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

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  • Schizophrenia Working Group of the Psychiatric Genomics Consortium
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<mark>Journal publication date</mark>04/2018
<mark>Journal</mark>Nature Genetics
Issue number4
Volume50
Number of pages11
Pages (from-to)538-548
Publication StatusPublished
Early online date9/04/18
<mark>Original language</mark>English

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.