TY  - JOUR
TI  - Mapping genomic loci implicates genes and synaptic biology in schizophrenia
AU  - Vassily Trubetskoy
AU  - Antonio F. Pardiñas
AU  - Ting Qi
AU  - Georgia Panagiotaropoulou
AU  - Swapnil Awasthi
AU  - Tim B. Bigdeli
AU  - Julien Bryois
AU  - Chia‐Yen Chen
AU  - Charlotte Dennison
AU  - Lynsey S. Hall
AU  - Max Lam
AU  - Kyoko Watanabe
AU  - Oleksandr Frei
AU  - Tian Ge
AU  - Janet Harwood
AU  - Frank Koopmans
AU  - Sigurður H. Magnússon
AU  - Alexander Richards
AU  - Julia Sidorenko
AU  - Yang Wu
AU  - Jian Zeng
AU  - Jakob Grove
AU  - Minsoo Kim
AU  - Zhiqiang Li
AU  - Georgios Voloudakis
AU  - Wen Zhang
AU  - Mark J. Adams
AU  - Ingrid Agartz
AU  - Elizabeth G. Atkinson
AU  - Esben Agerbo
AU  - Mariam Al Eissa
AU  - Margot Albus
AU  - Madeline Alexander
AU  - Behrooz Z. Alizadeh
AU  - Köksal Alptekın
AU  - Thomas D. Als
AU  - Farooq Amin
AU  - Volker Arolt
AU  - Manuel Arrojo
AU  - Lavinia Athanasiu
AU  - M.H. Azevedo
AU  - Silviu‐Alin Bacanu
AU  - Nicholas Bass
AU  - Martin Begemann
AU  - Richard A. Belliveau
AU  - Judit Bene
AU  - Beben Benyamin
AU  - Sarah E. Bergen
AU  - Giuseppe Blasi
AU  - Julio Bobes
AU  - Stefano Bonassi
AU  - Alice Braun
AU  - Rodrigo A. Bressan
AU  - Evelyn J. Bromet
AU  - Richard Bruggeman
AU  - P.F. Buckley
AU  - Randy L. Buckner
AU  - Jonas Bybjerg‐Grauholm
AU  - Wiepke Cahn
AU  - Murray J. Cairns
AU  - Monica E. Calkins
AU  - Vaughan J. Carr
AU  - David Castle
AU  - Stanley V. Catts
AU  - Kimberley D. Chambert
AU  - Raymond Chan
AU  - Boris Chaumette
AU  - Wei Cheng
AU  - Eric F.C. Cheung
AU  - Siow Ann Chong
AU  - David Cohen
AU  - Angèle Consoli
AU  - Quirino Cordeiro
AU  - Javier Costas
AU  - Charles Curtis
AU  - Michael Davidson
AU  - Kenneth L. Davis
AU  - Lieuwe de Haan
AU  - Franziska Degenhardt
AU  - Lynn E. DeLisi
AU  - Ditte Demontis
AU  - Faith Dickerson
AU  - Dimitris Dikeos
AU  - Timothy G. Dinan
AU  - Srdjan Djurovic
AU  - Jubao Duan
AU  - Giuseppe Ducci
AU  - Frank Dudbridge
AU  - Johan G. Eriksson
AU  - Lourdes Fañanás
AU  - Stephen V. Faraone
AU  - Alessia Fiorentino
AU  - Andreas J. Forstner
AU  - Josef Frank
AU  - Nelson B. Freimer
AU  - Menachem Fromer
AU  - Alessandra Frustaci
AU  - Ary Gadelha
AU  - Giulio Genovese
AU  - Elliot S. Gershon
PY  - 2022
JO  - Nature
DO  - 10.1038/s41586-022-04434-5
UR  - https://doi.org/10.1038/s41586-022-04434-5
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. 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.
ER  -