Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights.
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.
Gusev, A; Mancuso, N; Won, H; Kousi, M; Finucane, HK; Reshef, Y; Song, L; Safi, A; Schizophrenia Working Group of the Psychiatric Genomics Consortium, ; McCarroll, S; Neale, BM; Ophoff, RA; O'Donovan, MC; Crawford, GE; Geschwind, DH; Katsanis, N; Sullivan, PF; Pasaniuc, B; Price, AL
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