrew M., Lewis, Cathryn M., Hougaard, David M., Nordentoft, Merete, Mors, Ole, Mortensen, Preben B., Werge, Thomas, Als, Thomas D., Børglum, Anders D., Petryshen, Tracey L., Smoller, Jordan W., Goldstein, Jill M., Blokland, Gabriëlla A. M., Grove, Jakob, Chen, Chia-Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, 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, Anette 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., 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., Baune, Bernhard T., Air, Tracy, Preisig, Martin, Uher, Rudolf, Levinson, Douglas F., Weissman, Myrna M., Potash, James B., Shi, Jianxin, Knowles, James A., Perlis, Roy H., Lucae, Susanne, Boomsma, Dorret I, Penninx, Brenda W. J. H., Hottenga, Jouke-Jan, de Geus, Eco J. C., Willemsen, Gonneke, Milaneschi, Yuri, Tiemeier, Henning, Grabe, Hans J., Teumer, Alexander, Van der Auwera, Sandra, Völker, Uwe, Hamilton, Steven P., Magnusson, Patrik K. E., Viktorin, Alexander, Mehta, Divya, Mullins, Niamh, Adams, Mark J., Breen, Gerome, McIntosh, Andrew M., Lewis, Cathryn M., Hougaard, David M., Nordentoft, Merete, Mors, Ole, Mortensen, Preben B., Werge, Thomas, Als, Thomas D., Børglum, Anders D., Petryshen, Tracey L., Smoller, Jordan W., and Goldstein, Jill M.

Abstract

BACKGROUND: Sex 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. METHODS: We 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. RESULTS: Across 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). CONCLUSIONS: In 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 f

Published
2022
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48. Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Author

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, Pardiñas, Antonio F., Smart, Sophie E., Willcocks, Isabella R., Holmans, Peter A., Dennison, Charlotte A., Lynham, Amy, Legge, Sophie E., Baune, Bernhard T., Bigdeli, Tim B., Cairns, Murray J., Corvin, Aiden, Fanous, Ayman H., Frank, Josef, Kelly, Brian, McQuillin, Andrew, Melle, Ingrid, Mortensen, Preben B., Mowry, Bryan J., Pato, Carlos N., Periyasamy, Sathish, Rietschel, Marcella, Rujescu, Dan, Simonsen, Carmen, St Clair, David, Tooney, Paul, Wu, Jing Qin, Andreassen, Ole A., Kowalec, Kaarina, Sullivan, Patrick F., Murray, Robin M., Owen, Michael J., MacCabe, James H., O'Donovan, Michael C., Walters, James T. R., Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA), Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC), 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, Pardiñas, Antonio F., Smart, Sophie E., Willcocks, Isabella R., Holmans, Peter A., Dennison, Charlotte A., Lynham, Amy, Legge, Sophie E., Baune, Bernhard T., Bigdeli, Tim B., Cairns, Murray J., Corvin, Aiden, Fanous, Ayman H., Frank, Josef, Kelly, Brian, McQuillin, Andrew, Melle, Ingrid, Mortensen, Preben B., Mowry, Bryan J., Pato, Carlos N., Periyasamy, Sathish, Rietschel, Marcella, Rujescu, Dan, Simonsen, Carmen, St Clair, David, Tooney, Paul, Wu, Jing Qin, Andreassen, Ole A., Kowalec, Kaarina, Sullivan, Patrick F., Murray, Robin M., Owen, Michael J., MacCabe, James H., O'Donovan, Michael C., Walters, James T. R., Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA), and Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC)

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.

Published
2022

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

Author

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, Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey S., Lam, Max, Curtis, Charles, Nikitina-Zake, Liene, Davidson, Michael, Joa, Inge, Davis, Kenneth L., Yolken, Robert, Murray, Robin M., de Haan, Lieuwe, Legge, Sophie E., Serretti, Alessandro, van Os, Jim, Smoller, Jordan W., Agartz, Ingrid, Alizadeh, Behrooz Z., Degenhardt, Franziska, DeLisi, Lynn E., Demontis, Ditte, Dickerson, Faith, Zai, Clement C., Dikeos, Dimitris, Dinan, Timothy, Henskens, Frans A., Vaaler, Arne, Noto, Cristiano, Nimgaonkar, Vishwajit, Rautanen, Anna, Lehrer, Douglas S., Djurovic, Srdjan, Duan, Jubao, Julià, Antonio, Stahl, Eli A., Zhou, Wei, Vawter, Marquis P., Toncheva, Draga, Webb, Bradley T., Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanas Saura, Lourdes, Goldstein, Jacqueline I., Faraone, Stephen V., Lencer, Rebecca, Moreno, Carmen, Bacanu, Silviu A., Fiorentino, Alessia, Calkins, Monica E., Mitjans, Marina, Forstner, Andreas, Nuechterlein, Keith H., Frank, Josef, Tsuang, Debby W., Freimer, Nelson B., Tooney, Paul A., Belangero, Sintia Iole, Weinberger, Daniel R., Fromer, Menachem, Ge,Tian, Adolfsson, Rolf, Hakonarson, Hakon, Zhu, Feng, Frustaci, Alessandra, Nöthen, Markus M., Gadelha, Ary, Genovese, Giulio, Gershon, Elliot S., Quattrone, Diego, Kähler, Anna K., Kam-Thong, Tony, van Amelsvoort, Therese, Vilella, Elisabet, Molden, Espen, O'Brien, Niamh Louise, Zimprich, Fritz, Kamatani, Yoichiro, Braun, Alice, Melegh, Bela, Pirinen, Matti, Karachanak-Yankova, Sena, Ophoff, Roel A., Kebir, Oussama, Lerer, Bernard, Nordentoft, Merete, Fanous, Ayman H., Reichenberg, Abraham, Li, Miaoxin, Periyasamy, Sathish, Lieberman, Jeffrey, Werge, Thomas, Light, Gregory A., Limborska, Svetlana, Tosato, Sarah, Liu, Chih-Min, Olincy, Ann, Magnusson, Sigurdur, Gareeva, Anna, Bressan, Rodrigo Affonseca, Lönnqvist, Jouko, Roe, Cheryl, Cheng, Wei, Athanasiu, Lavinia, Gutiérrez, Blanca, Harvey, Carol, Loughland, Carmel M., Lubinski, Jan, Luykx, Jurjen J., Lynham, Amy, Gawlik, Micha, Macek, Milan, Mackinnon, Andrew, Buxbaum, Joseph D., Tura, Gian Battista, Bromet, Evelyn J., Atbaşoğlu, Eşref Cem, Roffman, Joshua L., Magnusson, Patrik K. E., Maher, Brion S., Ota, Vanessa Kiyomi, Paciga, Sara A., Gejman, Pablo V., Arango, Celso, Forti, Marta Di, Maier, Wolfgang, Richards, Alexander L., Malaspina, Dolores, Mallet, Jacques, Metspalu, Andres, Marder, Stephen R., Li, Zhiqiang, Takahashi, Atsushi, Marsal, Sara, Kučinskiene, Zita Ausrele, Suvisaari, Jaana, Martin, Alicia R., Turetsky, Bruce I., Martorell, Lourdes, Palotie, Aarno, Mattheisen, Manuel, Baune, Bernhard T., Saka, Meram C., McCarley, Robert W., Giusti-Rodríguez, Paola, Riley, Brien P., Murphy, Kieran C., Gill, Michael, McDonald, Colm, Bruggeman, Richard, McGrath, John J., Sidorenko, Julia, Medeiros, Helena, Pantelis, Christos, Grove, Jakob, Campion, Dominique, Pato, Carlos N., Svrakic, Dragan M., Üçok, Alp, Glatt, Stephen J., Papadimitriou, George N., Khrunin, Andrey, Straub, Richard E., Parellada, Mara, Buckley, Peter F., Paunio, Tiina, Roth, Julian, Morgan, Vera A., Wildenauer, Dieter B., Ayub, Muhammad, Rothermundt, Matthias, Weiser, Mark, Rutten, Bart P. F., Saker-Delye, Safaa, Salomaa, Veikko, Børglum, Anders D., Sanjuán, Julio, van Winkel, Ruud, González Peñas, Javier, Yu, Xin, Kim, Sung-Wan, Santoro, Marcos Leite, Benner, Christian, Ikeda, Masashi, Morley, Christopher P., Zeng, Jian, Savitz, Adam, Schall, Ulrich, Scott, Rodney J., Voloudakis, Georgios, Yue, Weihua, Seidman, Larry J., Sharp, Sally Isabel, Alptekin, Köksal, Klovins, Janis, Amin, Farooq, Bertolino, Alessandro, Shi, Jianxin, Siever, Larry J., Atkinson, Elizabeth G., Buckner, Randy L., Holmans, Peter A., Rivera, Margarita, Sigurdsson, Engilbert, González-Pinto, Ana, Sim, Kang, Skarabis, Nora, Stroup, T Scott, Slominsky, Petr, Guillin, Olivier, Wang, Shi-Heng, So, Hon-Cheong, Quested, Digby, Sobell, Janet L., Braff, David, Zhang, Wen, Bybjerg-Grauholm, Jonas, Söderman, Erik, Rujescu, Dan, Chambert, Kimberley D., Stain, Helen J., Melle, Ingrid, Carr, Vaughan J, Pocklington, Andrew J., Steen, Nils Eiel, Harwood, Janet, Steixner-Kumar, Agnes A., Gopal, Srihari, Stögmann, Elisabeth, Veijola, Juha, Watanabe, Kyoko, Sham, Pak C., Cahn, Wiepke, Bramon, Elvira, Roussos, Panos, Waddington, John, Perkins, Diana O., Pato, Michele T., Walter, Henrik, Kondratiev, Nikolay, Waterreus, Anna, Al Eissa, Mariam, Bobes, Julio, Golimbet, Vera, Black, Donald W., Als, Thomas D., Bray, Nicholas J., Breen, Gerome, Buccola, Nancy G., Sanders, Alan R., Byerley, William F., Cervilla, Jorge A., Michie, Patricia T., Pfuhlmann, Bruno, Chen, Wei J., Hong, Kyung Sue, O'Neill, F Anthony, Terao, Chikashi, Green, Michael F., Cloninger, C. Robert, Crespo-Facorro, Benedicto, Donohoe, Gary, Gülöksüz, Sinan, Freedman, Robert, Albus, Margot, Hayward, Caroline, Pietiläinen, Olli, Herms, Stefan, Hultman, Christina M., Galletly, Cherrie, Gandal, Michael J., Hahn, Eric, Konte, Bettina, Castle, David, Gennarelli, Massimo, Milani, Lili, Hougaard, David M., Hwu, Hai-Gwo, Pulver, Ann E., Jablensky, Assen V., Molina, Esther, Qin, Shengying, McCarroll, Steven A., Moran, Jennifer L., Azevedo, Maria Helena, Gur, Rachel E., Kraft, Julia, Mors, Ole, Catts, Stanley V., Lazzeroni, Laura C., Mortensen, Preben B., Streit, Fabian, Kusumawardhani, Agung, Alexander, Madeline, Godard, Stephanie, Müller-Myhsok, Bertram, Milanova, Vihra, Neil, Amanda L., Cichon, Sven, Giannitelli, Marianna, Cheung, Eric F. C., Kubo, Michiaki, Schwab, Sibylle G., Collier, David A., Williams, Nigel M., Morris, Derek W., Corvin, Aiden, Pimm, Jonathan, Curtis, David, Haroutunian, Vahram, Keller, Matthew C., Vassos, Evangelos, Hyman, Steven E., Iwata, Nakao, Jönsson, Erik G., Kahn, René S., Chan, Raymond C. K., Kennedy, James L., Shi, Yongyong, Adams, Mark, Witt, Stephanie H., Khusnutdinova, Elza, Verhage, Matthijs, Xu, Shuhua, Wu, Yang, Kirov, George, Arolt, Volker, Knowles, James A., Moltó, Maria Dolores, Krebs, Marie-Odile, Hartmann, Annette M., Nestadt, Gerald, Wormley, Brandon K., Bass, Nicholas J., Laurent-Levinson, Claudine, Lee, Jimmy, Muntané, Gerard, Porteous, David, Kuzelova-Ptackova, Hana, Lencz, Todd, Subramaniam, Mythily, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Swerdlow, Neal R., Cairns, Murray J., Malhotra, Anil K., Malhotra, Dheeraj, Iyegbe, Conrad, Mondelli, Valeria, Kim, Minsoo, Arrojo, Manuel, Landi, Stefano, McIntosh, Andrew M., Petryshen, Tracey L., Radant, Allen D., Frei, Oleksandr, Mesholam-Gately, Raquelle I., McQuillin, Andrew, Sugar, Catherine A., Menezes, Paulo Rossi, St Clair, David, Meier, Sandra, Powell, John, Chaumette, Boris, Stefansson, Hreinn, Domenici, Enrico, Bonassi, Stefano, Stefánsson, Kári, Wu, Jing Qin, Tsuang, Ming T., Myin-Germeys, Inez, Pellegrino, Renata, Visscher, Peter M., Yang, Jian, Posthuma, Danielle, Andreassen, Ole A., Koopmans, Frank, Kendler, Kenneth S., Chong, Siow Ann, Gur, Ruben C., Ehrenreich, Hannelore, Owen, Michael J., Rietschel, Marcella, Gratten, Jacob, Wray, Naomi R., Hoffmann, Per, Daly, Mark J., Szatkiewicz, Jin P., Huang, Hailiang, Nenadić, Igor, Torretta, Silvia, Escott-Price, Valentina, Neale, Benjamin M., Begemann, Martin, Thibaut, Florence, Agerbo, Esben, Rampino, Antonio, Sullivan, Patrick F., Schulze, Thomas G., Ripke, Stephan, Walters, James T. R., O'Donovan, Michael C., Kučinskas, Vaidutis, Belliveau, Richard A., Bene, Judit, Oh, Sang-Yun, Ta, Thi Minh Tam, Greenwood, Tiffany A., Howrigan, Daniel P., Rapaport, Mark H., Benyamin, Beben, Mowry, Bryan J., Giegling, Ina, Strengman, Eric, Bergen, Sarah E., Silverman, Jeremy M., Blasi, Giuseppe, Cohen, David, Stone, William S., Xu, Zhida, Lee, Phil H., Consoli, Angèle, Kelly, Brian J.., Cordeiro, Quirino, Esko, Tõnu, Costas, Javier, 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, Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey S., Lam, Max, Curtis, Charles, Nikitina-Zake, Liene, Davidson, Michael, Joa, Inge, Davis, Kenneth L., Yolken, Robert, Murray, Robin M., de Haan, Lieuwe, Legge, Sophie E., Serretti, Alessandro, van Os, Jim, Smoller, Jordan W., Agartz, Ingrid, Alizadeh, Behrooz Z., Degenhardt, Franziska, DeLisi, Lynn E., Demontis, Ditte, Dickerson, Faith, Zai, Clement C., Dikeos, Dimitris, Dinan, Timothy, Henskens, Frans A., Vaaler, Arne, Noto, Cristiano, Nimgaonkar, Vishwajit, Rautanen, Anna, Lehrer, Douglas S., Djurovic, Srdjan, Duan, Jubao, Julià, Antonio, Stahl, Eli A., Zhou, Wei, Vawter, Marquis P., Toncheva, Draga, Webb, Bradley T., Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanas Saura, Lourdes, Goldstein, Jacqueline I., Faraone, Stephen V., Lencer, Rebecca, Moreno, Carmen, Bacanu, Silviu A., Fiorentino, Alessia, Calkins, Monica E., Mitjans, Marina, Forstner, Andreas, Nuechterlein, Keith H., Frank, Josef, Tsuang, Debby W., Freimer, Nelson B., Tooney, Paul A., Belangero, Sintia Iole, Weinberger, Daniel R., Fromer, Menachem, Ge,Tian, Adolfsson, Rolf, Hakonarson, Hakon, Zhu, Feng, Frustaci, Alessandra, Nöthen, Markus M., Gadelha, Ary, Genovese, Giulio, Gershon, Elliot S., Quattrone, Diego, Kähler, Anna K., Kam-Thong, Tony, van Amelsvoort, Therese, Vilella, Elisabet, Molden, Espen, O'Brien, Niamh Louise, Zimprich, Fritz, Kamatani, Yoichiro, Braun, Alice, Melegh, Bela, Pirinen, Matti, Karachanak-Yankova, Sena, Ophoff, Roel A., Kebir, Oussama, Lerer, Bernard, Nordentoft, Merete, Fanous, Ayman H., Reichenberg, Abraham, Li, Miaoxin, Periyasamy, Sathish, Lieberman, Jeffrey, Werge, Thomas, Light, Gregory A., Limborska, Svetlana, Tosato, Sarah, Liu, Chih-Min, Olincy, Ann, Magnusson, Sigurdur, Gareeva, Anna, Bressan, Rodrigo Affonseca, Lönnqvist, Jouko, Roe, Cheryl, Cheng, Wei, Athanasiu, Lavinia, Gutiérrez, Blanca, Harvey, Carol, Loughland, Carmel M., Lubinski, Jan, Luykx, Jurjen J., Lynham, Amy, Gawlik, Micha, Macek, Milan, Mackinnon, Andrew, Buxbaum, Joseph D., Tura, Gian Battista, Bromet, Evelyn J., Atbaşoğlu, Eşref Cem, Roffman, Joshua L., Magnusson, Patrik K. E., Maher, Brion S., Ota, Vanessa Kiyomi, Paciga, Sara A., Gejman, Pablo V., Arango, Celso, Forti, Marta Di, Maier, Wolfgang, Richards, Alexander L., Malaspina, Dolores, Mallet, Jacques, Metspalu, Andres, Marder, Stephen R., Li, Zhiqiang, Takahashi, Atsushi, Marsal, Sara, Kučinskiene, Zita Ausrele, Suvisaari, Jaana, Martin, Alicia R., Turetsky, Bruce I., Martorell, Lourdes, Palotie, Aarno, Mattheisen, Manuel, Baune, Bernhard T., Saka, Meram C., McCarley, Robert W., Giusti-Rodríguez, Paola, Riley, Brien P., Murphy, Kieran C., Gill, Michael, McDonald, Colm, Bruggeman, Richard, McGrath, John J., Sidorenko, Julia, Medeiros, Helena, Pantelis, Christos, Grove, Jakob, Campion, Dominique, Pato, Carlos N., Svrakic, Dragan M., Üçok, Alp, Glatt, Stephen J., Papadimitriou, George N., Khrunin, Andrey, Straub, Richard E., Parellada, Mara, Buckley, Peter F., Paunio, Tiina, Roth, Julian, Morgan, Vera A., Wildenauer, Dieter B., Ayub, Muhammad, Rothermundt, Matthias, Weiser, Mark, Rutten, Bart P. F., Saker-Delye, Safaa, Salomaa, Veikko, Børglum, Anders D., Sanjuán, Julio, van Winkel, Ruud, González Peñas, Javier, Yu, Xin, Kim, Sung-Wan, Santoro, Marcos Leite, Benner, Christian, Ikeda, Masashi, Morley, Christopher P., Zeng, Jian, Savitz, Adam, Schall, Ulrich, Scott, Rodney J., Voloudakis, Georgios, Yue, Weihua, Seidman, Larry J., Sharp, Sally Isabel, Alptekin, Köksal, Klovins, Janis, Amin, Farooq, Bertolino, Alessandro, Shi, Jianxin, Siever, Larry J., Atkinson, Elizabeth G., Buckner, Randy L., Holmans, Peter A., Rivera, Margarita, Sigurdsson, Engilbert, González-Pinto, Ana, Sim, Kang, Skarabis, Nora, Stroup, T Scott, Slominsky, Petr, Guillin, Olivier, Wang, Shi-Heng, So, Hon-Cheong, Quested, Digby, Sobell, Janet L., Braff, David, Zhang, Wen, Bybjerg-Grauholm, Jonas, Söderman, Erik, Rujescu, Dan, Chambert, Kimberley D., Stain, Helen J., Melle, Ingrid, Carr, Vaughan J, Pocklington, Andrew J., Steen, Nils Eiel, Harwood, Janet, Steixner-Kumar, Agnes A., Gopal, Srihari, Stögmann, Elisabeth, Veijola, Juha, Watanabe, Kyoko, Sham, Pak C., Cahn, Wiepke, Bramon, Elvira, Roussos, Panos, Waddington, John, Perkins, Diana O., Pato, Michele T., Walter, Henrik, Kondratiev, Nikolay, Waterreus, Anna, Al Eissa, Mariam, Bobes, Julio, Golimbet, Vera, Black, Donald W., Als, Thomas D., Bray, Nicholas J., Breen, Gerome, Buccola, Nancy G., Sanders, Alan R., Byerley, William F., Cervilla, Jorge A., Michie, Patricia T., Pfuhlmann, Bruno, Chen, Wei J., Hong, Kyung Sue, O'Neill, F Anthony, Terao, Chikashi, Green, Michael F., Cloninger, C. Robert, Crespo-Facorro, Benedicto, Donohoe, Gary, Gülöksüz, Sinan, Freedman, Robert, Albus, Margot, Hayward, Caroline, Pietiläinen, Olli, Herms, Stefan, Hultman, Christina M., Galletly, Cherrie, Gandal, Michael J., Hahn, Eric, Konte, Bettina, Castle, David, Gennarelli, Massimo, Milani, Lili, Hougaard, David M., Hwu, Hai-Gwo, Pulver, Ann E., Jablensky, Assen V., Molina, Esther, Qin, Shengying, McCarroll, Steven A., Moran, Jennifer L., Azevedo, Maria Helena, Gur, Rachel E., Kraft, Julia, Mors, Ole, Catts, Stanley V., Lazzeroni, Laura C., Mortensen, Preben B., Streit, Fabian, Kusumawardhani, Agung, Alexander, Madeline, Godard, Stephanie, Müller-Myhsok, Bertram, Milanova, Vihra, Neil, Amanda L., Cichon, Sven, Giannitelli, Marianna, Cheung, Eric F. C., Kubo, Michiaki, Schwab, Sibylle G., Collier, David A., Williams, Nigel M., Morris, Derek W., Corvin, Aiden, Pimm, Jonathan, Curtis, David, Haroutunian, Vahram, Keller, Matthew C., Vassos, Evangelos, Hyman, Steven E., Iwata, Nakao, Jönsson, Erik G., Kahn, René S., Chan, Raymond C. K., Kennedy, James L., Shi, Yongyong, Adams, Mark, Witt, Stephanie H., Khusnutdinova, Elza, Verhage, Matthijs, Xu, Shuhua, Wu, Yang, Kirov, George, Arolt, Volker, Knowles, James A., Moltó, Maria Dolores, Krebs, Marie-Odile, Hartmann, Annette M., Nestadt, Gerald, Wormley, Brandon K., Bass, Nicholas J., Laurent-Levinson, Claudine, Lee, Jimmy, Muntané, Gerard, Porteous, David, Kuzelova-Ptackova, Hana, Lencz, Todd, Subramaniam, Mythily, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Swerdlow, Neal R., Cairns, Murray J., Malhotra, Anil K., Malhotra, Dheeraj, Iyegbe, Conrad, Mondelli, Valeria, Kim, Minsoo, Arrojo, Manuel, Landi, Stefano, McIntosh, Andrew M., Petryshen, Tracey L., Radant, Allen D., Frei, Oleksandr, Mesholam-Gately, Raquelle I., McQuillin, Andrew, Sugar, Catherine A., Menezes, Paulo Rossi, St Clair, David, Meier, Sandra, Powell, John, Chaumette, Boris, Stefansson, Hreinn, Domenici, Enrico, Bonassi, Stefano, Stefánsson, Kári, Wu, Jing Qin, Tsuang, Ming T., Myin-Germeys, Inez, Pellegrino, Renata, Visscher, Peter M., Yang, Jian, Posthuma, Danielle, Andreassen, Ole A., Koopmans, Frank, Kendler, Kenneth S., Chong, Siow Ann, Gur, Ruben C., Ehrenreich, Hannelore, Owen, Michael J., Rietschel, Marcella, Gratten, Jacob, Wray, Naomi R., Hoffmann, Per, Daly, Mark J., Szatkiewicz, Jin P., Huang, Hailiang, Nenadić, Igor, Torretta, Silvia, Escott-Price, Valentina, Neale, Benjamin M., Begemann, Martin, Thibaut, Florence, Agerbo, Esben, Rampino, Antonio, Sullivan, Patrick F., Schulze, Thomas G., Ripke, Stephan, Walters, James T. R., O'Donovan, Michael C., Kučinskas, Vaidutis, Belliveau, Richard A., Bene, Judit, Oh, Sang-Yun, Ta, Thi Minh Tam, Greenwood, Tiffany A., Howrigan, Daniel P., Rapaport, Mark H., Benyamin, Beben, Mowry, Bryan J., Giegling, Ina, Strengman, Eric, Bergen, Sarah E., Silverman, Jeremy M., Blasi, Giuseppe, Cohen, David, Stone, William S., Xu, Zhida, Lee, Phil H., Consoli, Angèle, Kelly, Brian J.., Cordeiro, Quirino, Esko, Tõnu, and Costas, Javier

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.

Published
2022

50. BrainGENIE: The Brain Gene Expression and Network Imputation Engine.

Author

Hess, Jonathan L., Quinn, Thomas P., Zhang, Chunling, Hearn, Gentry C., Chen, Samuel, Beveridge, Natalie Jane, Carr, Vaughan, de Jong, Simone, Gardiner, Erin, Kelly, Brian, Kumarasinghe, Nishantha, Ophoff, Roel, Schall, Ulrich, Scott, Rodney, Stamova, Boryana, Tooney, Paul, Kong, Sek Won, Cairns, Murray, Tsuang, Ming T., and Faraone, Stephen V.

Published
2023
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