Mapping genomic loci implicates genes and synaptic biology in schizophrenia.
Nature
Authors:
Vassily Trubetskoy, Antonio F Pardiñas, Ting Qi, Georgia Panagiotaropoulou, Swapnil Awasthi, Tim B Bigdeli, Julien Bryois, Chia-Yen Chen, Charlotte A Dennison, Lynsey S Hall, Max Lam, Kyoko Watanabe, Oleksandr Frei, Tian Ge, Janet C Harwood, Frank Koopmans, Sigurdur Magnusson, Alexander L Richards, Julia Sidorenko, Yang Wu, Jian Zeng, Jakob Grove, Minsoo Kim, Zhiqiang Li, Georgios Voloudakis, Wen Zhang, Mark Adams, Ingrid Agartz, Elizabeth G Atkinson, Esben Agerbo, Mariam Al Eissa, Margot Albus, Madeline Alexander, Behrooz Z Alizadeh, Köksal Alptekin, Thomas D Als, Farooq Amin, Volker Arolt, Manuel Arrojo, Lavinia Athanasiu, Maria Helena Azevedo, Silviu A Bacanu, Nicholas J Bass, Martin Begemann, Richard A Belliveau, Judit Bene, Beben Benyamin, Sarah E Bergen, Giuseppe Blasi, Julio Bobes, Stefano Bonassi, Alice Braun, Rodrigo Affonseca Bressan, Evelyn J Bromet, Richard Bruggeman, Peter F Buckley, Randy L Buckner, Jonas Bybjerg-Grauholm, Wiepke Cahn, Murray J Cairns, Monica E Calkins, Vaughan J Carr, David Castle, Stanley V Catts, Kimberley D Chambert, Raymond C K Chan, Boris Chaumette, Wei Cheng, Eric F C Cheung, Siow Ann Chong, David Cohen, Angèle Consoli, Quirino Cordeiro, Javier Costas, Charles Curtis, Michael Davidson, Kenneth L Davis, Lieuwe de Haan, Franziska Degenhardt, Lynn E DeLisi, Ditte Demontis, Faith Dickerson, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Jubao Duan, Giuseppe Ducci, Frank Dudbridge, Johan G Eriksson, Lourdes Fañanás, Stephen V Faraone, Alessia Fiorentino, Andreas Forstner, Josef Frank, Nelson B Freimer, Menachem Fromer, Alessandra Frustaci, Ary Gadelha, Giulio Genovese, Elliot S Gershon, Marianna Giannitelli, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I Goldstein, Javier González Peñas, Ana González-Pinto, Srihari Gopal, Jacob Gratten, Michael F Green, Tiffany A Greenwood, Olivier Guillin, Sinan Gülöksüz, Raquel E Gur, Ruben C Gur, Blanca Gutiérrez, Eric Hahn, Hakon Hakonarson, Vahram Haroutunian, Annette M Hartmann, Carol Harvey, Caroline Hayward, Frans A Henskens, Stefan Herms, Per Hoffmann, Daniel P Howrigan, Masashi Ikeda, Conrad Iyegbe, Inge Joa, Antonio Julià, Anna K Kähler, Tony Kam-Thong, Yoichiro Kamatani, Sena Karachanak-Yankova, Oussama Kebir, Matthew C Keller, Brian J Kelly, Andrey Khrunin, Sung-Wan Kim, Janis Klovins, Nikolay Kondratiev, Bettina Konte, Julia Kraft, Michiaki Kubo, Vaidutis Kučinskas, Zita Ausrele Kučinskiene, Agung Kusumawardhani, Hana Kuzelova-Ptackova, Stefano Landi, Laura C Lazzeroni, Phil H Lee, Sophie E Legge, Douglas S Lehrer, Rebecca Lencer, Bernard Lerer, Miaoxin Li, Jeffrey Lieberman, Gregory A Light, Svetlana Limborska, Chih-Min Liu, Jouko Lönnqvist, Carmel M Loughland, Jan Lubinski, Jurjen J Luykx, Amy Lynham, Milan Macek, Andrew Mackinnon, Patrik K E Magnusson, Brion S Maher, Wolfgang Maier, Dolores Malaspina, Jacques Mallet, Stephen R Marder, Sara Marsal, Alicia R Martin, Lourdes Martorell, Manuel Mattheisen, Robert W McCarley, Colm McDonald, John J McGrath, Helena Medeiros, Sandra Meier, Bela Melegh, Ingrid Melle, Raquelle I Mesholam-Gately, Andres Metspalu, Patricia T Michie, Lili Milani, Vihra Milanova, Marina Mitjans, Espen Molden, Esther Molina, María Dolores Molto, Valeria Mondelli, Carmen Moreno, Christopher P Morley, Gerard Muntané, Kieran C Murphy, Inez Myin-Germeys, Igor Nenadić, Gerald Nestadt, Liene Nikitina-Zake, Cristiano Noto, Keith H Nuechterlein, Niamh Louise O'Brien, F Anthony O'Neill, Sang-Yun Oh, Ann Olincy, Vanessa Kiyomi Ota, Christos Pantelis, George N Papadimitriou, Mara Parellada, Tiina Paunio, Renata Pellegrino, Sathish Periyasamy, Diana O Perkins, Bruno Pfuhlmann, Olli Pietiläinen, Jonathan Pimm, David Porteous, John Powell, Diego Quattrone, Digby Quested, Allen D Radant, Antonio Rampino, Mark H Rapaport, Anna Rautanen, Abraham Reichenberg, Cheryl Roe, Joshua L Roffman, Julian Roth, Matthias Rothermundt, Bart P F Rutten, Safaa Saker-Delye, Veikko Salomaa, Julio Sanjuan, Marcos Leite Santoro, Adam Savitz, Ulrich Schall, Rodney J Scott, Larry J Seidman, Sally Isabel Sharp, Jianxin Shi, Larry J Siever, Engilbert Sigurdsson, Kang Sim, Nora Skarabis, Petr Slominsky, Hon-Cheong So, Janet L Sobell, Erik Söderman, Helen J Stain, Nils Eiel Steen, Agnes A Steixner-Kumar, Elisabeth Stögmann, William S Stone, Richard E Straub, Fabian Streit, Eric Strengman, T Scott Stroup, Mythily Subramaniam, Catherine A Sugar, Jaana Suvisaari, Dragan M Svrakic, Neal R Swerdlow, Jin P Szatkiewicz, Thi Minh Tam Ta, Atsushi Takahashi, Chikashi Terao, Florence Thibaut, Draga Toncheva, Paul A Tooney, Silvia Torretta, Sarah Tosato, Gian Battista Tura, Bruce I Turetsky, Alp Üçok, Arne Vaaler, Therese van Amelsvoort, Ruud van Winkel, Juha Veijola, John Waddington, Henrik Walter, Anna Waterreus, Bradley T Webb, Mark Weiser, Nigel M Williams, Stephanie H Witt, Brandon K Wormley, Jing Qin Wu, Zhida Xu, Robert Yolken, Clement C Zai, Wei Zhou, Feng Zhu, Fritz Zimprich, Eşref Cem Atbaşoğlu, Muhammad Ayub, Christian Benner, Alessandro Bertolino, Donald W Black, Nicholas J Bray, Gerome Breen, Nancy G Buccola, William F Byerley, Wei J Chen, C Robert Cloninger, Benedicto Crespo-Facorro, Gary Donohoe, Robert Freedman, Cherrie Galletly, Michael J Gandal, Massimo Gennarelli, David M Hougaard, Hai-Gwo Hwu, Assen V Jablensky, Steven A McCarroll, Jennifer L Moran, Ole Mors, Preben B Mortensen, Bertram Müller-Myhsok, Amanda L Neil, Merete Nordentoft, Michele T Pato, Tracey L Petryshen, Matti Pirinen, Ann E Pulver, Thomas G Schulze, Jeremy M Silverman, Jordan W Smoller, Eli A Stahl, Debby W Tsuang, Elisabet Vilella, Shi-Heng Wang, Shuhua Xu, Rolf Adolfsson, Celso Arango, Bernhard T Baune, Sintia Iole Belangero, Anders D Børglum, David Braff, Elvira Bramon, Joseph D Buxbaum, Dominique Campion, Jorge A Cervilla, Sven Cichon, David A Collier, Aiden Corvin, David Curtis, Marta Di Forti, Enrico Domenici, Hannelore Ehrenreich, Valentina Escott-Price, Tõnu Esko, Ayman H Fanous, Anna Gareeva, Micha Gawlik, Pablo V Gejman, Michael Gill, Stephen J Glatt, Vera Golimbet, Kyung Sue Hong, Christina M Hultman, Steven E Hyman, Nakao Iwata, Erik G Jönsson, René S Kahn, James L Kennedy, Elza Khusnutdinova, George Kirov, James A Knowles, Marie-Odile Krebs, Claudine Laurent-Levinson, Jimmy Lee, Todd Lencz, Douglas F Levinson, Qingqin S Li, Jianjun Liu, Anil K Malhotra, Dheeraj Malhotra, Andrew McIntosh, Andrew McQuillin, Paulo R Menezes, Vera A Morgan, Derek W Morris, Bryan J Mowry, Robin M Murray, Vishwajit Nimgaonkar, Markus M Nöthen, Roel A Ophoff, Sara A Paciga, Aarno Palotie, Carlos N Pato, Shengying Qin, Marcella Rietschel, Brien P Riley, Margarita Rivera, Dan Rujescu, Meram C Saka, Alan R Sanders, Sibylle G Schwab, Alessandro Serretti, Pak C Sham, Yongyong Shi, David St Clair, Hreinn Stefánsson, Kari Stefansson, Ming T Tsuang, Jim van Os, Marquis P Vawter, Daniel R Weinberger, Thomas Werge, Dieter B Wildenauer, Xin Yu, Weihua Yue, Peter A Holmans, Andrew J Pocklington, Panos Roussos, Evangelos Vassos, Matthijs Verhage, Peter M Visscher, Jian Yang, Danielle Posthuma, Ole A Andreassen, Kenneth S Kendler, Michael J Owen, Naomi R Wray, Mark J Daly, Hailiang Huang, Benjamin M Neale, Patrick F Sullivan, Stephan Ripke, James T R Walters, Michael C O'Donovan
Schizophrenia has a heritability of 60-80%, 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.