Mapping genomic loci implicates genes and synaptic biology in schizophrenia

作者：V. Trubetskoy, A. Pardiñas, Ting Qi, G. Panagiotaropoulou, S. Awasthi, T. Bigdeli, J. Bryois, Chia-Yen Chen, Charlotte A. Dennison, L. Hall, Max W. Y. Lam, Kyoko Watanabe, O. Frei, T. Ge, J. Harwood, F. Koopmans, S. Magnússon, A. Richards, J. Sidorenko, Yang Wu, Jian Zeng, J. Grove, Minsoo Kim, Zhiqiang Li, G. Voloudakis, Wen Zhang, M. Adams, I. Agartz, Elizabeth G. Atkinson, E. Agerbo, M. A. Al Eissa, M. Albus, Madeline Alexander, B. Alizadeh, K. Alptekin, T. Als, F. Amin, V. Arolt, M. Arrojo, L. Athanasiu, M. Azevedo, S. Bacanu, N. Bass, M. Begemann, R. Belliveau, J. Bene, Beben Benyamin, Sarah E. Bergen, G. Blasi, J. Bobes, S. Bonassi, A. Braun, R. Bressan, E. Bromet, R. Bruggeman, P. Buckley, R. Buckner, J. Bybjerg-Grauholm, W. Cahn, M. Cairns, M. Calkins, V. Carr, D. Castle, S. Catts, Kimberley D. Chambert, R. Chan, B. Chaumette, Wei Cheng, E. Cheung, S. Chong, D. Cohen, A. Consoli, Q. Cordeiro, J. Costas, C. Curtis, Michal Davidson, K. Davis, L. de Haan, F. Degenhardt, L. DeLisi, D. Demontis, F. Dickerson, D. Dikeos, T. Dinan, S. Djurovic, J. Duan, G. Ducci, F. Dudbridge, J. Eriksson, L. Fañanás, S. Faraone, A. Fiorentino, A. Forstner, J. Frank, N. Freimer, M. Fromer, A. Frustaci, A. Gadelha, G. Genovese, E. Gershon, M. Giannitelli, I. Giegling, P. Giusti-Rodríguez, S. Godard, J. Goldstein, Javier González Peñas, A. González-Pinto, S. Gopal, J. Gratten, Michael F. Green, T. Greenwood, O. Guillin, S. Gülöksüz, R. Gur, R. Gur, B. Gutiérrez, E. Hahn, H. Hakonarson, V. Haroutunian, A. Hartmann, C. Harvey, C. Hayward, F. Henskens, S. Herms, P. Hoffmann, D. Howrigan, M. Ikeda, C. Iyegbe, I. Joa, A. Julià, A. Kähler, Tony Kam-Thong, Y. Kamatani, Sena Karachanak-Yankova, O. Kebir, M. Keller, Brian J. Kelly, A. Khrunin, Sung-Wan Kim, J. Kloviņš, N. Kondratiev, B. Konte, J. Kraft, M. Kubo, V. Kučinskas, Z. Kučinskienė, A. Kusumawardhani, Hana Kuzelova-Ptackova, S. Landi, L. Lazzeroni, Phil H. Lee, S. Legge, D. Lehrer, R. Lencer, B. Lerer, Miaoxin Li, J. Lieberman, G. Light, S. Limborska, Chih-Min Liu, J. Lönnqvist, C. Loughland, J. Lubiński, J. Luykx, A. Lynham, M. Macek, Andrew Mackinnon, P. Magnusson, B. Maher, W. Maier, D. Malaspina, J. Mallet, S. Marder, S. Marsal, Alicia R. Martin, L. Martorell, M. Mattheisen, R. McCarley, C. Mcdonald, J. McGrath, H. Medeiros, S. Meier, B. Melegh, I. Melle, R. Mesholam-Gately, A. Metspalu, P. Michie, L. Milani, V. Milanova, M. Mitjans, E. Molden, E. Molina, M. Moltó, V. Mondelli, C. Moreno, C. Morley, G. Muntané, K. Murphy, I. Myin-Germeys, I. Nenadić, G. Nestadt, L. Nikitina-Zake, Cristiano Noto, K. Nuechterlein, N. O’Brien, F. O'Neill, Sang-Yun Oh, A. Olincy, V. Ota, C. Pantelis, G. Papadimitriou, M. Parellada, T. Paunio, R. Pellegrino, S. Periyasamy, D. Perkins, B. Pfuhlmann, O. Pietiläinen, J. Pimm, D. Porteous, J. Powell, D. Quattrone, D. Quested, A. Radant, A. Rampino, M. Rapaport, A. Rautanen, A. Reichenberg, Cheryl A. Roe, J. Roffman, Julian Roth, M. Rothermundt, B. Rutten, Safa Saker-Delye, V. Salomaa, J. Sanjuán, M. Santoro, A. Savitz, U. Schall, Rodney J. Scott, L. Seidman, S. Sharp, Jianxin Shi, L. Siever, E. Sigurdsson, K. Sim, Nora Skarabis, P. Slominsky, H. So, J. Sobell, E. Söderman, H. Stain, N. E. Steen, Agnes A. Steixner-Kumar, Elisabeth Stögmann, W. Stone, R. Straub, F. Streit, E. Strengman, T. Stroup, M. Subramaniam, Catherine A. Sugar, J. Suvisaari, D. Svrakic, N. Swerdlow, J. Szatkiewicz, T. Ta, A. Takahashi, C. Terao, F. Thibaut, D. Toncheva, P. Tooney, Silvia Torretta, S. Tosato, G. Tura, B. Turetsky, A. Üçok, A. Vaaler, T. van Amelsvoort, R. van Winkel, J. Veijola, J. Waddington, H. Walter, A. Waterreus, B. Webb, M. Weiser, Nigel M Williams, S. Witt, B. Wormley, J. Wu, Zhida Xu, R. Yolken, C. Zai, Wei Zhou, Feng Zhu, F. Zimprich, E. Atbasoglu, M. Ayub, C. Benner, A. Bertolino, D. Black, N. Bray, G. Breen, N. Buccola, W. Byerley, Wei J. Chen, C. Cloninger, B. Crespo-Facorro, G. Donohoe, R. Freedman, C. Galletly, Michael Jeffrey Gandal, M. Gennarelli, D. Hougaard, H. Hwu, A. Jablensky, S. Mccarroll, J. Moran, O. Mors, P. Mortensen, B. Müller-Myhsok, A. Neil, M. Nordentoft, M. Pato, T. Petryshen, M. Pirinen, A. Pulver, T. Schulze, J. Silverman, J. Smoller, E. Stahl, D. Tsuang, E. Vilella, Shi-Heng Wang, Shuhua Xu, R. Adolfsson, C. Arango, B. Baune, S. Belangero, A. Børglum, D. Braff, E. Bramon, J. Buxbaum, D. Campion, J. Cervilla, S. Cichon, David A. Collier, A. Corvin, D. Curtis, M. Forti, E. Domenici, H. Ehrenreich, V. Escott-Price, T. Esko, A. Fanous, A. Gareeva, M. Gawlik, P. Gejman, M. Gill, S. Glatt, V. Golimbet, K. Hong, C. Hultman, S. Hyman, N. Iwata, E. Jönsson, R. Kahn, James L. Kennedy, E. Khusnutdinova, G. Kirov, J. Knowles, M. Krebs, C. Laurent-Levinson, Jimmy Lee, T. Lencz, D. Levinson, Qingqin S. Li, J. Liu, A. Malhotra, D. Malhotra, A. McIntosh, A. McQuillin, P. Menezes, V. Morgan, D. Morris, B. Mowry, Robin M. Murray, V. Nimgaonkar, M. Nöthen, R. Ophoff, S. Paciga, A. Palotie, C. Pato, Shengying Qin, M. Rietschel, B. Riley, M. Rivera, D. Rujescu, M. Saka, A. Sanders, S. Schwab, A. Serretti, P. Sham, Yongyong Shi, D. St. Clair, H. Stefánsson, K. Stefánsson, M. Tsuang, J. van os, M. Vawter, D. Weinberger, T. Werge, D. Wildenauer, Xin Yu, W. Yue, P. Holmans, A. Pocklington, P. Roussos, E. Vassos, M. Verhage, P. Visscher, Jian Yang, D. Posthuma, O. Andreassen, K. Kendler, M. Owen, N. Wray, M. Daly, Hailiang Huang, B. Neale, Patrick F. Sullivan, S. Ripke, J. Walters, M. O’Donovan · 发表于：Nature · 年份：2022 · DOI：10.1038/s41586-022-04434-5 · 被引用次数：2277 · 研究领域：Medicine

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. A genome-wide association study including over 76,000 individuals with schizophrenia...