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

Gusev, Alexander; Mancuso, Nicholas; Ophoff, Roel A.; O'Donovan, Miuchael C.; Crawford, Gregory E.; Geschwind, Daniel H.; Katsanis, Nicholas; Sullivan, Patrick F.; Pasaniuc, Bogdan; Price, Alkes L.; Henskens, Frans A.; Loughland, Carmel M.; Won, Hyejung; Michie, Patricia T.; Schall, Ulrich; Scott, Rodney J.; Kousi, Maria; Finucane, Hilary K.; Reshef, Yakir; Song, Lingyun; Safi, Alexias; McCarroll, Steven; Neale, Benjamin M.

Title: Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights
Creator: Gusev, Alexander; Mancuso, Nicholas; Ophoff, Roel A.; O'Donovan, Miuchael C.; Crawford, Gregory E.; Geschwind, Daniel H.; Katsanis, Nicholas; Sullivan, Patrick F.; Pasaniuc, Bogdan; Price, Alkes L.; Henskens, Frans A.; Loughland, Carmel M.; Won, Hyejung; Michie, Patricia T.; Schall, Ulrich; Scott, Rodney J.; Kousi, Maria; Finucane, Hilary K.; Reshef, Yakir; Song, Lingyun; Safi, Alexias; McCarroll, Steven; Neale, Benjamin M.
Relation: Nature Genetics Vol. 50, Issue 4, p. 538-548
Publisher Link: http://dx.doi.org/10.1038/s41588-018-0092-1
Publisher: Nature Publishing Group
Resource Type: journal article
Date: 2018
Description: 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.
Subject: Genome-wide association studies (GWAS); schizophrenia; transcriptome-wide association study (TWAS); brain
Identifier: http://hdl.handle.net/1959.13/1477856
Identifier: uon:50043
Identifier: ISSN:1061-4036
Language: eng
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