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Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights
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Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights
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Journal Article
Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights
2018
Overview
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.
A transcriptome-wide association study integrating genome-wide association data with expression data from brain, blood and adipose tissues identifies new candidate susceptibility genes for schizophrenia, providing a step toward understanding the underlying biology.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 38/43
/ Analysis
/ Animal Genetics and Genomics
/ Animals
/ Biomedical and Life Sciences
/ Brain
/ Disease
/ Gene Expression Profiling - methods
/ Genes
/ Genetic Predisposition to Disease
/ Genome-wide association studies
/ Genome-Wide Association Study - methods
/ Genomes
/ Genomics
/ Humans
/ Kinesins
/ Loci
/ Microtubule-Associated Proteins - genetics
/ Mitogen-Activated Protein Kinase 3 - genetics
/ Protein Phosphatase 2 - genetics
/ Splicing
