Mapping genomic loci implicates genes and synaptic biology in schizophrenia

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 WuJian 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, Richard Bruggeman, Sinan Gülöksüz, Jurjen J Luykx, Inez Myin-Germeys, Bart P F Rutten, Therese van Amelsvoort, Ruud van Winkel, Jim van Os, Indonesia Schizophrenia Consortium

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

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 languageEnglish
Pages (from-to)502-508
Number of pages24
JournalNature
Volume604
Issue number7906
Early online date8 Apr 2022
DOIs
Publication statusPublished - 21 Apr 2022

Keywords

  • ARCHITECTURE
  • ASSOCIATION
  • DISEASE
  • INDIVIDUALS
  • INTEGRATION
  • MUTATIONS
  • PROFILE
  • RISK
  • STATISTICS
  • VARIANTS

Cite this