TY - JOUR
T1 - Mapping genomic loci implicates genes and synaptic biology in schizophrenia
AU - Psychosis Endophenotypes International Consortium
AU - The SynGO Consortium
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium
AU - Indonesia Schizophrenia Consortium
AU - PsychENCODE
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 - Zhu, Feng
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 - https://www.scopus.com/pages/publications/85127650703
U2 - 10.1038/s41586-022-04434-5
DO - 10.1038/s41586-022-04434-5
M3 - 文章
C2 - 35396580
AN - SCOPUS:85127650703
SN - 0028-0836
VL - 604
SP - 502
EP - 508
JO - Nature
JF - Nature
IS - 7906
ER -