Mapping genomic loci implicates genes and synaptic biology in schizophrenia.

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Trubetskoy V., Pardiñas A. F., Qi T., Panagiotaropoulou G., Awasthi S., Bigdeli T. B., ...Daha Fazla

Nature, cilt.604, sa.7906, ss.502-508, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 604 Sayı: 7906
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1038/s41586-022-04434-5
  • Dergi Adı: Nature
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, International Bibliography of Social Sciences, Aerospace Database, Agricultural & Environmental Science Database, Animal Behavior Abstracts, Applied Science & Technology Source, Aqualine, Aquatic Science & Fisheries Abstracts (ASFA), Art Source, Artic & Antarctic Regions, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Communication Abstracts, EBSCO Education Source, EMBASE, Environment Index, Food Science & Technology Abstracts, Gender Studies Database, Geobase, INSPEC, MEDLINE, Metadex, MLA - Modern Language Association Database, Pollution Abstracts, Psycinfo, Public Affairs Index, Veterinary Science Database, zbMATH, DIALNET, Civil Engineering Abstracts
  • Sayfa Sayıları: ss.502-508
  • İstanbul Üniversitesi Adresli: Evet

Özet

© 2022, The Author(s), under exclusive licence to Springer Nature Limited.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.