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Gusev, Alexander; Mancuso, Nicholas; Won, Hyejung; Kousi, Maria; Finucane, Hilary K; Reshef, Yakir; Song, Lingyun; Safi, Alexias; McCarroll, Steven; Neale, Benjamin M; Ophoff, Roel A; O'Donovan, Michael C; Crawford, Gregory E; Geschwind, Daniel H; Katsanis, Nicholas; Sullivan, Patrick F; Pasaniuc, Bogdan; Price, Alkes L
Nature genetics, 04/2018, Volume: 50, Issue: 4Journal Article
Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS.
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