Mapping genomic loci implicates genes and synaptic biology in schizophrenia

著者: Vassily Trubetskoy, Antonio F. Pardiñas, Ting Qi, Georgia Panagiotaropoulou, Swapnil Awasthi, Tim B. Bigdeli, Julien Bryois, Chia‐Yen Chen, Charlotte Dennison, Lynsey S. Hall, Max Lam, Kyoko Watanabe, Oleksandr Frei, Tian Ge, Janet Harwood, Frank Koopmans, Sigurður H. Magnússon, Alexander Richards, Julia Sidorenko, Yang Wu, Jian Zeng, Jakob Grove, Minsoo Kim, Zhiqiang Li, Georgios Voloudakis, Wen Zhang, Mark J. Adams, Ingrid Agartz, Elizabeth G. Atkinson, Esben Agerbo, Mariam Al Eissa, Margot Albus, Madeline Alexander, Behrooz Z. Alizadeh, Köksal Alptekın, Thomas D. Als, Farooq Amin, Volker Arolt, Manuel Arrojo, Lavinia Athanasiu, M.H. Azevedo, Silviu‐Alin Bacanu, Nicholas Bass, Martin Begemann, Richard A. Belliveau, Judit Bene, Beben Benyamin, Sarah E. Bergen, Giuseppe Blasi, Julio Bobes, Stefano Bonassi, Alice Braun, Rodrigo A. Bressan, Evelyn J. Bromet, Richard Bruggeman, P.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 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 G. Dinan, Srdjan Djurovic, Jubao Duan, Giuseppe Ducci, Frank Dudbridge, Johan G. Eriksson, Lourdes Fañanás, Stephen V. Faraone, Alessia Fiorentino, Andreas J. 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, Håkon Håkonarson, 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 Kébir, Matthew C. Keller, Brian Kelly, Andrey Khrunin, Sung‐Wan Kim, Jānis Kloviņš, N V Kondratiev, Bettina Konte, Julia Kraft, Michiaki Kubo, Vaidutis Kučinskas, Zita Aušrelė Kučinskienė, 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 A. Lieberman, Gregory A. Light, Limborskaia Sa, Chih‐Min Liu, Jouko Lönnqvist, Carmel M. Loughland, Jan Lubiński, Jurjen J. Luykx, Amy Lynham, Milan Maçek, 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, Béla Melegh, Ingrid Melle, Raquelle I. Mesholam‐Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Marina Mitjans, Espen Molden, Esther Molina, María Dolores Moltó, Valeria Mondelli, Carmen Moreno, Christopher P. Morley, Gerard Muntané, Kieran C. Murphy, Inez Myin‐Germeys, Igor Nenadić, Gerald Nestadt, Liene Ņikitina-Zaķe, Cristiano Noto, Keith H. Nuechterlein, Niamh L. O’Brien, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Vanessa Ota, Christos Pantelis, George N. Papadimitriou, Mara Parellada, Tiina Paunio, Renata Pellegrino, Sathish Periyasamy, Diana O. Perkins, Bruno Pfuhlmann, Olli Pietiläinen, Jonathan Pimm, David J. Porteous, John Powell, Diego Quattrone, Digby Quested, Allen D. Radant, Antonio Rampino, Mark Hyman Rapaport, Anna Rautanen, Abraham Reichenberg, Cheryl Roe, Joshua L. Roffman, Julian Roth, Matthias Rothermundt, Bart P. F. Rutten, Safaa Saker-Delye, Veikko Salomaa, Julio Sanjuán, Marcos Santoro, Adam Savitz, Ulrich Schall, Rodney J. Scott, Larry J. Seidman, Sally I. Sharp, Jianxin Shi, Larry J. Siever, Engilbert Sigurðsson, Kang Sim, Nora Skarabis, P. A. 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. Švrakić, Neal R. Swerdlow, Jin Szatkiewicz, Thi Minh Tam Ta, Atsushi Takahashi, Chikashi Terao, Florence Thibaut, Драга Тончева, Paul A. Tooney, Silvia Torretta, Sarah Tosato, Gian Battista Tura, Bruce I. Turetsky, Alp Üçok, Arne Vaaler, Thérèse van Amelsvoort, Ruud van Winkel, Juha Veijola, John L. Waddington, Henrik Walter, Anna Waterreus, Bradley T. Webb, Mark Weiser, Nigel Williams, Stephanie H. Witt, Brandon K. Wormley, Jing Wu, Zhida Xu, Robert H. 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 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 Bo 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, Nan Dai, Qin Wenwen, Dieter B. Wildenauer, Feranindhya Agiananda, Nurmiati Amir, Ronald Antoni, Tiana Arsianti, Asmarahadi Asmarahadi, H. Diatri, Prianto Djatmiko, Irmansyah Irmansyah, Siti Khalimah, Irmia Kusumadewi, Profitasari Kusumaningrum, Petrin Redayani Lukman, Martina Wiwie Setiawan Nasrun, N. S. Safyuni, Prasetyawan Prasetyawan, G. Semen, Kristiana Siste, Heriani Tobing, Natalia Widiasih, Tjhin Wiguna, Desi Wulandari, None Evalina, Arga Hananto, Joni H. Ismoyo, T. M. Marini, Supiyani Henuhili, Muhammad Reza, Suzy Yusnadewi, PsychENCODE, Alexej Abyzov, Schahram Akbarian, Allison E. Ashley‐Koch, Harm van Bakel, Michael S. Breen, Miguel Brown, Julien Bryois, Becky C. Carlyle, Alex Charney, Gerard Coetzee, Gregory E. Crawford, Stella Dracheva, Prashant S. Emani, Peggy Farnham, Menachem Fromer, Timur R. Galeev, Mike Gandal, Mark Gerstein, Gina Giase, Kiran Girdhar, Fernando S. Goes, Kay Grennan, Mengting Gu, Brittney Guerra, Gamze Gürsoy, Gabriel E. Hoffman, Thomas M. Hyde, Andrew E. Jaffe, Shan Jiang, Yan Jiang, Amira Kefi, Yunjung Kim, Robert R. Kitchen, James A. Knowles, Fides D. Lay, Donghoon Lee, Mingfeng Li, Chunyu Liu, Shuang Liu, Eugenio Mattei, Fábio C. P. Navarro, Xinghua Pan, Mette A. Peters, Dalila Pinto, Sirisha Pochareddy, Damon Polioudakis, Michael Purcaro, Shaun Purcell, Henry Pratt, T. Sanjeeva Reddy, Suhn K. Rhie, Panagiotis Roussos, Joel Rozowsky, Stephan Sanders, Nenad Šestan, Anurag Sethi, Xu Shi, Annie W. Shieh, Vivek Swarup, Anna Szekely, Daifeng Wang, Jonathan Warrell, Sherman M. Weissman, Zhiping Weng, Kevin P. White, Jennifer Wiseman, Heather Witt, Hyejung Won, Shannon N. Wood, Feinan Wu, Xuming Xu, Lijing Yao, Peter P. Zandi, María J. Arranz, Steven C. Bakker, Stephan Bender, Elvira Bramon, David Collier, Benedicto Crepo-Facorro, Jérémy Hall, Conrad Iyegbe, René S. Kahn, Stephen M. Lawrie, Cathryn M. Lewis, Kuang Lin, Don Linszen, Ignácio F. Mata, Andrew M. McIntosh, Robin Murray, Roel A. Ophoff, Jim van Os, John Powell, Dan Rujescu, Muriel Walshe, Matthias Weisbrod, Tilmann Achsel, Maria Andres‐Alonso, Claudia Bagni, Àlex Bayés, Thomas Biederer, Nils Brose, Tyler C. Brown, John Jia En Chua, Marcelo P. Coba, L. Niels Cornelisse, Arthur P.H. de Jong, Jaime de Juan‐Sanz, Daniela C. Dieterich, Guoping Feng, Hana L. Goldschmidt, Eckart D. Gundelfinger, Casper C. Hoogenraad, Richard L. Huganir, Steven E. Hyman, Cordelia Imig, Reinhard Jahn, Hwajin Jung, Pascal S. Kaeser, Eunjoon Kim, Frank Koopmans, Michael R. Kreutz, Noa Lipstein, Harold D. MacGillavry, Robert C. Malenka, Peter S. McPherson, Vincent O’Connor, Rainer Pielot, Timothy P. Ryan, Dnyanada Sahasrabudhe, Carlo Sala, Morgan Sheng, Karl‐Heinz Smalla, August B. Smit, Thomas C. Südhof, Paul D. Thomas, Ruud F. Toonen, Jan R.T. van Weering, Matthijs Verhage, Chiara Verpelli, Rolf Adolfsson, Celso Arango, Bernhard T. Baune, Síntia Belangero, Anders D. Børglum, David Braff, Elvira Bramon, Joseph D. Buxbaum, Dominique Campion, Jorge A. Cervilla, Sven Cichon, David 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, В. Е. Голимбет, Kyung Sue Hong, Christina M. Hultman, Steven E. Hyman, Nakao Iwata, Erik G. Jönsson, René S. Kahn, James L. Kennedy, Э. К. Хуснутдинова, 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 M. McIntosh, Andrew McQuillin, Paulo Rossi Menezes, Vera A. Morgan, Derek W. Morris, Bryan Mowry, Robin Murray, Vishwajit L. 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 Can 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, D.R. Weinberger, Thomas Werge, Dieter B. Wildenauer, Xin Yu, Weihua Yue, Peter Holmans, Andrew Pocklington, Panos Roussos, Evangelos Vassos, Matthijs Verhage, Peter M. Visscher, Jian Yang, Daniëlle 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 Walters, Michael O‘Donovan, Lieuwe de Haan, Therese van Amelsvoort, Ruud van Winkel, Anna Gareeva, Pak C. Sham, Yongyong Shi, David St Clair, Jim van Os - Nature 2022 被引用: 2,857

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 and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.