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1. 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 CK, Chaumette, Boris, Cheng, Wei, Cheung, Eric FC, 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, and Gershon, Elliot S

Subjects
Brain Disorders, Human Genome, Mental Health, Schizophrenia, Serious Mental Illness, Biotechnology, Neurosciences, Genetics, Aetiology, 2.1 Biological and endogenous factors, Alleles, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Indonesia Schizophrenia Consortium, PsychENCODE, Psychosis Endophenotypes International Consortium, SynGO Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, General Science & Technology
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

2. 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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3. Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry

Author

Bigdeli, Tim B, Genovese, Giulio, Georgakopoulos, Penelope, Meyers, Jacquelyn L, Peterson, Roseann E, Iyegbe, Conrad O, Medeiros, Helena, Valderrama, Jorge, Achtyes, Eric D, Kotov, Roman, Stahl, Eli A, Abbott, Colony, Azevedo, Maria Helena, Belliveau, Richard A, Bevilacqua, Elizabeth, Bromet, Evelyn J, Byerley, William, Carvalho, Celia Barreto, Chapman, Sinéad B, DeLisi, Lynn E, Dumont, Ashley L, O’Dushlaine, Colm, Evgrafov, Oleg V, Fochtmann, Laura J, Gage, Diane, Kennedy, James L, Kinkead, Becky, Macedo, Antonio, Moran, Jennifer L, Morley, Christopher P, Dewan, Mantosh J, Nemesh, James, Perkins, Diana O, Purcell, Shaun M, Rakofsky, Jeffrey J, Scolnick, Edward M, Sklar, Brooke M, Sklar, Pamela, Smoller, Jordan W, Sullivan, Patrick F, Macciardi, Fabio, Marder, Stephen R, Gur, Ruben C, Gur, Raquel E, Braff, David L, Nicolini, Humberto, Escamilla, Michael A, Vawter, Marquis P, Sobell, Janet L, Malaspina, Dolores, Lehrer, Douglas S, Buckley, Peter F, Rapaport, Mark H, Knowles, James A, Fanous, Ayman H, Pato, Michele T, McCarroll, Steven A, and Pato, Carlos N

Subjects
Human Genome, Serious Mental Illness, Clinical Research, Schizophrenia, Brain Disorders, Genetics, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Black People, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic or Latino, Humans, Male, Polymorphism, Single Nucleotide, Consortium on the Genetics of Schizophrenia (COGS) Investigators, Genomic Psychiatry Cohort (GPC) Consortium, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R2 = 0.032; liability R2 = 0.017; P

Published
2020

4. What Should a Psychiatrist Know About Genetics? Review and Recommendations From the Residency Education Committee of the International Society of Psychiatric Genetics.

Author

Nurnberger, John I, Austin, Jehannine, Berrettini, Wade H, Besterman, Aaron D, DeLisi, Lynn E, Grice, Dorothy E, Kennedy, James L, Moreno-De-Luca, Daniel, Potash, James B, Ross, David A, Schulze, Thomas G, and Zai, Gwyneth

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Mental Health, Brain Disorders, Human Genome, Intellectual and Developmental Disabilities (IDD), Autism, Genetic Testing, Mental health, Quality Education, Humans, Internship and Residency, Mental Disorders, Psychiatry, Psychotropic Drugs, Societies, Medical, Medical and Health Sciences, Psychology and Cognitive Sciences, Clinical sciences
Abstract

The International Society of Psychiatric Genetics (ISPG) created a Residency Education Committee with the purpose of identifying key genetic knowledge that should be taught in psychiatric training programs. Thirteen committee members were appointed by the ISPG Board of Directors, based on varied training, expertise, gender, and national origin. The Committee has met quarterly for the past 2 years, with periodic reports to the Board and to the members of the Society. The information summarized includes the existing literature in the field of psychiatric genetics and the output of ongoing large genomics consortia. An outline of clinically relevant areas of genetic knowledge was developed, circulated, and approved. This document was expanded and annotated with appropriate references, and the manuscript was developed. Specific information regarding the contribution of common and rare genetic variants to major psychiatric disorders and treatment response is now available. Current challenges include the following: (1) Genetic testing is recommended in the evaluation of autism and intellectual disability, but its use is limited in current clinical practice. (2) Commercial pharmacogenomic testing is widely available, but its utility has not yet been clearly established. (3) Other methods, such as whole exome and whole genome sequencing, will soon be clinically applicable. The need for informed genetic counseling in psychiatry is greater than ever before, knowledge in the field is rapidly growing, and genetic education should become an integral part of psychiatric training.

Published
2019

5. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Author

Marshall, Christian R, Howrigan, Daniel P, Merico, Daniele, Thiruvahindrapuram, Bhooma, Wu, Wenting, Greer, Douglas S, Antaki, Danny, Shetty, Aniket, Holmans, Peter A, Pinto, Dalila, Gujral, Madhusudan, Brandler, William M, Malhotra, Dheeraj, Wang, Zhouzhi, Fajarado, Karin V Fuentes, Maile, Michelle S, Ripke, Stephan, Agartz, Ingrid, Albus, Margot, Alexander, Madeline, Amin, Farooq, Atkins, Joshua, Bacanu, Silviu A, Belliveau, Richard A, Bergen, Sarah E, Bertalan, Marcelo, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Bulik-Sullivan, Brendan, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Cheng, Wei, Cloninger, C Robert, Cohen, David, Cormican, Paul, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farh, Kai-How, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedman, Joseph I, Forstner, Andreas J, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Gratten, Jacob, de Haan, Lieuwe, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Huang, Hailiang, Ikeda, Masashi, Joa, Inge, and Kähler, Anna K

Subjects
Serious Mental Illness, Human Genome, Schizophrenia, Genetics, Biotechnology, Prevention, Mental Health, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Mental health, Case-Control Studies, DNA Copy Number Variations, Female, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Risk Factors, Psychosis Endophenotypes International Consortium, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Published
2017

6. 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

7. Quantitative Trait Locus and Brain Expression of HLA-DPA1 Offers Evidence of Shared Immune Alterations in Psychiatric Disorders.

Author

Morgan, Ling Z, Rollins, Brandi, Sequeira, Adolfo, Byerley, William, DeLisi, Lynn E, Schatzberg, Alan F, Barchas, Jack D, Myers, Richard M, Watson, Stanley J, Akil, Huda, Bunney, William E, and Vawter, Marquis P

Subjects
alternative splicing, exon array, expression quantitative trait locus, major histocompatibility locus II, Medical Biotechnology
Abstract

Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.

Published
2016

9. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Author

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

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

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

Published
2015

10. A rare functional noncoding variant at the GWAS-implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder.

Author

Duan, Jubao, Shi, Jianxin, Fiorentino, Alessia, Leites, Catherine, Chen, Xiangning, Moy, Winton, Chen, Jingchun, Alexandrov, Boian S, Usheva, Anny, He, Deli, Freda, Jessica, O'Brien, Niamh L, Molecular Genetics of Schizophrenia collaboration, Genomic Psychiatric Cohort consortium, McQuillin, Andrew, Sanders, Alan R, Gershon, Elliot S, DeLisi, Lynn E, Bishop, Alan R, Gurling, Hugh MD, Pato, Michele T, Levinson, Douglas F, Kendler, Kenneth S, Pato, Carlos N, and Gejman, Pablo V

Subjects
Molecular Genetics of Schizophrenia collaboration, Genomic Psychiatric Cohort consortium, Cell Line, Tumor, Humans, Genetic Predisposition to Disease, MicroRNAs, Risk, Sequence Analysis, DNA, Bipolar Disorder, Schizophrenia, Gene Expression Regulation, Base Sequence, Gene Frequency, Polymorphism, Single Nucleotide, Alleles, Genes, Reporter, Molecular Sequence Data, Promoter Regions, Genetic, Genetic Variation, Genome-Wide Association Study, Genetic Loci, Biotechnology, Serious Mental Illness, Clinical Research, Genetics, Mental Health, Brain Disorders, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Mental health, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10(-4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression.

Published
2014

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

Author

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

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

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

Published
2014

12. Evidence of allelic imbalance in the schizophrenia susceptibility gene ZNF804A in human dorsolateral prefrontal cortex

Author

Guella, Ilaria, Sequeira, Adolfo, Rollins, Brandi, Morgan, Ling, Myers, Richard M, Watson, Stanley J, Akil, Huda, Bunney, William E, Delisi, Lynn E, Byerley, William, and Vawter, Marquis P

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Brain Disorders, Biotechnology, Neurosciences, Genetics, Mental Health, Schizophrenia, Serious Mental Illness, Aetiology, 2.1 Biological and endogenous factors, Mental health, Allelic Imbalance, Bipolar Disorder, Cohort Studies, Costa Rica, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Kruppel-Like Transcription Factors, Male, Polymorphism, Single Nucleotide, Postmortem Changes, Prefrontal Cortex, Bipolar disorder, ZNF804A, Association study, rs1344706, Allelic-specific expression, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences
Abstract

The rs1344706, an intronic SNP within the zinc-finger protein 804A gene (ZNF804A), was identified as one of the most compelling risk SNPs for schizophrenia (SZ) and bipolar disorder (BD). It is however not clear by which molecular mechanisms ZNF804A increases disease risk. We evaluated the role of ZNF804A in SZ and BD by genotyping the originally associated rs1344706 SNP and an exonic SNP (rs12476147) located in exon four of ZNF804A in a sample of 422 SZ, 382 BD, and 507 controls from the isolated population of the Costa Rica Central Valley. We also investigated the rs1344706 SNP for allelic specific expression (ASE) imbalance in the dorsolateral prefrontal cortex (DLPFC) of 46 heterozygous postmortem brains. While no significant association between rs1344706 and SZ or BD was observed in the Costa Rica sample, we observed an increased risk of SZ for the minor allele (A) of the exonic rs12476147 SNP (p=0.026). Our ASE assay detected a significant over-expression of the rs12476147 A allele in DLPFC of rs1344706 heterozygous subjects. Interestingly, cDNA allele ratios were significantly different according to the intronic rs1344706 genotypes (p-value=0.03), with the rs1344706 A allele associated with increased ZNF804A rs12476147 A allele expression (average 1.06, p-value=0.02, for heterozygous subjects vs. genomic DNA). In conclusion, we have demonstrated a significant association of rs12476147 with SZ, and using a powerful within-subject design, an allelic expression imbalance of ZNF804A exonic SNP rs12476147 in the DLPFC. Although this data does not preclude the possibility of other functional variants in ZNF804A, it provides evidence that the rs1344706 SZ risk allele is the cis-regulatory variant directly responsible for this allelic expression imbalance in adult cortex.

Published
2014

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

Author

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

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

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

Published
2011

14. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

Author

Girirajan, Santhosh, Rosenfeld, Jill A, Cooper, Gregory M, Antonacci, Francesca, Siswara, Priscillia, Itsara, Andy, Vives, Laura, Walsh, Tom, McCarthy, Shane E, Baker, Carl, Mefford, Heather C, Kidd, Jeffrey M, Browning, Sharon R, Browning, Brian L, Dickel, Diane E, Levy, Deborah L, Ballif, Blake C, Platky, Kathryn, Farber, Darren M, Gowans, Gordon C, Wetherbee, Jessica J, Asamoah, Alexander, Weaver, David D, Mark, Paul R, Dickerson, Jennifer, Garg, Bhuwan P, Ellingwood, Sara A, Smith, Rosemarie, Banks, Valerie C, Smith, Wendy, McDonald, Marie T, Hoo, Joe J, French, Beatrice N, Hudson, Cindy, Johnson, John P, Ozmore, Jillian R, Moeschler, John B, Surti, Urvashi, Escobar, Luis F, El-Khechen, Dima, Gorski, Jerome L, Kussmann, Jennifer, Salbert, Bonnie, Lacassie, Yves, Biser, Alisha, McDonald-McGinn, Donna M, Zackai, Elaine H, Deardorff, Matthew A, Shaikh, Tamim H, Haan, Eric, Friend, Kathryn L, Fichera, Marco, Romano, Corrado, Gécz, Jozef, DeLisi, Lynn E, Sebat, Jonathan, King, Mary-Claire, Shaffer, Lisa G, and Eichler, Evan E

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Agricultural Biotechnology, Neurosciences, Brain Disorders, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Adult, Case-Control Studies, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 16, Comparative Genomic Hybridization, Developmental Disabilities, Family, Gene Frequency, Humans, Infant, Models, Genetic, Oligonucleotide Array Sequence Analysis, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Recurrence, Severity of Illness Index, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

Published
2010

15. Microduplications of 16p11.2 are associated with schizophrenia

Author

McCarthy, Shane E, Makarov, Vladimir, Kirov, George, Addington, Anjene M, McClellan, Jon, Yoon, Seungtai, Perkins, Diana O, Dickel, Diane E, Kusenda, Mary, Krastoshevsky, Olga, Krause, Verena, Kumar, Ravinesh A, Grozeva, Detelina, Malhotra, Dheeraj, Walsh, Tom, Zackai, Elaine H, Kaplan, Paige, Ganesh, Jaya, Krantz, Ian D, Spinner, Nancy B, Roccanova, Patricia, Bhandari, Abhishek, Pavon, Kevin, Lakshmi, B, Leotta, Anthony, Kendall, Jude, Lee, Yoon-ha, Vacic, Vladimir, Gary, Sydney, Iakoucheva, Lilia M, Crow, Timothy J, Christian, Susan L, Lieberman, Jeffrey A, Stroup, T Scott, Lehtimäki, Terho, Puura, Kaija, Haldeman-Englert, Chad, Pearl, Justin, Goodell, Meredith, Willour, Virginia L, DeRosse, Pamela, Steele, Jo, Kassem, Layla, Wolff, Jessica, Chitkara, Nisha, McMahon, Francis J, Malhotra, Anil K, Potash, James B, Schulze, Thomas G, Nöthen, Markus M, Cichon, Sven, Rietschel, Marcella, Leibenluft, Ellen, Kustanovich, Vlad, Lajonchere, Clara M, Sutcliffe, James S, Skuse, David, Gill, Michael, Gallagher, Louise, Mendell, Nancy R, Craddock, Nick, Owen, Michael J, O'Donovan, Michael C, Shaikh, Tamim H, Susser, Ezra, DeLisi, Lynn E, Sullivan, Patrick F, Deutsch, Curtis K, Rapoport, Judith, Levy, Deborah L, King, Mary-Claire, and Sebat, Jonathan

Subjects
Mental health, Chromosomes, Human, Pair 16, Gene Duplication, Genetic Predisposition to Disease, Humans, Risk Factors, Schizophrenia, Wellcome Trust Case Control Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

Published
2009

16. 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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17. Exon expression in lymphoblastoid cell lines from subjects with schizophrenia before and after glucose deprivation

Author

Martin, Maureen V, Rollins, Brandi, Sequeira, P Adolfo, Mesen, Andrea, Byerley, William, Stein, Richard, Moon, Emily A, Akil, Huda, Jones, Edward G, Watson, Stanley J, Barchas, Jack, DeLisi, Lynn E, Myers, Richard M, Schatzberg, Alan, Bunney, William E, and Vawter, Marquis P

Subjects
global gene-expression, bipolar disorder, prefrontal-cortex, psychiatric-disorders, brain disorders, messenger-rna, blood, disease, microarrays, stress
Abstract

Background: The purpose of this study was to examine the effects of glucose reduction stress on lymphoblastic cell line (LCL) gene expression in subjects with schizophrenia compared to non-psychotic relatives. Methods: LCLs were grown under two glucose conditions to measure the effects of glucose reduction stress on exon expression in subjects with schizophrenia compared to unaffected family member controls. A second aim of this project was to identify cis-regulated transcripts associated with diagnosis. Results: There were a total of 122 transcripts with significant diagnosis by probeset interaction effects and 328 transcripts with glucose deprivation by probeset interaction probeset effects after corrections for multiple comparisons. There were 8 transcripts with expression significantly affected by the interaction between diagnosis and glucose deprivation and probeset after correction for multiple comparisons. The overall validation rate by qPCR of 13 diagnosis effect genes identified through microarray was 62%, and all genes tested by qPCR showed concordant up- or down-regulation by qPCR and microarray. We assessed brain gene expression of five genes found to be altered by diagnosis and glucose deprivation in LCLs and found a significant decrease in expression of one gene, glutaminase, in the dorsolateral prefrontal cortex (DLPFC). One SNP with previously identified regulation by a 3' UTR SNP was found to influence IRF5 expression in both brain and lymphocytes. The relationship between the 3' UTR rs10954213 genotype and IRF5 expression was significant in LCLs (p = 0.0001), DLPFC (p = 0.007), and anterior cingulate cortex (p = 0.002). Conclusion: Experimental manipulation of cells lines from subjects with schizophrenia may be a useful approach to explore stress related gene expression alterations in schizophrenia and to identify SNP variants associated with gene expression.

Published
2009

18. An international research agenda for clozapine-resistant schizophrenia

Author

Ontwikkelingsstoornissen Med., Affectieve & Psychotische Med., Brain, Onderzoeksgroep 2, Luykx, Jurjen J, Gonzalez-Diaz, Jairo M, Guu, Ta-Wei, van der Horst, Marte Z, van Dellen, Edwin, Boks, Marco P, Guloksuz, Sinan, DeLisi, Lynn E, Sommer, Iris E, Cummins, Russel, Shiers, David, Lee, Jimmy, Every-Palmer, Susanna, Mhalla, Ahmed, Chadly, Zohra, Chan, Sherry K W, Cotes, Robert O, Takahashi, Shun, Benros, Michael E, Wagner, Elias, Correll, Christoph U, Hasan, Alkomiet, Siskind, Dan, Endres, Dominique, MacCabe, James, Tiihonen, Jari, Ontwikkelingsstoornissen Med., Affectieve & Psychotische Med., Brain, Onderzoeksgroep 2, Luykx, Jurjen J, Gonzalez-Diaz, Jairo M, Guu, Ta-Wei, van der Horst, Marte Z, van Dellen, Edwin, Boks, Marco P, Guloksuz, Sinan, DeLisi, Lynn E, Sommer, Iris E, Cummins, Russel, Shiers, David, Lee, Jimmy, Every-Palmer, Susanna, Mhalla, Ahmed, Chadly, Zohra, Chan, Sherry K W, Cotes, Robert O, Takahashi, Shun, Benros, Michael E, Wagner, Elias, Correll, Christoph U, Hasan, Alkomiet, Siskind, Dan, Endres, Dominique, MacCabe, James, and Tiihonen, Jari

Published
2023

19. An international research agenda for clozapine-resistant schizophrenia

Author

Luykx, Jurjen J, Gonzalez-Diaz, Jairo M, Guu, Ta-Wei, van der Horst, Marte Z, van Dellen, Edwin, Boks, Marco P, Guloksuz, Sinan, DeLisi, Lynn E, Sommer, Iris E, Cummins, Russel, Shiers, David, Lee, Jimmy, Every-Palmer, Susanna, Mhalla, Ahmed, Chadly, Zohra, Chan, Sherry K W, Cotes, Robert O, Takahashi, Shun, Benros, Michael E, Wagner, Elias, Correll, Christoph U, Hasan, Alkomiet, Siskind, Dan, Endres, Dominique, MacCabe, James, Tiihonen, Jari, Luykx, Jurjen J, Gonzalez-Diaz, Jairo M, Guu, Ta-Wei, van der Horst, Marte Z, van Dellen, Edwin, Boks, Marco P, Guloksuz, Sinan, DeLisi, Lynn E, Sommer, Iris E, Cummins, Russel, Shiers, David, Lee, Jimmy, Every-Palmer, Susanna, Mhalla, Ahmed, Chadly, Zohra, Chan, Sherry K W, Cotes, Robert O, Takahashi, Shun, Benros, Michael E, Wagner, Elias, Correll, Christoph U, Hasan, Alkomiet, Siskind, Dan, Endres, Dominique, MacCabe, James, and Tiihonen, Jari

Abstract

Treatment-resistant symptoms occur in about a third of patients with schizophrenia and are associated with a substantial reduction in their quality of life. The development of new treatment options for clozapine-resistant schizophrenia constitutes a crucial, unmet need in psychiatry. Additionally, an overview of past and possible future research avenues to optimise the early detection, diagnosis, and management of clozapine-resistant schizophrenia is unavailable. In this Health Policy, we discuss the ongoing challenges associated with clozapine-resistant schizophrenia faced by patients and health-care providers worldwide to improve the understanding of this condition. We then revisit several clozapine guidelines, the diagnostic tests and treatment options for clozapine-resistant schizophrenia, and currently applied research approaches in clozapine-resistant schizophrenia. We also suggest methodologies and targets for future research, divided into innovative nosology-oriented field trials (eg, examining dimensional symptom staging), translational approaches (eg, genetics), epidemiological research (eg, real-world studies), and interventional studies (eg, non-traditional trial designs incorporating lived experiences and caregivers' perspectives). Finally, we note that low-income and middle-income countries are under-represented in studies on clozapine-resistant schizophrenia and propose an agenda to guide multinational research on the cause and treatment of clozapine-resistant schizophrenia. We hope that this research agenda will empower better global representation of patients living with clozapine-resistant schizophrenia and ultimately improve their functional outcomes and quality of life.

Published
2023

20. 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

21. Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Author

Trubetskoy, Vassily, Pardinas, Antonio, Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey, Lam, Max, Watanabe, Kyoto, 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, Affonseca Bressan, Rodrigo, 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, Angele, 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., Fananas, 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, Gopa, 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, Ausrele Kučinskiene, Zita, Kusumawardhani, Agung, Kuzelov a-Ptackova, Hana, Land, 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., Lubiski, Jan, Luykx, Jurjen J., Lynham, Amy, Macel 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, Vihara, 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, Neuchterlein, Keith H., O'Brien, Niamh Louise, O'Neill, F. Anthony., Oh, Sang-Yun, Olincy, Ann, Ota, Vanessa Kiyomi, Pantelis, Christos, Papadimitrou, George N., Paredella, Mara, Paurio, Tiina, Pellegrino, Renata, Periyasamy, Sathish, Perkins, Diana O., Pfuhlmann, Bruno, Pietilainen, 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, Veiko, Sanjuan, Julio, Santoro, Marcos Leite, Savitz, Adam, Schall, Ulrich, Scott, Rodney J., Seidman, Larry J., Sharp, Sally Isabel, Shi, Jianxin, Sigurdsson, Engilbert, Sim, Kang, Skarabis, Nora, Slominsky, Petr, So, Hon-Cheong, Sobell, Janet L., Soderman, Erik, Stain, Helen J., Steen, Nils Eiel, Steixner-Kumar, Agnes, Stogmann, Elisabeth, Stone, William S., Straub, Richard E., Streit, Fabian, Stregman, Eric, Stroup, T. Scott, Subramaniam, Mythily, Sugar, Catherine A., Suvisaari, Jaana, Svrakic, Dragan M., Swerdlow, Neal R., Szatkiewicz, Jin P., Ta, Thi Minh Tam, and Takahashi, Atsushi

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

22. 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

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

Author

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

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

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

Published
2022

24. De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia

Author

Gauthier, Julie, Champagne, Nathalie, Lafrenière, Ronald G., Xiong, Lan, Spiegelman, Dan, Brustein, Edna, Lapointe, Mathieu, Peng, Huashan, Côté, Mélanie, Noreau, Anne, Hamdan, Fadi F., Addington, Anjené M., Rapoport, Judith L., DeLisi, Lynn E., Krebs, Marie-Odile, Joober, Ridha, Fathalli, Ferid, Mouaffak, Fayçal, Haghighi, Ali P., Néri, Christian, Dubé, Marie-Pierre, Samuels, Mark E., Marineau, Claude, Stone, Eric A., Awadalla, Philip, Barker, Philip A., Carbonetto, Salvatore, Drapeau, Pierre, Rouleau, Guy A., and Housman, David E.

Published
2010

27. Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia

Author

Gauthier, Julie, Siddiqui, Tabrez J., Huashan, Peng, Yokomaku, Daisaku, Hamdan, Fadi F., Champagne, Nathalie, Lapointe, Mathieu, Spiegelman, Dan, Noreau, Anne, Lafrenière, Ronald G., Fathalli, Ferid, Joober, Ridha, Krebs, Marie-Odile, DeLisi, Lynn E., Mottron, Laurent, Fombonne, Éric, Michaud, Jacques L., Drapeau, Pierre, Carbonetto, Salvatore, Craig, Ann Marie, and Rouleau, Guy A.

Published
2011
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28. Complement genes contribute sex-biased vulnerability in diverse disorders

Author

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

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

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

Published
2020

29. Genome scan meta-analysis of schizophrenia and bipolar disorder, Part II: schizophrenia

Author

Lewis, Cathryn M., Levinson, Douglas F., Wise, Lesley H., DeLisi, Lynn E., Straub, Richard E., Hovatta, Iiris, Williams, Nigel M., Schwab, Sibylle G., Pulver, Ann E., Faraone, Stephen V., Brzustowicz, Linda M., Kaufmann, Charles A., Garver, David L., Gurling, Hugh M.D., Lindholm, Eva, Coon, Hilary, Moises, Hans W., Byerley, William, Shaw, Sarah H., Mesen, Andrea, Sherrington, Robin, O'Neill, F. Anthony, Walsh, Dermot, Kendler, Kenneth S., Ekelund, Jesper, Paunio, Tiina, Lonnqvist, Jouko, Peltonen, Leena, O'Donovan, Michael C., Owen, Michael J., Wildenauer, Dieter B., Maier, Wolfgang, Nestadt, Gerald, Blouin, Jean-Louis, Antonarakis, Stylianos E., Mowry, Bryan J., Silverman, Jeremy M., Crowe, Raymond R., Cloninger, C. Robert, Tsuang, Ming T., Malaspina, Dolores, Harkavy-Friedman, Jill M., Svrakic, Dragan M., Bassett, Anne S., Holcomb, Jennifer, Kalsi, Gursharan, McQuillin, Andrew, Brynjolfson, Jon, Sigmundsson, Thordur, Petursson, Hannes, Jazin, Elena, Zoega, Tomas, and Helgason, Tomas

Subjects
Bipolar disorder -- Research, Bipolar disorder -- Genetic aspects, Schizophrenia -- Research, Schizophrenia -- Genetic aspects, Biological sciences
Published
2003

32. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Author

Lee, Phil H., primary, Anttila, Verneri, additional, Won, Hyejung, additional, Feng, Yen-Chen A., additional, Rosenthal, Jacob, additional, Zhu, Zhaozhong, additional, Tucker-Drob, Elliot M., additional, Nivard, Michel G., additional, Grotzinger, Andrew D., additional, Posthuma, Danielle, additional, Wang, Meg M.-J., additional, Yu, Dongmei, additional, Stahl, Eli A., additional, Walters, Raymond K., additional, Anney, Richard J.L., additional, Duncan, Laramie E., additional, Ge, Tian, additional, Adolfsson, Rolf, additional, Banaschewski, Tobias, additional, Belangero, Sintia, additional, Cook, Edwin H., additional, Coppola, Giovanni, additional, Derks, Eske M., additional, Hoekstra, Pieter J., additional, Kaprio, Jaakko, additional, Keski-Rahkonen, Anna, additional, Kirov, George, additional, Kranzler, Henry R., additional, Luykx, Jurjen J., additional, Rohde, Luis A., additional, Zai, Clement C., additional, Agerbo, Esben, additional, Arranz, M.J., additional, Asherson, Philip, additional, Bækvad-Hansen, Marie, additional, Baldursson, Gísli, additional, Bellgrove, Mark, additional, Belliveau, Richard A., additional, Buitelaar, Jan, additional, Burton, Christie L., additional, Bybjerg-Grauholm, Jonas, additional, Casas, Miquel, additional, Cerrato, Felecia, additional, Chambert, Kimberly, additional, Churchhouse, Claire, additional, Cormand, Bru, additional, Crosbie, Jennifer, additional, Dalsgaard, Søren, additional, Demontis, Ditte, additional, Doyle, Alysa E., additional, Dumont, Ashley, additional, Elia, Josephine, additional, Grove, Jakob, additional, Gudmundsson, Olafur O., additional, Haavik, Jan, additional, Hakonarson, Hakon, additional, Hansen, Christine S., additional, Hartman, Catharina A., additional, Hawi, Ziarih, additional, Hervás, Amaia, additional, Hougaard, David M., additional, Howrigan, Daniel P., additional, Huang, Hailiang, additional, Kuntsi, Jonna, additional, Langley, Kate, additional, Lesch, Klaus-Peter, additional, Leung, Patrick W.L., additional, Loo, Sandra K., additional, Martin, Joanna, additional, Martin, Alicia R., additional, McGough, James J., additional, Medland, Sarah E., additional, Moran, Jennifer L., additional, Mors, Ole, additional, Mortensen, Preben B., additional, Oades, Robert D., additional, Palmer, Duncan S., additional, Pedersen, Carsten B., additional, Pedersen, Marianne G., additional, Peters, Triinu, additional, Poterba, Timothy, additional, Poulsen, Jesper B., additional, Ramos-Quiroga, Josep Antoni, additional, Reif, Andreas, additional, Ribasés, Marta, additional, Rothenberger, Aribert, additional, Rovira, Paula, additional, Sánchez-Mora, Cristina, additional, Satterstrom, F. Kyle, additional, Schachar, Russell, additional, Artigas, Maria Soler, additional, Steinberg, Stacy, additional, Stefansson, Hreinn, additional, Turley, Patrick, additional, Walters, G. Bragi, additional, Werge, Thomas, additional, Zayats, Tetyana, additional, Arking, Dan E., additional, Bettella, Francesco, additional, Buxbaum, Joseph D., additional, Christensen, Jane H., additional, Collins, Ryan L., additional, Coon, Hilary, additional, De Rubeis, Silvia, additional, Delorme, Richard, additional, Grice, Dorothy E., additional, Hansen, Thomas F., additional, Holmans, Peter A., additional, Hope, Sigrun, additional, Hultman, Christina M., additional, Klei, Lambertus, additional, Ladd-Acosta, Christine, additional, Magnusson, Pall, additional, Nærland, Terje, additional, Nyegaard, Mette, additional, Pinto, Dalila, additional, Qvist, Per, additional, Rehnström, Karola, additional, Reichenberg, Abraham, additional, Reichert, Jennifer, additional, Roeder, Kathryn, additional, Rouleau, Guy A., additional, Saemundsen, Evald, additional, Sanders, Stephan J., additional, Sandin, Sven, additional, St Pourcain, Beate, additional, Stefansson, Kari, additional, Sutcliffe, James S., additional, Talkowski, Michael E., additional, Weiss, Lauren A., additional, Willsey, A. Jeremy, additional, Agartz, Ingrid, additional, Akil, Huda, additional, Albani, Diego, additional, Alda, Martin, additional, Als, Thomas D., additional, Anjorin, Adebayo, additional, Backlund, Lena, additional, Bass, Nicholas, additional, Bauer, Michael, additional, Baune, Bernhard T., additional, Bellivier, Frank, additional, Bergen, Sarah E., additional, Berrettini, Wade H., additional, Biernacka, Joanna M., additional, Blackwood, Douglas H.R., additional, Bøen, Erlend, additional, Budde, Monika, additional, Bunney, William, additional, Burmeister, Margit, additional, Byerley, William, additional, Byrne, Enda M., additional, Cichon, Sven, additional, Clarke, Toni-Kim, additional, Coleman, Jonathan R.I., additional, Craddock, Nicholas, additional, Curtis, David, additional, Czerski, Piotr M., additional, Dale, Anders M., additional, Dalkner, Nina, additional, Dannlowski, Udo, additional, Degenhardt, Franziska, additional, Di Florio, Arianna, additional, Elvsåshagen, Torbjørn, additional, Etain, Bruno, additional, Fischer, Sascha B., additional, Forstner, Andreas J., additional, Forty, Liz, additional, Frank, Josef, additional, Frye, Mark, additional, Fullerton, Janice M., additional, Gade, Katrin, additional, Gaspar, Héléna A., additional, Gershon, Elliot S., additional, Gill, Michael, additional, Goes, Fernando S., additional, Gordon, Scott D., additional, Gordon-Smith, Katherine, additional, Green, Melissa J., additional, Greenwood, Tiffany A., additional, Grigoroiu-Serbanescu, Maria, additional, Guzman-Parra, José, additional, Hauser, Joanna, additional, Hautzinger, Martin, additional, Heilbronner, Urs, additional, Herms, Stefan, additional, Hoffmann, Per, additional, Holland, Dominic, additional, Jamain, Stéphane, additional, Jones, Ian, additional, Jones, Lisa A., additional, Kandaswamy, Radhika, additional, Kelsoe, John R., additional, Kennedy, James L., additional, Joachim, Oedegaard Ketil, additional, Kittel-Schneider, Sarah, additional, Kogevinas, Manolis, additional, Koller, Anna C., additional, Lavebratt, Catharina, additional, Lewis, Cathryn M., additional, Li, Qingqin S., additional, Lissowska, Jolanta, additional, Loohuis, Loes M.O., additional, Lucae, Susanne, additional, Maaser, Anna, additional, Malt, Ulrik F., additional, Martin, Nicholas G., additional, Martinsson, Lina, additional, McElroy, Susan L., additional, McMahon, Francis J., additional, McQuillin, Andrew, additional, Melle, Ingrid, additional, Metspalu, Andres, additional, Millischer, Vincent, additional, Mitchell, Philip B., additional, Montgomery, Grant W., additional, Morken, Gunnar, additional, Morris, Derek W., additional, Müller-Myhsok, Bertram, additional, Mullins, Niamh, additional, Myers, Richard M., additional, Nievergelt, Caroline M., additional, Nordentoft, Merete, additional, Adolfsson, Annelie Nordin, additional, Nöthen, Markus M., additional, Ophoff, Roel A., additional, Owen, Michael J., additional, Paciga, Sara A., additional, Pato, Carlos N., additional, Pato, Michele T., additional, Perlis, Roy H., additional, Perry, Amy, additional, Potash, James B., additional, Reinbold, Céline S., additional, Rietschel, Marcella, additional, Rivera, Margarita, additional, Roberson, Mary, additional, Schalling, Martin, additional, Schofield, Peter R., additional, Schulze, Thomas G., additional, Scott, Laura J., additional, Serretti, Alessandro, additional, Sigurdsson, Engilbert, additional, Smeland, Olav B., additional, Stordal, Eystein, additional, Streit, Fabian, additional, Strohmaier, Jana, additional, Thorgeirsson, Thorgeir E., additional, Treutlein, Jens, additional, Turecki, Gustavo, additional, Vaaler, Arne E., additional, Vieta, Eduard, additional, Vincent, John B., additional, Wang, Yunpeng, additional, Witt, Stephanie H., additional, Zandi, Peter, additional, Adan, Roger A.H., additional, Alfredsson, Lars, additional, Ando, Tetsuya, additional, Aschauer, Harald, additional, Baker, Jessica H., additional, Bencko, Vladimir, additional, Bergen, Andrew W., additional, Birgegård, Andreas, additional, Perica, Vesna Boraska, additional, Brandt, Harry, additional, Burghardt, Roland, additional, Carlberg, Laura, additional, Cassina, Matteo, additional, Clementi, Maurizio, additional, Courtet, Philippe, additional, Crawford, Steven, additional, Crow, Scott, additional, Crowley, James J., additional, Danner, Unna N., additional, Davis, Oliver S.P., additional, Degortes, Daniela, additional, DeSocio, Janiece E., additional, Dick, Danielle M., additional, Dina, Christian, additional, Docampo, Elisa, additional, Egberts, Karin, additional, Ehrlich, Stefan, additional, Espeseth, Thomas, additional, Fernández-Aranda, Fernando, additional, Fichter, Manfred M., additional, Foretova, Lenka, additional, Forzan, Monica, additional, Gambaro, Giovanni, additional, Giegling, Ina, additional, Gonidakis, Fragiskos, additional, Gorwood, Philip, additional, Mayora, Monica Gratacos, additional, Guo, Yiran, additional, Halmi, Katherine A., additional, Hatzikotoulas, Konstantinos, additional, Hebebrand, Johannes, additional, Helder, Sietske G., additional, Herpertz-Dahlmann, Beate, additional, Herzog, Wolfgang, additional, Hinney, Anke, additional, Imgart, Hartmut, additional, Jiménez-Murcia, Susana, additional, Johnson, Craig, additional, Jordan, Jennifer, additional, Julià, Antonio, additional, Kaminská, Deborah, additional, Karhunen, Leila, additional, Karwautz, Andreas, additional, Kas, Martien J.H., additional, Kaye, Walter H., additional, Kennedy, Martin A., additional, Kim, Youl-Ri, additional, Klareskog, Lars, additional, Klump, Kelly L., additional, Knudsen, Gun Peggy S., additional, Landén, Mikael, additional, Le Hellard, Stephanie, additional, Levitan, Robert D., additional, Li, Dong, additional, Lichtenstein, Paul, additional, Maj, Mario, additional, Marsal, Sara, additional, McDevitt, Sara, additional, Mitchell, James, additional, Monteleone, Palmiero, additional, Monteleone, Alessio Maria, additional, Munn-Chernoff, Melissa A., additional, Nacmias, Benedetta, additional, Navratilova, Marie, additional, O’Toole, Julie K., additional, Padyukov, Leonid, additional, Pantel, Jacques, additional, Papezova, Hana, additional, Rabionet, Raquel, additional, Raevuori, Anu, additional, Ramoz, Nicolas, additional, Reichborn-Kjennerud, Ted, additional, Ricca, Valdo, additional, Roberts, Marion, additional, Rujescu, Dan, additional, Rybakowski, Filip, additional, Scherag, André, additional, Schmidt, Ulrike, additional, Seitz, Jochen, additional, Slachtova, Lenka, additional, Slof-Op‘t Landt, Margarita C.T., additional, Slopien, Agnieszka, additional, Sorbi, Sandro, additional, Southam, Lorraine, additional, Strober, Michael, additional, Tortorella, Alfonso, additional, Tozzi, Federica, additional, Treasure, Janet, additional, Tziouvas, Konstantinos, additional, van Elburg, Annemarie A., additional, Wade, Tracey D., additional, Wagner, Gudrun, additional, Walton, Esther, additional, Watson, Hunna J., additional, Wichmann, H-Erich, additional, Woodside, D. Blake, additional, Zeggini, Eleftheria, additional, Zerwas, Stephanie, additional, Zipfel, Stephan, additional, Adams, Mark J., additional, Andlauer, Till F.M., additional, Berger, Klaus, additional, Binder, Elisabeth B., additional, Boomsma, Dorret I., additional, Castelao, Enrique, additional, Colodro-Conde, Lucía, additional, Direk, Nese, additional, Docherty, Anna R., additional, Domenici, Enrico, additional, Domschke, Katharina, additional, Dunn, Erin C., additional, Foo, Jerome C., additional, de. Geus, E.J.C., additional, Grabe, Hans J., additional, Hamilton, Steven P., additional, Horn, Carsten, additional, Hottenga, Jouke-Jan, additional, Howard, David, additional, Ising, Marcus, additional, Kloiber, Stefan, additional, Levinson, Douglas F., additional, Lewis, Glyn, additional, Magnusson, Patrik K.E., additional, Mbarek, Hamdi, additional, Middeldorp, Christel M., additional, Mostafavi, Sara, additional, Nyholt, Dale R., additional, Penninx, Brenda WJH., additional, Peterson, Roseann E., additional, Pistis, Giorgio, additional, Porteous, David J., additional, Preisig, Martin, additional, Quiroz, Jorge A., additional, Schaefer, Catherine, additional, Schulte, Eva C., additional, Shi, Jianxin, additional, Smith, Daniel J., additional, Thomson, Pippa A., additional, Tiemeier, Henning, additional, Uher, Rudolf, additional, van der Auwera, Sandra, additional, Weissman, Myrna M., additional, Alexander, Madeline, additional, Begemann, Martin, additional, Bramon, Elvira, additional, Buccola, Nancy G., additional, Cairns, Murray J., additional, Campion, Dominique, additional, Carr, Vaughan J., additional, Cloninger, C. Robert, additional, Cohen, David, additional, Collier, David A., additional, Corvin, Aiden, additional, DeLisi, Lynn E., additional, Donohoe, Gary, additional, Dudbridge, Frank, additional, Duan, Jubao, additional, Freedman, Robert, additional, Gejman, Pablo V., additional, Golimbet, Vera, additional, Godard, Stephanie, additional, Ehrenreich, Hannelore, additional, Hartmann, Annette M., additional, Henskens, Frans A., additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Jablensky, Assen V., additional, Joa, Inge, additional, Jönsson, Erik G., additional, Kelly, Brian J., additional, Knight, Jo, additional, Konte, Bettina, additional, Laurent-Levinson, Claudine, additional, Lee, Jimmy, additional, Lencz, Todd, additional, Lerer, Bernard, additional, Loughland, Carmel M., additional, Malhotra, Anil K., additional, Mallet, Jacques, additional, McDonald, Colm, additional, Mitjans, Marina, additional, Mowry, Bryan J., additional, Murphy, Kieran C., additional, Murray, Robin M., additional, O’Neill, F. Anthony, additional, Oh, Sang-Yun, additional, Palotie, Aarno, additional, Pantelis, Christos, additional, Pulver, Ann E., additional, Petryshen, Tracey L., additional, Quested, Digby J., additional, Riley, Brien, additional, Sanders, Alan R., additional, Schall, Ulrich, additional, Schwab, Sibylle G., additional, Scott, Rodney J., additional, Sham, Pak C., additional, Silverman, Jeremy M., additional, Sim, Kang, additional, Steixner, Agnes A., additional, Tooney, Paul A., additional, van Os, Jim, additional, Vawter, Marquis P., additional, Walsh, Dermot, additional, Weiser, Mark, additional, Wildenauer, Dieter B., additional, Williams, Nigel M., additional, Wormley, Brandon K., additional, Zhang, Fuquan, additional, Androutsos, Christos, additional, Arnold, Paul D., additional, Barr, Cathy L., additional, Barta, Csaba, additional, Bey, Katharina, additional, Bienvenu, O. 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2019
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36. Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept

Author

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

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

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

Published
2016

38. Correlates to the variable effects of cannabis in young adults: a preliminary study

Author

Camera Ariella A, Tomaselli Veronica, Fleming Jerry, Jabbar Gul A, Trachtenberg Melissa, Galvez-Buccollini Juan A, Proal Ashley C, Rosenthal Richard N, and DeLisi Lynn E

Subjects
Public aspects of medicine, RA1-1270
Abstract

Abstract Background Cannabis use can frequently have adverse affects in those that use it and these can be amplified by various characteristics of an individual, from demographic and environmental variations to familial predisposition for mental illnesses. Methods The current study of 100 individuals, who were cannabis users during their adolescence and may still be users, was a survey of the self perceived effects of cannabis and their correlates. A reliable family member was also interviewed for determination of family history of various major mental illnesses and substance use. Results As many as 40% of cannabis users had paranoid feelings (suspiciousness) when using cannabis, although the most frequent effect was feeling relaxed (46%). Having a familial background for mental illnesses such as depression or schizophrenia did not determine the effects of cannabis nor its pattern of use, although the number of subjects with such a history was small. An age at which an individual began using cannabis did have an effect on how heavily it was used and the heavier the cannabis use, the more likely the individual was also to have had psychotic symptoms after use. There were no sex differences in effects of cannabis. These results are tempered by the reliance on self-report for many of the variables ascertained. Conclusion Cannabis can frequently have negative effects in its users, which can be amplified by certain demographic and/or psychosocial factors. Thus, users with a specific profile may be at a higher risk of unpleasant effects from cannabis use and caution should be noted when cannabis is administered to young people for medicinal purposes.

Published
2012
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39. Cerebral bioenergetic differences measured by phosphorus‐31 magnetic resonance spectroscopy between bipolar disorder and healthy subjects living in two different regions suggesting possible effects of altitude

Author

Hwang, Jaeuk, primary, DeLisi, Lynn E., additional, Öngür, Dost, additional, Riley, Colin, additional, Zuo, Chun, additional, Shi, Xianfeng, additional, Sung, Young‐Hoon, additional, Kondo, Douglas, additional, Kim, Tae‐Suk, additional, Villafuerte, Rosemond, additional, Smedberg, Diane, additional, Yurgelun‐Todd, Deborah, additional, and Renshaw, Perry F., additional

Published
2019
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41. Pursuit of the 'truth' about mental illness: the significance of findings in neuropsychiatric research, and lessons from the past

Author

DeLisi, Lynn E.

Subjects
Pharmacogenetics, Mental Disorders, Research, PGC, GWAS, Humans, Guest Editorial, ethical issues in genetics, genetic risk
Abstract

Technology in genetics and brain imaging has advanced so rapidly that it is difficult to be knowledgeable about all the new tools being used in the pursuit of progress toward understanding and treating mental illness. While findings from new studies remain promising, caution is needed with regard to their current applicability to clinical use, both to predict who is likely to become ill and who is likely to respond to medication. A perspective on the past, using schizophrenia as an example, illustrates important findings that were published, had much visibility, and caused a flurry of new related studies, but then slowly disappeared, either to be abandoned as an artifact of the assay or study design, an epiphenomenon, or as simply nonreplicated findings not leading to further progress. Remembering that good science is "the pursuit of the truth" and not joining the latest "bandwagon fad" of "believers" is an important principle to adhere to when participating in the politics of science.

Published
2014

42. A preliminary DTI study showing no brain structural change associated with adolescent cannabis use

Author

Brown Kyle, Majcher Magda, Szulc Kamila U, Bertisch Hilary C, DeLisi Lynn E, Bappal Arthika, and Ardekani Babak A

Subjects
Public aspects of medicine, RA1-1270
Abstract

Abstract Analyses were performed on brain MRI scans from individuals who were frequent cannabis users (N = 10; 9 males, 1 female, mean age 21.1 ± 2.9, range: 18–27) in adolescence and similar age and sex matched young adults who never used cannabis (N = 10; 9 males, 1 female, mean age of 23.0 ± 4.4, range: 17–30). Cerebral atrophy and white matter integrity were determined using diffusion tensor imaging (DTI) to quantify the apparent diffusion coefficient (ADC) and the fractional anisotropy (FA). Whole brain volumes, lateral ventricular volumes, and gray matter volumes of the amygdala-hippocampal complex, superior temporal gyrus, and entire temporal lobes (excluding the amygdala-hippocampal complex) were also measured. While differences existed between groups, no pattern consistent with evidence of cerebral atrophy or loss of white matter integrity was detected. It is concluded that frequent cannabis use is unlikely to be neurotoxic to the normal developing adolescent brain.

Published
2006
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46. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Author

Marshall, Christian R. Howrigan, Daniel P. Merico, Daniele and Thiruvahindrapuram, Bhooma Wu, Wenting Greer, Douglas S. and Antaki, Danny Shetty, Aniket Holmans, Peter A. Pinto, Dalila and Gujral, Madhusudan Brandler, William M. Malhotra, Dheeraj and Wang, Zhouzhi Fajarado, Karin V. Fuentes Maile, Michelle S. and Ripke, Stephan Agartz, Ingrid Albus, Margot Alexander, Madeline Amin, Farooq Atkins, Joshua Bacanu, Silviu A. and Belliveau, Jr., Richard A. Bergen, Sarah E. Ertalan, Marcelo and Bevilacqua, Elizabeth Bigdeli, Tim B. Black, Donald W. and Bruggeman, Richard Buccola, Nancy G. Buckner, Randy L. and Bulik-Sullivan, Brendan Byerley, William Cahn, Wiepke Cai, Guiqing Cairns, Murray J. Campion, Dominique Cantor, Rita M. and Carr, Vaughan J. Carrera, Noa Catts, Stanley V. and Chambert, Kimberley D. Cheng, Wei Cloninger, C. Robert and Cohen, David Cormican, Paul Craddock, Nick Crespo-Facorro, Benedicto Crowley, James J. Curtis, David Davidson, Michael and Davis, Kenneth L. Degenhardt, Franziska Del Favero, Jurgen and DeLisi, Lynn E. Dikeos, Dimitris Dinan, Timothy and Djurovic, Srdjan Donohoe, Gary Drapeau, Elodie Duan, Jubao and Dudbridge, Frank Eichhammer, Peter Eriksson, Johan and Escott-Price, Valentina Essioux, Laurent Fanous, Ayman H. and Farh, Kai-How Farrell, Martilias S. Frank, Josef Franke, Lude Freedman, Robert Freimer, Nelson B. Friedman, Joseph I. and Forstner, Andreas J. Fromer, Menachem Genovese, Giulio and Georgieva, Lyudmila Gershon, Elliot S. Giegling, Ina and Giusti-Rodriguez, Paola Godard, Stephanie Goldstein, Jacqueline I. Gratten, Jacob de Haan, Lieuwe Hamshere, Marian L. and Hansen, Mark Hansen, Thomas Haroutunian, Vahram Hartmann, Annette M. Henskens, Frans A. Herms, Stefan Hirschhorn, Joel N. Hoffinann, Per Hofman, Andrea Huang, Hailiang Ikeda, Masashi Joa, Inge Kahler, Anna K. Kahn, Rene S. and Kalaydjieva, Luba Karjalainen, Juha Kavanagh, David Keller, Matthew C. Kelly, Brian J. Kennedy, James L. Kim, Yunjung and Knowles, James A. Konte, Bettina Laurent, Claudine Lee, Phil Lee, S. Hong Legge, Sophie E. Lerer, Bernard Levy, Deborah L. Liang, Kung-Yee Lieberman, Jeffrey Lonnqvist, Jouko Loughland, Carmel M. Magnusson, Patrik K. E. Maher, Brion S. Maier, Wolfgang Mallet, Jacques Mattheisen, Manuel and Mattingsdal, Morten McCarley, Robert W. McDonald, Colm and McIntosh, Andrew M. Meier, Sandra Meijer, Carin J. Melle, Ingrid Mesholam-Gately, Raquelle I. Metspalu, Andres Michie, Patricia T. Milani, Lili Milanova, Vihra Mokrab, Younes and Morris, Derek W. Muller-Myhsok, Bertram Murphy, Kieran C. and Murray, Robin M. Myin-Germeys, Inez Nenadic, Igor Nertney, Deborah A. Nestadt, Gerald Nicodemus, Kristin K. Nisenbaum, Laura Nordin, Annelie O'Callaghan, Eadbhard O'Dushlaine, Colm Oh, Sang-Yun Olincy, Ann Olsen, Line O'Neill, F. Anthony Van Os, Jim Pantelis, Christos Papadimitriou, George N. Parkhomenko, Elena Pato, Michele T. Paunio, Tiina and Perkins, Diana O. Pers, Tune H. Pietilainen, Olli Pimm, Jonathan Pocklington, Andrew J. Powell, John Price, Alkes and Pulver, Ann E. Purcell, Shaun M. Quested, Digby and Rasmussen, Henrik B. Reichenberg, Abraham Reimers, Mark A. and Richards, Alexander L. Roffman, Joshua L. Roussos, Panos and Ruderfer, Douglas M. Salomaa, Veikko Sanders, Alan R. and Savitz, Adam Schall, Ulrich Schulze, Thomas G. Schwab, Sibylle G. Scolnick, Edward M. Scott, Rodney J. Seidman, Larry J. Shi, Jianxin Silverman, Jeremy M. Smoller, Jordan W. Soderman, Erik Spencer, Chris C. A. Stahl, Eli A. and Strengman, Eric Strohmaier, Jana Stroup, T. Scott Suvisaari, Jaana Svrakic, Dragan M. Szatkiewicz, Jin P. Thirumalai, Srinivas Tooney, Paul A. Veijola, Juha Visscher, Peter M. and Waddington, John Walsh, Dermot Webb, Bradley T. Weiser, Mark Wildenauer, Dieter B. Williams, Nigel M. Williams, Stephanie Witt, Stephanie H. Wolen, Aaron R. Wormley, Brandon K. Wray, Naomi R. Wu, Jing Qin Zai, Clement C. and Adolfsson, Rolf Andreassen, Ole A. Blackwood, Douglas H. R. and Bramon, Elvira Buxbaum, Joseph D. Cichon, Sven Collier, David A. Corvin, Aiden Daly, Mark J. Darvasi, Ariel and Domenici, Enrico Esko, Tonu Gejman, Pablo V. Gill, Michael and Gurling, Hugh Hultman, Christina M. Iwata, Nakao and Jablensky, Assen V. Jonsson, Erik G. Kendler, Kenneth S. and Kirov, George Knight, Jo Levinson, Douglas F. Li, Qingqin S. and McCarroll, Steven A. McQuillin, Andrew Moran, Jennifer L. and Mowry, Bryan J. Nothen, Markus M. Ophoff, Roel A. Owen, Michael J. Palotie, Aarno Pato, Carlos N. Petryshen, Tracey L. Posthuma, Danielle Rietschel, Marcella Riley, Brien P. and Rujescu, Dan Sklar, Pamela St Clair, David Walters, James T. R. Werge, Thomas Siillivan, Patrick F. O'Donovan, Michael C. Scherer, Stephen W. Neale, Benjamin M. Sebat, Jonathan CNV Schizophrenia Working Grp Psychosis Endophenotypes

Abstract

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Published
2017

47. Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Author

Ruderfer, Douglas M., primary, Ripke, Stephan, additional, McQuillin, Andrew, additional, Boocock, James, additional, Stahl, Eli A., additional, Pavlides, Jennifer M. Whitehead, additional, Mullins, Niamh, additional, Charney, Alexander W., additional, Ori, Anil P.S., additional, Loohuis, Loes M. Olde, additional, Domenici, Enrico, additional, Di Florio, Arianna, additional, Papiol, Sergi, additional, Kalman, Janos L., additional, Trubetskoy, Vassily, additional, Adolfsson, Rolf, additional, Agartz, Ingrid, additional, Agerbo, Esben, additional, Akil, Huda, additional, Albani, Diego, additional, Albus, Margot, additional, Alda, Martin, additional, Alexander, Madeline, additional, Alliey-Rodriguez, Ney, additional, Als, Thomas D., additional, Amin, Farooq, additional, Anjorin, Adebayo, additional, Arranz, Maria J., additional, Awasthi, Swapnil, additional, Bacanu, Silviu A., additional, Badner, Judith A., additional, Baekvad-Hansen, Marie, additional, Bakker, Steven, additional, Band, Gavin, additional, Barchas, Jack D., additional, Barroso, Ines, additional, Bass, Nicholas, additional, Bauer, Michael, additional, Baune, Bernhard T., additional, Begemann, Martin, additional, Bellenguez, Celine, additional, Belliveau, Richard A., additional, Bellivier, Frank, additional, Bender, Stephan, additional, Bene, Judit, additional, Bergen, Sarah E., additional, Berrettini, Wade H., additional, Bevilacqua, Elizabeth, additional, Biernacka, Joanna M., additional, Bigdeli, Tim B., additional, Black, Donald W., additional, Blackburn, Hannah, additional, Blackwell, Jenefer M., additional, Blackwood, Douglas H.R., additional, Pedersen, Carsten Bocker, additional, Boehnke, Michael, additional, Boks, Marco, additional, Borglum, Anders D., additional, Bramon, Elvira, additional, Breen, Gerome, additional, Brown, Matthew A., additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buckner, Randy L., additional, Budde, Monika, additional, Bulik-Sullivan, Brendan, additional, Bumpstead, Suzannah J., additional, Bunney, William, additional, Burmeister, Margit, additional, Buxbaum, Joseph D., additional, Bybjerg-Grauholm, Jonas, additional, Byerley, William, additional, Cahn, Wiepke, additional, Cai, Guiqing, additional, Cairns, Murray J., additional, Campion, Dominique, additional, Cantor, Rita M., additional, Carr, Vaughan J., additional, Carrera, Noa, additional, Casas, Juan P., additional, Casas, Miquel, additional, Catts, Stanley V., additional, Cervantes, Pablo, additional, Chambert, Kimberley D., additional, Chan, Raymond C.K., additional, Chen, Eric Y.H., additional, Chen, Ronald Y.L., additional, Cheng, Wei, additional, Cheung, Eric F.C., additional, Chong, Siow Ann, additional, Clarke, Toni-Kim, additional, Cloninger, C. Robert, additional, Cohen, David, additional, Cohen, Nadine, additional, Coleman, Jonathan R.I., additional, Collier, David A., additional, Cormican, Paul, additional, Coryell, William, additional, Craddock, Nicholas, additional, Craig, David W., additional, Crespo-Facorro, Benedicto, additional, Crowley, James J., additional, Cruceanu, Cristiana, additional, Curtis, David, additional, Czerski, Piotr M., additional, Dale, Anders M., additional, Daly, Mark J., additional, Dannlowski, Udo, additional, Darvasi, Ariel, additional, Davidson, Michael, additional, Davis, Kenneth L., additional, de Leeuw, Christiaan A., additional, Degenhardt, Franziska, additional, Del Favero, Jurgen, additional, DeLisi, Lynn E., additional, Deloukas, Panos, additional, Demontis, Ditte, additional, DePaulo, J. Raymond, additional, di Forti, Marta, additional, Dikeos, Dimitris, additional, Dinan, Timothy, additional, Djurovic, Srdjan, additional, Dobbyn, Amanda L., additional, Donnelly, Peter, additional, Donohoe, Gary, additional, Drapeau, Elodie, additional, Dronov, Serge, additional, Duan, Jubao, additional, Dudbridge, Frank, additional, Duncanson, Audrey, additional, Edenberg, Howard, additional, Edkins, Sarah, additional, Ehrenreich, Hannelore, additional, Eichhammer, Peter, additional, Elvsashagen, Torbjorn, additional, Eriksson, Johan, additional, Escott-Price, Valentina, additional, Esko, Tonu, additional, Essioux, Laurent, additional, Etain, Bruno, additional, Fan, Chun Chieh, additional, Farh, Kai-How, additional, Farrell, Martilias S., additional, Flickinger, Matthew, additional, Foroud, Tatiana M., additional, Forty, Liz, additional, Frank, Josef, additional, Franke, Lude, additional, Fraser, Christine, additional, Freedman, Robert, additional, Freeman, Colin, additional, Freimer, Nelson B., additional, Friedman, Joseph I., additional, Fromer, Menachem, additional, Frye, Mark A., additional, Fullerton, Janice M., additional, Gade, Katrin, additional, Garnham, Julie, additional, Gaspar, Helena A., additional, Gejman, Pablo V., additional, Genovese, Giulio, additional, Georgieva, Lyudmila, additional, Giambartolomei, Claudia, additional, Giannoulatou, Eleni, additional, Giegling, Ina, additional, Gill, Michael, additional, Gillman, Matthew, additional, Pedersen, Marianne Giortz, additional, Giusti-Rodriguez, Paola, additional, Godard, Stephanie, additional, Goes, Fernando, additional, Goldstein, Jacqueline I., additional, Gopal, Srihari, additional, Gordon, Scott D., additional, Gordon-Smith, Katherine, additional, Gratten, Jacob, additional, Gray, Emma, additional, Green, Elaine K., additional, Green, Melissa J., additional, Greenwood, Tiffany A., additional, Grigoroiu-Serbanescu, Maria, additional, Grove, Jakob, additional, Guan, Weihua, additional, Gurling, Hugh, additional, Parra, Jose Guzman, additional, Gwilliam, Rhian, additional, de Haan, Lieuwe, additional, Hall, Jeremy, additional, Hall, Mei-Hua, additional, Hammer, Christian, additional, Hammond, Naomi, additional, Hamshere, Marian L., additional, Hansen, Mark, additional, Hansen, Thomas, additional, Haroutunian, Vahram, additional, Hartmann, Annette M., additional, Hauser, Joanna, additional, Hautzinger, Martin, additional, Heilbronner, Urs, additional, Hellenthal, Garrett, additional, Henskens, Frans A., additional, Herms, Stefan, additional, Hipolito, Maria, additional, Hirschhorn, Joel N., additional, Hoffmann, Per, additional, Hollegaard, Mads V., additional, Hougaard, David M., additional, Huang, Hailiang, additional, Huckins, Laura, additional, Hultman, Christina M., additional, Hunt, Sarah E., additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Iyegbe, Conrad, additional, Jablensky, Assen V., additional, Jamain, Stephane, additional, Jankowski, Janusz, additional, Jayakumar, Alagurevathi, additional, Joa, Inge, additional, Jones, Ian, additional, Jones, Lisa A., additional, Jonsson, Erik G., additional, Julia, Antonio, additional, Jureus, Anders, additional, Kahler, Anna K., additional, Kahn, Rene S., additional, Kalaydjieva, Luba, additional, Kandaswamy, Radhika, additional, Karachanak-Yankova, Sena, additional, Karjalainen, Juha, additional, Karlsson, Robert, additional, Kavanagh, David, additional, Keller, Matthew C., additional, Kelly, Brian J., additional, Kelsoe, John, additional, Kennedy, James L., additional, Khrunin, Andrey, additional, Kim, Yunjung, additional, Kirov, George, additional, Kittel-Schneider, Sarah, additional, Klovins, Janis, additional, Knight, Jo, additional, Knott, Sarah V., additional, Knowles, James A., additional, Kogevinas, Manolis, additional, Konte, Bettina, additional, Kravariti, Eugenia, additional, Kucinskas, Vaidutis, additional, Kucinskiene, Zita Ausrele, additional, Kupka, Ralph, additional, Kuzelova-Ptackova, Hana, additional, Landen, Mikael, additional, Langford, Cordelia, additional, Laurent, Claudine, additional, Lawrence, Jacob, additional, Lawrie, Stephen, additional, Lawson, William B., additional, Leber, Markus, additional, Leboyer, Marion, additional, Lee, Phil H., additional, Keong, Jimmy Lee Chee, additional, Legge, Sophie E., additional, Lencz, Todd, additional, Lerer, Bernard, additional, Levinson, Douglas F., additional, Levy, Shawn E., additional, Lewis, Cathryn M., additional, Li, Jun Z., additional, Li, Miaoxin, additional, Li, Qingqin S., additional, Li, Tao, additional, Liang, Kung-Yee, additional, Liddle, Jennifer, additional, Lieberman, Jeffrey, additional, Limborska, Svetlana, additional, Lin, Kuang, additional, Linszen, Don H., additional, Lissowska, Jolanta, additional, Liu, Chunyu, additional, Liu, Jianjun, additional, Lonnqvist, Jouko, additional, Loughland, Carmel M., additional, Lubinski, Jan, additional, Lucae, Susanne, additional, Macek, Milan, additional, MacIntyre, Donald J., additional, Magnusson, Patrik K.E., additional, Maher, Brion S., additional, Mahon, Pamela B., additional, Maier, Wolfgang, additional, Malhotra, Anil K., additional, Mallet, Jacques, additional, Malt, Ulrik F., additional, Markus, Hugh S., additional, Marsal, Sara, additional, Martin, Nicholas G., additional, Mata, Ignacio, additional, Mathew, Christopher G., additional, Mattheisen, Manuel, additional, Mattingsdal, Morten, additional, Mayoral, Fermin, additional, McCann, Owen T., additional, McCarley, Robert W., additional, McCarroll, Steven A., additional, McCarthy, Mark I., additional, McDonald, Colm, additional, McElroy, Susan L., additional, McGuffin, Peter, additional, McInnis, Melvin G., additional, McIntosh, Andrew M., additional, McKay, James D., additional, McMahon, Francis J., additional, Medeiros, Helena, additional, Medland, Sarah E., additional, Meier, Sandra, additional, Meijer, Carin J., additional, Melegh, Bela, additional, Melle, Ingrid, additional, Meng, Fan, additional, Mesholam-Gately, Raquelle I., additional, Metspalu, Andres, additional, Michie, Patricia T., additional, Milani, Lili, additional, Milanova, Vihra, additional, Mitchell, Philip B., additional, Mokrab, Younes, additional, Montgomery, Grant W., additional, Moran, Jennifer L., additional, Morken, Gunnar, additional, Morris, Derek W., additional, Mors, Ole, additional, Mortensen, Preben B., additional, Mowry, Bryan J., additional, Mühleisen, Thomas W., additional, Müller-Myhsok, Bertram, additional, Murphy, Kieran C., additional, Murray, Robin M., additional, Myers, Richard M., additional, Myin-Germeys, Inez, additional, Neale, Benjamin M., additional, Nelis, Mari, additional, Nenadic, Igor, additional, Nertney, Deborah A., additional, Nestadt, Gerald, additional, Nicodemus, Kristin K., additional, Nievergelt, Caroline M., additional, Nikitina-Zake, Liene, additional, Nimgaonkar, Vishwajit, additional, Nisenbaum, Laura, additional, Nordentoft, Merete, additional, Nordin, Annelie, additional, Nöthen, Markus M., additional, Nwulia, Evaristus A., additional, O’Callaghan, Eadbhard, additional, O’Donovan, Claire, additional, O’Dushlaine, Colm, additional, O’Neill, F. Anthony, additional, Oedegaard, Ketil J., additional, Oh, Sang-Yun, additional, Olincy, Ann, additional, Olsen, Line, additional, Oruc, Lilijana, additional, Van Os, Jim, additional, Owen, Michael J., additional, Paciga, Sara A., additional, Palmer, Colin N.A., additional, Palotie, Aarno, additional, Pantelis, Christos, additional, Papadimitriou, George N., additional, Parkhomenko, Elena, additional, Pato, Carlos, additional, Pato, Michele T., additional, Paunio, Tiina, additional, Pearson, Richard, additional, Perkins, Diana O., additional, Perlis, Roy H., additional, Perry, Amy, additional, Pers, Tune H., additional, Petryshen, Tracey L., additional, Pfennig, Andrea, additional, Picchioni, Marco, additional, Pietilainen, Olli, additional, Pimm, Jonathan, additional, Pirinen, Matti, additional, Plomin, Robert, additional, Pocklington, Andrew J., additional, Posthuma, Danielle, additional, Potash, James B., additional, Potter, Simon C., additional, Powell, John, additional, Price, Alkes, additional, Pulver, Ann E., additional, Purcell, Shaun M., additional, Quested, Digby, additional, Ramos-Quiroga, Josep Antoni, additional, Rasmussen, Henrik B., additional, Rautanen, Anna, additional, Ravindrarajah, Radhi, additional, Regeer, Eline J., additional, Reichenberg, Abraham, additional, Reif, Andreas, additional, Reimers, Mark A., additional, Ribases, Marta, additional, Rice, John P., additional, Richards, Alexander L., additional, Ricketts, Michelle, additional, Riley, Brien P., additional, Rivas, Fabio, additional, Rivera, Margarita, additional, Roffman, Joshua L., additional, Rouleau, Guy A., additional, Roussos, Panos, additional, Rujescu, Dan, additional, Salomaa, Veikko, additional, Sanchez-Mora, Cristina, additional, Sanders, Alan R., additional, Sawcer, Stephen J., additional, Schall, Ulrich, additional, Schatzberg, Alan F., additional, Scheftner, William A., additional, Schofield, Peter R., additional, Schork, Nicholas J., additional, Schwab, Sibylle G., additional, Scolnick, Edward M., additional, Scott, Laura J., additional, Scott, Rodney J., additional, Seidman, Larry J., additional, Serretti, Alessandro, additional, Sham, Pak C., additional, Weickert, Cynthia Shannon, additional, Shehktman, Tatyana, additional, Shi, Jianxin, additional, Shilling, Paul D., additional, Sigurdsson, Engilbert, additional, Silverman, Jeremy M., additional, Sim, Kang, additional, Slaney, Claire, additional, Slominsky, Petr, additional, Smeland, Olav B., additional, Smoller, Jordan W., additional, So, Hon-Cheong, additional, Sobell, Janet L., additional, Soderman, Erik, additional, Hansen, Christine Soholm, additional, Spencer, Chris C.A., additional, Spijker, Anne T., additional, St Clair, David, additional, Stefansson, Hreinn, additional, Stefansson, Kari, additional, Steinberg, Stacy, additional, Stogmann, Elisabeth, additional, Stordal, Eystein, additional, Strange, Amy, additional, Straub, Richard E., additional, Strauss, John S., additional, Streit, Fabian, additional, Strengman, Eric, additional, Strohmaier, Jana, additional, Stroup, T. Scott, additional, Su, Zhan, additional, Subramaniam, Mythily, additional, Suvisaari, Jaana, additional, Svrakic, Dragan M., additional, Szatkiewicz, Jin P., additional, Szelinger, Szabolcs, additional, Tashakkori-Ghanbaria, Avazeh, additional, Thirumalai, Srinivas, additional, Thompson, Robert C., additional, Thorgeirsson, Thorgeir E., additional, Toncheva, Draga, additional, Tooney, Paul A., additional, Tosato, Sarah, additional, Toulopoulou, Timothea, additional, Trembath, Richard C., additional, Treutlein, Jens, additional, Turecki, Gustavo, additional, Vaaler, Arne E., additional, Vedder, Helmut, additional, Vieta, Eduard, additional, Vincent, John, additional, Visscher, Peter M., additional, Viswanathan, Ananth C., additional, Vukcevic, Damjan, additional, Waddington, John, additional, Waller, Matthew, additional, Walsh, Dermot, additional, Walshe, Muriel, additional, Walters, James T.R., additional, Wang, Dai, additional, Wang, Qiang, additional, Wang, Weiqing, additional, Wang, Yunpeng, additional, Watson, Stanley J., additional, Webb, Bradley T., additional, Weickert, Thomas W., additional, Weinberger, Daniel R., additional, Weisbrod, Matthias, additional, Weiser, Mark, additional, Werge, Thomas, additional, Weston, Paul, additional, Whittaker, Pamela, additional, Widaa, Sara, additional, Wiersma, Durk, additional, Wildenauer, Dieter B., additional, Williams, Nigel M., additional, Williams, Stephanie, additional, Witt, Stephanie H., additional, Wolen, Aaron R., additional, Wong, Emily H.M., additional, Wood, Nicholas W., additional, Wormley, Brandon K., additional, Wu, Jing Qin, additional, Xi, Simon, additional, Xu, Wei, additional, Young, Allan H., additional, Zai, Clement C., additional, Zandi, Peter, additional, Zhang, Peng, additional, Zheng, Xuebin, additional, Zimprich, Fritz, additional, Zollner, Sebastian, additional, Corvin, Aiden, additional, Fanous, Ayman H., additional, Cichon, Sven, additional, Rietschel, Marcella, additional, Gershon, Elliot S., additional, Schulze, Thomas G., additional, Cuellar-Barboza, Alfredo B., additional, Forstner, Andreas J., additional, Holmans, Peter A., additional, Nurnberger, John I., additional, Andreassen, Ole A., additional, Lee, S. Hong, additional, O’Donovan, Michael C., additional, Sullivan, Patrick F., additional, Ophoff, Roel A., additional, Wray, Naomi R., additional, Sklar, Pamela, additional, and Kendler, Kenneth S., additional

Published
2018
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49. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Author

Marshall, Christian R., Howrigan, Daniel P., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Holmans, Peter A., Pinto, Dalila, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Wang, Zhouzhi, Fajarado, Karin V. Fuentes, Maile, Michelle S., Ripke, Stephan, Agartz, Ingrid, Albus, Margot, Alexander, Madeline, Amin, Farooq, Atkins, Joshua, Bacanu, Silviu A., Belliveau, Richard A., Jr., Bergen, Sarah E., Ertalan, Marcelo, Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Bulik-Sullivan, Brendan, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J., Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberley D., Cheng, Wei, Cloninger, C. Robert, Cohen, David, Cormican, Paul, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E., Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farh, Kai-How, Farrell, Martilias S., Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedman, Joseph I., Forstner, Andreas J., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S., Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Gratten, Jacob, de Haan, Lieuwe, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffinann, Per, Hofman, Andrea, Huang, Hailiang, Ikeda, Masashi, Joa, Inge, Kahler, Anna K., Kahn, Rene S., Kalaydjieva, Luba, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kelly, Brian J., Kennedy, James L., Kim, Yunjung, Knowles, James A., Konte, Bettina, Laurent, Claudine, Lee, Phil, Lee, S. Hong, Legge, Sophie E., Lerer, Bernard, Levy, Deborah L., Liang, Kung-Yee, Lieberman, Jeffrey, Lonnqvist, Jouko, Loughland, Carmel M., Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Muller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, O'Neill, F. Anthony, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Perkins, Diana O., Pers, Tune H., Pietilainen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Savitz, Adam, Schall, Ulrich, Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Silverman, Jeremy M., Smoller, Jordan W., Soderman, Erik, Spencer, Chris C. A., Stahl, Eli A., Strengman, Eric, Strohmaier, Jana, Stroup, T. Scott, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Thirumalai, Srinivas, Tooney, Paul A., Veijola, Juha, Visscher, Peter M., Waddington, John, Walsh, Dermot, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wormley, Brandon K., Wray, Naomi R., Wu, Jing Qin, Zai, Clement C., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H. R., Bramon, Elvira, Buxbaum, Joseph D., Cichon, Sven, Collier, David A., Corvin, Aiden, Daly, Mark J., Darvasi, Ariel, Domenici, Enrico, Esko, Tonu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jonsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Levinson, Douglas F., Li, Qingqin S., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mowry, Bryan J., Nothen, Markus M., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P., Rujescu, Dan, Sklar, Pamela, St Clair, David, Walters, James T. R., Werge, Thomas, Siillivan, Patrick F., O'Donovan, Michael C., Scherer, Stephen W., Neale, Benjamin M., Sebat, Jonathan, Marshall, Christian R., Howrigan, Daniel P., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Holmans, Peter A., Pinto, Dalila, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Wang, Zhouzhi, Fajarado, Karin V. Fuentes, Maile, Michelle S., Ripke, Stephan, Agartz, Ingrid, Albus, Margot, Alexander, Madeline, Amin, Farooq, Atkins, Joshua, Bacanu, Silviu A., Belliveau, Richard A., Jr., Bergen, Sarah E., Ertalan, Marcelo, Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Bulik-Sullivan, Brendan, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J., Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberley D., Cheng, Wei, Cloninger, C. Robert, Cohen, David, Cormican, Paul, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E., Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farh, Kai-How, Farrell, Martilias S., Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedman, Joseph I., Forstner, Andreas J., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S., Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Gratten, Jacob, de Haan, Lieuwe, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffinann, Per, Hofman, Andrea, Huang, Hailiang, Ikeda, Masashi, Joa, Inge, Kahler, Anna K., Kahn, Rene S., Kalaydjieva, Luba, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kelly, Brian J., Kennedy, James L., Kim, Yunjung, Knowles, James A., Konte, Bettina, Laurent, Claudine, Lee, Phil, Lee, S. Hong, Legge, Sophie E., Lerer, Bernard, Levy, Deborah L., Liang, Kung-Yee, Lieberman, Jeffrey, Lonnqvist, Jouko, Loughland, Carmel M., Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Muller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, O'Neill, F. Anthony, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Perkins, Diana O., Pers, Tune H., Pietilainen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Savitz, Adam, Schall, Ulrich, Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Silverman, Jeremy M., Smoller, Jordan W., Soderman, Erik, Spencer, Chris C. A., Stahl, Eli A., Strengman, Eric, Strohmaier, Jana, Stroup, T. Scott, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Thirumalai, Srinivas, Tooney, Paul A., Veijola, Juha, Visscher, Peter M., Waddington, John, Walsh, Dermot, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wormley, Brandon K., Wray, Naomi R., Wu, Jing Qin, Zai, Clement C., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H. R., Bramon, Elvira, Buxbaum, Joseph D., Cichon, Sven, Collier, David A., Corvin, Aiden, Daly, Mark J., Darvasi, Ariel, Domenici, Enrico, Esko, Tonu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jonsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Levinson, Douglas F., Li, Qingqin S., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mowry, Bryan J., Nothen, Markus M., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P., Rujescu, Dan, Sklar, Pamela, St Clair, David, Walters, James T. R., Werge, Thomas, Siillivan, Patrick F., O'Donovan, Michael C., Scherer, Stephen W., Neale, Benjamin M., and Sebat, Jonathan

Abstract

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Published
2017
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