Mapping genomic loci implicates genes and synaptic biology in schizophrenia

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Trubetskoy, Vassily ; Pardinas, 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, Koksal ; Als, Thomas D. ; Amin, Farooq ; Arolt, Volker ; Arrojo, Manuel ; Athanasiu, Lavinia ; Azevedo, Maria Helena ; Bacanu, Silviu A. ; Bass, Nicholas J. ; Begemann, Martin ; Belliveau, Richard A. ; Bene, Judit ; Benyamin, Beben ; Bergen, Sarah E. ; Blasi, Giuseppe ; Bobes, Julio ; Bonassi, Stefano ; Braun, Alice ; Bressan, Rodrigo Affonseca ; Bromet, Evelyn J. ; Bruggeman, Richard ; Buckley, Peter F. ; Buckner, Randy L. ; Bybjerg-Grauholm, Jonas ; Cahn, Wiepke ; Cairns, Murray J. ; Calkins, Monica E. ; Carr, Vaughan J. ; Castle, David ; Catts, Stanley, V ; Chambert, Kimberley D. ; Chan, Raymond C. K. ; Chaumette, Boris ; Cheng, Wei ; Cheung, Eric F. C. ; Chong, Siow Ann ; Cohen, David ; Consoli, 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-Rodriguez, Paola ; Godard, Stephanie ; Goldstein, Jacqueline, I ; Penas, Javier Gonzalez ; Gonzalez-Pinto, Ana ; Gopal, Srihari ; Gratten, Jacob ; Green, Michael F. ; Greenwood, Tiffany A. ; Guillin, Olivier ; Guloksuz, Sinan ; Gur, Raquel E. ; Gur, Ruben C. ; Gutierrez, 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 ; Julia, Antonio ; Kahler, 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 ; Kucinskas, Vaidutis ; Kucinskiene, Zita Ausrele ; Kusumawardhani, Agung ; A-Ptackova, Hana Kuzelov ; Landi, Stefano ; Lazzeroni, Laura C. ; Lee, Phil H. ; Legge, Sophie E. ; Lehrer, Douglas S. ; Lencer, Rebecca ; Lerer, Bernard ; Li, Miaoxin ; Lieberman, Jeffrey ; Light, Gregory A. ; Limborska, Svetlana ; Liu, Chih-Min ; Lonnqvist, Jouko ; Loughland, Carmel M. ; Lubinski, Jan ; Luykx, Jurjen J. ; Lynham, Amy ; Macek, Milan, Jr. ; Mackinnon, Andrew ; Magnusson, Patrik K. E. ; Maher, Brion S. ; Maier, Wolfgang ; Malaspina, Dolores ; Mallet, Jacques ; Marder, Stephen R. ; Marsal, Sara ; Martin, Alicia R. ; Martorell, Lourdes ; Mattheisen, Manuel ; McCarley, Robert W. ; McDonald, Colm ; McGrath, John J. ; Medeiros, Helena ; Meier, Sandra ; Melegh, Bela ; Melle, Ingrid ; Mesholam-Gately, Raquelle, I ; Metspalu, Andres ; Michie, Patricia T. ; Milani, Lili ; Milanova, Vihra ; Mitjans, Marina ; Molden, Espen ; Molina, Esther ; Molto, Maria Dolores ; Mondelli, Valeria ; Moreno, Carmen ; Morley, Christopher P. ; Muntane, Gerard ; Murphy, Kieran C. ; Myin-Germeys, Inez ; Nenadic, Igor ; Nestadt, Gerald ; Nikitina-Zake, Liene ; Noto, Cristiano ; Nuechterlein, Keith H. ; O'Brien, Niamh Louise ; O'Neill, F. Anthony ; Oh, Sang-Yun ; Olincy, Ann ; Ota, Vanessa Kiyomi ; Pantelis, Christos ; Papadimitriou, George N. ; Parellada, Mara ; Paunio, Tiina ; Pellegrino, Renata ; Periyasamy, Sathish ; Perkins, Diana O. ; Pfuhlmann, Bruno ; 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, Veikko ; Sanjuan, Julio ; Santoro, Marcos Leite ; Savitz, Adam ; Schall, Ulrich ; Scott, Rodney J. ; Seidman, Larry J. ; Sharp, Sally Isabel ; Shi, Jianxin ; Siever, Larry J. ; Sigurdsson, Engilbert ; Sim, Kang ; Skarabis, Nora ; Slominsky, Petr ; So, Hon-Cheong ; Sobell, Janet L. ; Soderman, Erik ; Stain, Helen J. ; Steen, Nils Eiel ; Steixner-Kumar, Agnes A. ; Stogmann, Elisabeth ; Stone, William S. ; Straub, Richard E. ; Streit, Fabian ; Strengman, Eric ; Stroup, T. Scott ; Subramaniam, Mythily ; Sugar, Catherine A. ; Suvisaari, Jaana ; Svrakic, Dragan M. ; Swerdlow, Neal R. ; Szatkiewicz, Jin P. ; Thi Minh Tam Ta ; Takahashi, Atsushi ; Terao, Chikashi ; Thibaut, Florence ; Toncheva, Draga ; Tooney, Paul A. ; Torretta, Silvia ; Tosato, Sarah ; Tura, Gian Battista ; Turetsky, Bruce, I ; Ucok, Alp ; Vaaler, Arne ; van Amelsvoort, Therese ; van Winkel, Ruud ; Veijola, Juha ; Waddington, John ; Walter, Henrik ; Waterreus, Anna ; Webb, Bradley T. ; Weiser, Mark ; Williams, Nigel M. ; Witt, Stephanie H. ; Wormley, Brandon K. ; Wu, Jing Qin ; Xu, Zhida ; Yolken, Robert ; Zai, Clement C. ; Zhou, Wei ; Zhu, Feng ; Zimprich, Fritz ; Ayub, Muhammad ; Benner, Christian ; Bertolino, Alessandro ; Black, Donald W. ; Bray, Nicholas J. ; Breen, Gerome ; Buccola, Nancy G. ; Byerley, William F. ; Chen, Wei J. ; Cloninger, C. Robert ; Crespo-Facorro, Benedicto ; Donohoe, Gary ; Freedman, Robert ; Galletly, Cherrie ; Gandal, Michael J. ; Gennarelli, Massimo ; Hougaard, David M. ; Hwu, Hai-Gwo ; Jablensky, Assen, V ; McCarroll, Steven A. ; Moran, Jennifer L. ; Mors, Ole ; Mortensen, Preben B. ; Muller-Myhsok, Bertram ; Neil, Amanda L. ; Nordentoft, Merete ; Pato, Michele T. ; Petryshen, Tracey L. ; Pirinen, Matti ; Pulver, Ann E. ; Schulze, Thomas G. ; Silverman, Jeremy M. ; Smoller, Jordan W. ; Stahl, Eli A. ; Tsuang, Debby W. ; Vilella, Elisabet ; Wang, Shi-Heng ; Xu, Shuhua ; Adolfsson, Rolf ; Arango, Celso ; Baune, Bernhard T. ; Belangero, Sintia Iole ; Borglum, Anders D. ; Braff, David ; Bramon, Elvira ; Buxbaum, Joseph D. ; Campion, Dominique ; Cervilla, Jorge A. ; Cichon, Sven ; Collier, David A. ; Corvin, Aiden ; Curtis, David ; Di Forti, Marta ; Domenici, Enrico ; Ehrenreich, Hannelore ; Escott-Price, Valentina ; Esko, Tonu ; Fanous, Ayman H. ; Gareeva, Anna ; Gawlik, Micha ; Gejman, Pablo, V ; Gill, Michael ; Glatt, Stephen J. ; Golimbet, Vera ; Hong, Kyung Sue ; Hultman, Christina M. ; Hyman, Steven E. ; Iwata, Nakao ; Jonsson, Erik G. ; Kahn, Rene S. ; Kennedy, James L. ; Khusnutdinova, Elza ; Kirov, George ; Knowles, James A. ; Krebs, Marie-Odile ; Laurent-Levinson, Claudine ; Lee, Jimmy ; Lencz, Todd ; Levinson, Douglas F. ; Li, Qingqin S. ; Liu, Jianjun ; Malhotra, Anil K. ; Malhotra, Dheeraj ; McIntosh, Andrew ; McQuillin, Andrew ; Menezes, Paulo R. ; Morgan, Vera A. ; Morris, Derek W. ; Mowry, Bryan J. ; Murray, Robin M. ; Nimgaonkar, Vishwajit ; Nothen, Markus M. ; Ophoff, Roel A. ; Paciga, Sara A. ; Palotie, Aarno ; Pato, Carlos N. ; Qin, Shengying ; Rietschel, Marcella ; Riley, Brien P. ; Rivera, Margarita ; Rujescu, Dan ; Saka, Meram C. ; Sanders, Alan R. ; Schwab, Sibylle G. ; Serretti, Alessandro ; Sham, Pak C. ; Shi, Yongyong ; St Clair, David ; Stefansson, Hreinn ; Stefansson, Kari ; Tsuang, Ming T. ; van Os, Jim ; Vawter, Marquis P. ; Weinberger, Daniel R. ; Werge, Thomas ; Wildenauer, Dieter B. ; Yu, Xin ; Yue, Weihua ; Holmans, Peter A. ; Pocklington, Andrew J. ; Roussos, Panos ; Vassos, Evangelos ; Verhage, Matthijs ; Visscher, Peter M. ; Yang, Jian ; Posthuma, Danielle ; Andreassen, Ole A. ; Kendler, Kenneth S. ; Owen, Michael J. ; Wray, Naomi R. ; Daly, Mark J. ; Huang, Hailiang ; Neale, Benjamin M. ; Sullivan, Patrick F. ; Ripke, Stephan ; Walters, James T. R. ; O'Donovan, Michael C. ; Indonesia Schizophrenia Consortium ; PsychENCODE ; Psychosis Endophenotypes Int Conso ; SynGO Consortium ; Psychiat Genomics Consortium

• Document type: Journal article
• Source: Nature; v. 604, n. 7906, p. 24-pg., 2022-04-08.

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 identify120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including16 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 factorSP4, 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. (AU)

• FAPESP's process: 14/07280-1 - Search for genetic markers of risk, progression and response to treatment
• Grantee: Síntia Iole Nogueira Belangero
• Support Opportunities: Regular Research Grants
• FAPESP's process: 10/08968-6 - Investigation of genetic and epigenetic markers: a translational approach for schizophrenia treatment
• Grantee: Síntia Iole Nogueira Belangero
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/50740-5 - Prevention in schizophrenia and bipolar disorder from neuroscience to the community: a multiphase, multimodal and translational platform for research and intervention
• Grantee: Rodrigo Affonseca Bressan
• Support Opportunities: Research Projects - Thematic Grants