Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Indonesia Schizophrenia Consortium; PsychENCODE; Psychosis Endophenotypes International Consortium; SynGO Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; 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; Anna Waterreus; Assen Jablensky; Vera Morgan; Dieter Wildenauer

doi:10.1038/s41586-022-04434-5

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Indonesia Schizophrenia Consortium, PsychENCODE, Psychosis Endophenotypes International Consortium, SynGO Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, 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. HarwoodFrank 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, Anna Waterreus, Assen Jablensky, Vera Morgan, Dieter Wildenauer

Research output: Contribution to journal › Article › peer-review

1262 Citations (Scopus)

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 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.

Original language	English
Pages (from-to)	502-508
Number of pages	7
Journal	Nature
Volume	604
Issue number	7906
DOIs	https://doi.org/10.1038/s41586-022-04434-5
Publication status	Published - 21 Apr 2022

Access to Document

10.1038/s41586-022-04434-5

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9392466/

Cite this

Indonesia Schizophrenia Consortium, PsychENCODE, Psychosis Endophenotypes International Consortium, SynGO Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Trubetskoy, V., Pardiñas, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., Bryois, J., Chen, C. Y., Dennison, C. A., Hall, L. S., Lam, M., Watanabe, K., Frei, O., Ge, T., ... Wildenauer, D. (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature, 604(7906), 502-508. https://doi.org/10.1038/s41586-022-04434-5

@article{0b6c985dcf844cd99648ef3e1ded035b,

title = "Mapping genomic loci implicates genes and synaptic biology in schizophrenia",

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 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.",

author = "{Indonesia Schizophrenia Consortium} and PsychENCODE and {Psychosis Endophenotypes International Consortium} and {SynGO Consortium} and {Schizophrenia Working Group of the Psychiatric Genomics Consortium} and Vassily Trubetskoy and Pardi{\~n}as, {Antonio F.} and Ting Qi and Georgia Panagiotaropoulou and Swapnil Awasthi and Bigdeli, {Tim B.} and Julien Bryois and Chen, {Chia Yen} and Dennison, {Charlotte A.} and Hall, {Lynsey S.} and Max Lam and Kyoko Watanabe and Oleksandr Frei and Tian Ge and Harwood, {Janet C.} and Frank Koopmans and Sigurdur Magnusson and Richards, {Alexander L.} and Julia Sidorenko and Yang Wu and Jian Zeng and Jakob Grove and Minsoo Kim and Zhiqiang Li and Georgios Voloudakis and Wen Zhang and Mark Adams and Ingrid Agartz and Atkinson, {Elizabeth G.} and Esben Agerbo and {Al Eissa}, Mariam and Margot Albus and Madeline Alexander and Alizadeh, {Behrooz Z.} and K{\"o}ksal Alptekin and Als, {Thomas D.} and Farooq Amin and Volker Arolt and Manuel Arrojo and Lavinia Athanasiu and Azevedo, {Maria Helena} and Bacanu, {Silviu A.} and Bass, {Nicholas J.} and Martin Begemann and Belliveau, {Richard A.} and Judit Bene and Beben Benyamin and Bergen, {Sarah E.} and Giuseppe Blasi and Julio Bobes and Stefano Bonassi and Alice Braun and Bressan, {Rodrigo Affonseca} and Bromet, {Evelyn J.} and Richard Bruggeman and Buckley, {Peter F.} and Buckner, {Randy L.} and Jonas Bybjerg-Grauholm and Wiepke Cahn and Cairns, {Murray J.} and Calkins, {Monica E.} and Carr, {Vaughan J.} and David Castle and Catts, {Stanley V.} and Chambert, {Kimberley D.} and Chan, {Raymond C.K.} and Boris Chaumette and Wei Cheng and Cheung, {Eric F.C.} and Chong, {Siow Ann} and David Cohen and Ang{\`e}le Consoli and Quirino Cordeiro and Javier Costas and Charles Curtis and Michael Davidson and Davis, {Kenneth L.} and {de Haan}, Lieuwe and Franziska Degenhardt and DeLisi, {Lynn E.} and Ditte Demontis and Faith Dickerson and Dimitris Dikeos and Timothy Dinan and Srdjan Djurovic and Jubao Duan and Giuseppe Ducci and Frank Dudbridge and Eriksson, {Johan G.} and Lourdes Fa{\~n}an{\'a}s and Faraone, {Stephen V.} and Alessia Fiorentino and Andreas Forstner and Josef Frank and Freimer, {Nelson B.} and Menachem Fromer and Alessandra Frustaci and Ary Gadelha and Giulio Genovese and Gershon, {Elliot S.} and Marianna Giannitelli and Ina Giegling and Paola Giusti-Rodr{\'i}guez and Stephanie Godard and Goldstein, {Jacqueline I.} and {Gonz{\'a}lez Pe{\~n}as}, Javier and Ana Gonz{\'a}lez-Pinto and Srihari Gopal and Jacob Gratten and Green, {Michael F.} and Greenwood, {Tiffany A.} and Olivier Guillin and Sinan G{\"u}l{\"o}ks{\"u}z and Gur, {Raquel E.} and Gur, {Ruben C.} and Blanca Guti{\'e}rrez and Eric Hahn and Hakon Hakonarson and Vahram Haroutunian and Hartmann, {Annette M.} and Carol Harvey and Caroline Hayward and Henskens, {Frans A.} and Stefan Herms and Per Hoffmann and Howrigan, {Daniel P.} and Masashi Ikeda and Conrad Iyegbe and Inge Joa and Antonio Juli{\`a} and K{\"a}hler, {Anna K.} and Tony Kam-Thong and Yoichiro Kamatani and Sena Karachanak-Yankova and Oussama Kebir and Keller, {Matthew C.} and Kelly, {Brian J.} and Andrey Khrunin and Kim, {Sung Wan} and Janis Klovins and Nikolay Kondratiev and Bettina Konte and Julia Kraft and Michiaki Kubo and Vaidutis Ku{\v c}inskas and Ku{\v c}inskiene, {Zita Ausrele} and Agung Kusumawardhani and Hana Kuzelova-Ptackova and Stefano Landi and Lazzeroni, {Laura C.} and Lee, {Phil H.} and Legge, {Sophie E.} and Lehrer, {Douglas S.} and Rebecca Lencer and Bernard Lerer and Miaoxin Li and Jeffrey Lieberman and Light, {Gregory A.} and Svetlana Limborska and Liu, {Chih Min} and Jouko L{\"o}nnqvist and Loughland, {Carmel M.} and Jan Lubinski and Luykx, {Jurjen J.} and Amy Lynham and Milan Macek and Andrew Mackinnon and Magnusson, {Patrik K.E.} and Maher, {Brion S.} and Wolfgang Maier and Dolores Malaspina and Jacques Mallet and Marder, {Stephen R.} and Sara Marsal and Martin, {Alicia R.} and Lourdes Martorell and Manuel Mattheisen and McCarley, {Robert W.} and Colm McDonald and McGrath, {John J.} and Helena Medeiros and Sandra Meier and Bela Melegh and Ingrid Melle and Mesholam-Gately, {Raquelle I.} and Andres Metspalu and Michie, {Patricia T.} and Lili Milani and Vihra Milanova and Marina Mitjans and Espen Molden and Esther Molina and Molto, {Mar{\'i}a Dolores} and Valeria Mondelli and Carmen Moreno and Morley, {Christopher P.} and Gerard Muntan{\'e} and Murphy, {Kieran C.} and Inez Myin-Germeys and Igor Nenadi{\'c} and Gerald Nestadt and Liene Nikitina-Zake and Cristiano Noto and Nuechterlein, {Keith H.} and O'Brien, {Niamh Louise} and O'Neill, {F. Anthony} and Oh, {Sang Yun} and Ann Olincy and Ota, {Vanessa Kiyomi} and Christos Pantelis and Papadimitriou, {George N.} and Mara Parellada and Tiina Paunio and Renata Pellegrino and Sathish Periyasamy and Perkins, {Diana O.} and Bruno Pfuhlmann and Olli Pietil{\"a}inen and Jonathan Pimm and David Porteous and John Powell and Diego Quattrone and Digby Quested and Radant, {Allen D.} and Antonio Rampino and Rapaport, {Mark H.} and Anna Rautanen and Abraham Reichenberg and Cheryl Roe and Roffman, {Joshua L.} and Julian Roth and Matthias Rothermundt and Rutten, {Bart P.F.} and Safaa Saker-Delye and Veikko Salomaa and Julio Sanjuan and Santoro, {Marcos Leite} and Adam Savitz and Ulrich Schall and Scott, {Rodney J.} and Seidman, {Larry J.} and Sharp, {Sally Isabel} and Jianxin Shi and Siever, {Larry J.} and Engilbert Sigurdsson and Kang Sim and Nora Skarabis and Petr Slominsky and Anna Waterreus and Assen Jablensky and Vera Morgan and Dieter Wildenauer and Nan Dai and Wenwen Qin",

note = "Publisher Copyright: {\textcopyright} 2022. The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = apr,

day = "21",

doi = "10.1038/s41586-022-04434-5",

language = "English",

volume = "604",

pages = "502--508",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "7906",

}

Indonesia Schizophrenia Consortium, PsychENCODE, Psychosis Endophenotypes International Consortium, SynGO Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Trubetskoy, V, Pardiñas, AF, Qi, T, Panagiotaropoulou, G, Awasthi, S, Bigdeli, TB, Bryois, J, Chen, CY, Dennison, CA, Hall, LS, Lam, M, Watanabe, K, Frei, O, Ge, T, Harwood, JC, Koopmans, F, Magnusson, S, Richards, AL, Sidorenko, J, Wu, Y, Zeng, J, Grove, J, Kim, M, Li, Z, Voloudakis, G, Zhang, W, Adams, M, Agartz, I, Atkinson, EG, Agerbo, E, Al Eissa, M, Albus, M, Alexander, M, Alizadeh, BZ, Alptekin, K, Als, TD, Amin, F, Arolt, V, Arrojo, M, Athanasiu, L, Azevedo, MH, Bacanu, SA, Bass, NJ, Begemann, M, Belliveau, RA, Bene, J, Benyamin, B, Bergen, SE, Blasi, G, Bobes, J, Bonassi, S, Braun, A, Bressan, RA, Bromet, EJ, Bruggeman, R, Buckley, PF, Buckner, RL, Bybjerg-Grauholm, J, Cahn, W, Cairns, MJ, Calkins, ME, Carr, VJ, Castle, D, Catts, SV, Chambert, KD, Chan, RCK, Chaumette, B, Cheng, W, Cheung, EFC, Chong, SA, Cohen, D, Consoli, A, Cordeiro, Q, Costas, J, Curtis, C, Davidson, M, Davis, KL, de Haan, L, Degenhardt, F, DeLisi, LE, Demontis, D, Dickerson, F, Dikeos, D, Dinan, T, Djurovic, S, Duan, J, Ducci, G, Dudbridge, F, Eriksson, JG, Fañanás, L, Faraone, SV, Fiorentino, A, Forstner, A, Frank, J, Freimer, NB, Fromer, M, Frustaci, A, Gadelha, A, Genovese, G, Gershon, ES, Giannitelli, M, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, JI, González Peñas, J, González-Pinto, A, Gopal, S, Gratten, J, Green, MF, Greenwood, TA, Guillin, O, Gülöksüz, S, Gur, RE, Gur, RC, Gutiérrez, B, Hahn, E, Hakonarson, H, Haroutunian, V, Hartmann, AM, Harvey, C, Hayward, C, Henskens, FA, Herms, S, Hoffmann, P, Howrigan, DP, Ikeda, M, Iyegbe, C, Joa, I, Julià, A, Kähler, AK, Kam-Thong, T, Kamatani, Y, Karachanak-Yankova, S, Kebir, O, Keller, MC, Kelly, BJ, Khrunin, A, Kim, SW, Klovins, J, Kondratiev, N, Konte, B, Kraft, J, Kubo, M, Kučinskas, V, Kučinskiene, ZA, Kusumawardhani, A, Kuzelova-Ptackova, H, Landi, S, Lazzeroni, LC, Lee, PH, Legge, SE, Lehrer, DS, Lencer, R, Lerer, B, Li, M, Lieberman, J, Light, GA, Limborska, S, Liu, CM, Lönnqvist, J, Loughland, CM, Lubinski, J, Luykx, JJ, Lynham, A, Macek, M, Mackinnon, A, Magnusson, PKE, Maher, BS, Maier, W, Malaspina, D, Mallet, J, Marder, SR, Marsal, S, Martin, AR, Martorell, L, Mattheisen, M, McCarley, RW, McDonald, C, McGrath, JJ, Medeiros, H, Meier, S, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mitjans, M, Molden, E, Molina, E, Molto, MD, Mondelli, V, Moreno, C, Morley, CP, Muntané, G, Murphy, KC, Myin-Germeys, I, Nenadić, I, Nestadt, G, Nikitina-Zake, L, Noto, C, Nuechterlein, KH, O'Brien, NL, O'Neill, FA, Oh, SY, Olincy, A, Ota, VK, Pantelis, C, Papadimitriou, GN, Parellada, M, Paunio, T, Pellegrino, R, Periyasamy, S, Perkins, DO, Pfuhlmann, B, Pietiläinen, O, Pimm, J, Porteous, D, Powell, J, Quattrone, D, Quested, D, Radant, AD, Rampino, A, Rapaport, MH, Rautanen, A, Reichenberg, A, Roe, C, Roffman, JL, Roth, J, Rothermundt, M, Rutten, BPF, Saker-Delye, S, Salomaa, V, Sanjuan, J, Santoro, ML, Savitz, A, Schall, U, Scott, RJ, Seidman, LJ, Sharp, SI, Shi, J, Siever, LJ, Sigurdsson, E, Sim, K, Skarabis, N, Slominsky, P, Waterreus, A, Jablensky, A, Morgan, V & Wildenauer, D 2022, 'Mapping genomic loci implicates genes and synaptic biology in schizophrenia', Nature, vol. 604, no. 7906, pp. 502-508. https://doi.org/10.1038/s41586-022-04434-5

TY - JOUR

T1 - Mapping genomic loci implicates genes and synaptic biology in schizophrenia

AU - Indonesia Schizophrenia Consortium

AU - PsychENCODE

AU - Psychosis Endophenotypes International Consortium

AU - SynGO Consortium

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

AU - Trubetskoy, Vassily

AU - Pardiñas, Antonio F.

AU - Qi, Ting

AU - Panagiotaropoulou, Georgia

AU - Awasthi, Swapnil

AU - Bigdeli, Tim B.

AU - Bryois, Julien

AU - Chen, Chia Yen

AU - Dennison, Charlotte A.

AU - Hall, Lynsey S.

AU - Lam, Max

AU - Watanabe, Kyoko

AU - Frei, Oleksandr

AU - Ge, Tian

AU - Harwood, Janet C.

AU - Koopmans, Frank

AU - Magnusson, Sigurdur

AU - Richards, Alexander L.

AU - Sidorenko, Julia

AU - Wu, Yang

AU - Zeng, Jian

AU - Grove, Jakob

AU - Kim, Minsoo

AU - Li, Zhiqiang

AU - Voloudakis, Georgios

AU - Zhang, Wen

AU - Adams, Mark

AU - Agartz, Ingrid

AU - Atkinson, Elizabeth G.

AU - Agerbo, Esben

AU - Al Eissa, Mariam

AU - Albus, Margot

AU - Alexander, Madeline

AU - Alizadeh, Behrooz Z.

AU - Alptekin, Köksal

AU - Als, Thomas D.

AU - Amin, Farooq

AU - Arolt, Volker

AU - Arrojo, Manuel

AU - Athanasiu, Lavinia

AU - Azevedo, Maria Helena

AU - Bacanu, Silviu A.

AU - Bass, Nicholas J.

AU - Begemann, Martin

AU - Belliveau, Richard A.

AU - Bene, Judit

AU - Benyamin, Beben

AU - Bergen, Sarah E.

AU - Blasi, Giuseppe

AU - Bobes, Julio

AU - Bonassi, Stefano

AU - Braun, Alice

AU - Bressan, Rodrigo Affonseca

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AU - Bruggeman, Richard

AU - Buckley, Peter F.

AU - Buckner, Randy L.

AU - Bybjerg-Grauholm, Jonas

AU - Cahn, Wiepke

AU - Cairns, Murray J.

AU - Calkins, Monica E.

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AU - Catts, Stanley V.

AU - Chambert, Kimberley D.

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AU - Chong, Siow Ann

AU - Cohen, David

AU - Consoli, Angèle

AU - Cordeiro, Quirino

AU - Costas, Javier

AU - Curtis, Charles

AU - Davidson, Michael

AU - Davis, Kenneth L.

AU - de Haan, Lieuwe

AU - Degenhardt, Franziska

AU - DeLisi, Lynn E.

AU - Demontis, Ditte

AU - Dickerson, Faith

AU - Dikeos, Dimitris

AU - Dinan, Timothy

AU - Djurovic, Srdjan

AU - Duan, Jubao

AU - Ducci, Giuseppe

AU - Dudbridge, Frank

AU - Eriksson, Johan G.

AU - Fañanás, Lourdes

AU - Faraone, Stephen V.

AU - Fiorentino, Alessia

AU - Forstner, Andreas

AU - Frank, Josef

AU - Freimer, Nelson B.

AU - Fromer, Menachem

AU - Frustaci, Alessandra

AU - Gadelha, Ary

AU - Genovese, Giulio

AU - Gershon, Elliot S.

AU - Giannitelli, Marianna

AU - Giegling, Ina

AU - Giusti-Rodríguez, Paola

AU - Godard, Stephanie

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AU - González Peñas, Javier

AU - González-Pinto, Ana

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AU - Nenadić, Igor

AU - Nestadt, Gerald

AU - Nikitina-Zake, Liene

AU - Noto, Cristiano

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AU - O'Neill, F. Anthony

AU - Oh, Sang Yun

AU - Olincy, Ann

AU - Ota, Vanessa Kiyomi

AU - Pantelis, Christos

AU - Papadimitriou, George N.

AU - Parellada, Mara

AU - Paunio, Tiina

AU - Pellegrino, Renata

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AU - Perkins, Diana O.

AU - Pfuhlmann, Bruno

AU - Pietiläinen, Olli

AU - Pimm, Jonathan

AU - Porteous, David

AU - Powell, John

AU - Quattrone, Diego

AU - Quested, Digby

AU - Radant, Allen D.

AU - Rampino, Antonio

AU - Rapaport, Mark H.

AU - Rautanen, Anna

AU - Reichenberg, Abraham

AU - Roe, Cheryl

AU - Roffman, Joshua L.

AU - Roth, Julian

AU - Rothermundt, Matthias

AU - Rutten, Bart P.F.

AU - Saker-Delye, Safaa

AU - Salomaa, Veikko

AU - Sanjuan, Julio

AU - Santoro, Marcos Leite

AU - Savitz, Adam

AU - Schall, Ulrich

AU - Scott, Rodney J.

AU - Seidman, Larry J.

AU - Sharp, Sally Isabel

AU - Shi, Jianxin

AU - Siever, Larry J.

AU - Sigurdsson, Engilbert

AU - Sim, Kang

AU - Skarabis, Nora

AU - Slominsky, Petr

AU - Waterreus, Anna

AU - Jablensky, Assen

AU - Morgan, Vera

AU - Wildenauer, Dieter

AU - Dai, Nan

AU - Qin, Wenwen

PY - 2022/4/21

Y1 - 2022/4/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85127650703&partnerID=8YFLogxK

U2 - 10.1038/s41586-022-04434-5

DO - 10.1038/s41586-022-04434-5

M3 - Article

C2 - 35396580

AN - SCOPUS:85127650703

SN - 0028-0836

VL - 604

SP - 502

EP - 508

JO - Nature

JF - Nature

IS - 7906

ER -

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

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