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 | |
| Publication status | Published - 21 Apr 2022 |
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Mapping genomic loci implicates genes and synaptic biology in schizophrenia. / Indonesia Schizophrenia Consortium; PsychENCODE; Psychosis Endophenotypes International Consortium et al.
In: Nature, Vol. 604, No. 7906, 21.04.2022, p. 502-508.Research output: Contribution to journal › Article › peer-review
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
AU - Bromet, Evelyn J.
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.
AU - Carr, Vaughan J.
AU - Castle, David
AU - Catts, Stanley V.
AU - Chambert, Kimberley D.
AU - Chan, Raymond C.K.
AU - Chaumette, Boris
AU - Cheng, Wei
AU - Cheung, Eric F.C.
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
AU - Goldstein, Jacqueline I.
AU - González Peñas, Javier
AU - González-Pinto, Ana
AU - Gopal, Srihari
AU - Gratten, Jacob
AU - Green, Michael F.
AU - Greenwood, Tiffany A.
AU - Guillin, Olivier
AU - Gülöksüz, Sinan
AU - Gur, Raquel E.
AU - Gur, Ruben C.
AU - Gutiérrez, Blanca
AU - Hahn, Eric
AU - Hakonarson, Hakon
AU - Haroutunian, Vahram
AU - Hartmann, Annette M.
AU - Harvey, Carol
AU - Hayward, Caroline
AU - Henskens, Frans A.
AU - Herms, Stefan
AU - Hoffmann, Per
AU - Howrigan, Daniel P.
AU - Ikeda, Masashi
AU - Iyegbe, Conrad
AU - Joa, Inge
AU - Julià, Antonio
AU - Kähler, Anna K.
AU - Kam-Thong, Tony
AU - Kamatani, Yoichiro
AU - Karachanak-Yankova, Sena
AU - Kebir, Oussama
AU - Keller, Matthew C.
AU - Kelly, Brian J.
AU - Khrunin, Andrey
AU - Kim, Sung Wan
AU - Klovins, Janis
AU - Kondratiev, Nikolay
AU - Konte, Bettina
AU - Kraft, Julia
AU - Kubo, Michiaki
AU - Kučinskas, Vaidutis
AU - Kučinskiene, Zita Ausrele
AU - Kusumawardhani, Agung
AU - Kuzelova-Ptackova, Hana
AU - Landi, Stefano
AU - Lazzeroni, Laura C.
AU - Lee, Phil H.
AU - Legge, Sophie E.
AU - Lehrer, Douglas S.
AU - Lencer, Rebecca
AU - Lerer, Bernard
AU - Li, Miaoxin
AU - Lieberman, Jeffrey
AU - Light, Gregory A.
AU - Limborska, Svetlana
AU - Liu, Chih Min
AU - Lönnqvist, Jouko
AU - Loughland, Carmel M.
AU - Lubinski, Jan
AU - Luykx, Jurjen J.
AU - Lynham, Amy
AU - Macek, Milan
AU - Mackinnon, Andrew
AU - Magnusson, Patrik K.E.
AU - Maher, Brion S.
AU - Maier, Wolfgang
AU - Malaspina, Dolores
AU - Mallet, Jacques
AU - Marder, Stephen R.
AU - Marsal, Sara
AU - Martin, Alicia R.
AU - Martorell, Lourdes
AU - Mattheisen, Manuel
AU - McCarley, Robert W.
AU - McDonald, Colm
AU - McGrath, John J.
AU - Medeiros, Helena
AU - Meier, Sandra
AU - Melegh, Bela
AU - Melle, Ingrid
AU - Mesholam-Gately, Raquelle I.
AU - Metspalu, Andres
AU - Michie, Patricia T.
AU - Milani, Lili
AU - Milanova, Vihra
AU - Mitjans, Marina
AU - Molden, Espen
AU - Molina, Esther
AU - Molto, María Dolores
AU - Mondelli, Valeria
AU - Moreno, Carmen
AU - Morley, Christopher P.
AU - Muntané, Gerard
AU - Murphy, Kieran C.
AU - Myin-Germeys, Inez
AU - Nenadić, Igor
AU - Nestadt, Gerald
AU - Nikitina-Zake, Liene
AU - Noto, Cristiano
AU - Nuechterlein, Keith H.
AU - O'Brien, Niamh Louise
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
AU - Periyasamy, Sathish
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
N1 - Publisher Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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
VL - 604
SP - 502
EP - 508
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7906
ER -