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Mapping genomic loci implicates genes and synaptic biology in schizophrenia

journal contribution
posted on 2022-06-14, 09:33 authored by Vassily Trubetskoy, Antonio F Pardinas, 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, Koksal 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 Catts, Kimberley D Chambert, Raymond CK Chan, Boris Chaumette, Wei Cheng, Eric FC Cheung, Siow Ann Chong, David Cohen, Angele 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 Fananas, Stephen 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-Rodriguez, Stephanie Godard, Jacqueline Goldstein, Javier Gonzalez Penas, Ana Gonzalez-Pinto, Srihari Gopal, Jacob Gratten, Michael F Green, Tiffany A Greenwood, Olivier Guillin, Sinan Guloksuz, Raquel E Gur, Ruben C Gur, Blanca Gutierrez, 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 Julia, Anna K Kahler, 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 Kucinskas, Zita Ausrele Kucinskiene, Agung Kusumawardhani, Hana Kuzelov A-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 Lonnqvist, Carmel M Loughland, Jan Lubinski, Jurjen J Luykx, Amy Lynham, Milan Macek, Andrew Mackinnon, Patrik KE 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 Mesholam-Gately, Andres Metspalu, Patricia T Michie, Lili Milani, Vihra Milanova, Marina Mitjans, Espen Molden, Esther Molina, Maria Dolores Molto, Valeria Mondelli, Carmen Moreno, Christopher P Morley, Gerard Muntane, Kieran C Murphy, Inez Myin-Germeys, Igor Nenadic, 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 Pietilainen, 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 PF 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 Soderman, Helen J Stain, Nils Eiel Steen, Agnes A Steixner-Kumar, Elisabeth Stogmann, 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, Minh Tam Ta Thi, Atsushi Takahashi, Chikashi Terao, Florence Thibaut, Draga Toncheva, Paul A Tooney, Silvia Torretta, Sarah Tosato, Gian Battista Tura, Bruce Turetsky, Alp Ucok, 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, 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 Jablensky, Steven A McCarroll, Jennifer L Moran, Ole Mors, Preben B Mortensen, Bertram Muller-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 Borglum, 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, Tonu Esko, Ayman H Fanous, Anna Gareeva, Micha Gawlik, Pablo Gejman, Michael Gill, Stephen J Glatt, Vera Golimbet, Kyung Sue Hong, Christina M Hultman, Steven E Hyman, Nakao Iwata, Erik G Jonsson, Rene 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 Nothen, 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 Stefansson, 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 TR Walters, Michael C O'Donovan
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.

Funding

The National Institute of Mental Health (USA) provides core funding for the PGC under award no. U01MH109514. The content is the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The work of the contributing groups was supported by numerous grants from governmental and charitable bodies as well as philanthropic donation (details in Supplementary Note). We acknowledge a substantial contribution from P. Sklar (deceased) as one of the PGC principal investigators, and E. Scolnick, whose support for this study was vital. We acknowledge the Wellcome Trust Case Control Consortium for the provision of control genotype information. Membership of the Psychosis Endophenotypes International Consortium, the SynGO consortium, the PsychENCODE Consortium, the eQTLGen consortium, the BIOS Consortium and the Indonesia Consortium are provided in the author list. We are grateful to C. Hopkins for illustrations. The work at Cardiff University was additionally supported by Medical Research Council Centre grant no. MR/L010305/1 and program grant no. G0800509. S. Xu also gratefully acknowledges the support of the National Natural Science Foundation of China (NSFC) grants (31525014, 91731303, 31771388, 31961130380 and 32041008), the UK Royal Society-Newton Advanced Fellowship (NAF\R1\191094), the Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) and the Strategic Priority Research Program (XDB38000000) of the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). O. A. Andreassen was supported by the Research Council of Norway (283798, 262656, 248980, 273291, 248828, 248778, 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, EU H2020 no. 847776. B. Melegh was supported in part by the National Scientific Research Program (NKFIH) K 138669. S. V. Faraone is supported by the European Union’s Seventh Framework Programme for research, technologi

History

Citation

Nature 604, 502–508 (2022). https://doi.org/10.1038/s41586-022-04434-5

Author affiliation

Department of Health Sciences, University of Leicester

Version

  • AM (Accepted Manuscript)

Published in

NATURE

Volume

604

Issue

7906

Pagination

502–508

Publisher

NATURE PORTFOLIO

issn

0028-0836

eissn

1476-4687

Acceptance date

2022-01-10

Copyright date

2022

Available date

2022-10-08

Spatial coverage

England

Language

English