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

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 and Price, Alkes L. 2018. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nature Genetics 50 (4) , pp. 538-548. 10.1038/s41588-018-0092-1

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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: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Nature Publishing Group
ISSN: 1061-4036
Date of First Compliant Deposit: 19 April 2018
Date of Acceptance: 9 February 2018
Last Modified: 09 Oct 2018 01:30
URI: http://orca.cf.ac.uk/id/eprint/110793

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