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

Gusev, Alexander and Mancuso, Nicholas and Won, Hyejung and Kousi, Maria and Finucane, Hilary K and Reshef, Yakir and Song, Lingyun and Safi, Alexias and McCarroll, Steven and Neale, Benjamin M and Ophoff, Roel A and O'Donovan, Michael C and Crawford, Gregory E and Geschwind, Daniel H and Katsanis, Nicholas and Sullivan, Patrick F and Pasaniuc, Bogdan and Price, Alkes L and Knight, Jo (2018) Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nature Genetics, 50 (4). pp. 538-548. ISSN 1061-4036

[img]
Preview
PDF (GUSEV.main_text.FORMATTED)
GUSEV.main_text.FORMATTED.pdf - Accepted Version

Download (382kB)

Abstract

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.

Item Type:
Journal Article
Journal or Publication Title:
Nature Genetics
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1311
Subjects:
ID Code:
126538
Deposited By:
Deposited On:
24 Aug 2018 07:58
Refereed?:
Yes
Published?:
Published
Last Modified:
19 Sep 2020 05:19