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Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights.

Nat Genet. 2018 Apr;50(4):538-548

Authors: 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

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.

PMID: 29632383 [PubMed – in process]

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