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Functional genomics reveal gene regulatory mechanisms underlying schizophrenia risk
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Journal Article
Functional genomics reveal gene regulatory mechanisms underlying schizophrenia risk
2019
Overview
Genome-wide association studies (GWASs) have identified over 180 independent schizophrenia risk loci. Nevertheless, how the risk variants in the reported loci confer schizophrenia susceptibility remains largely unknown. Here we systematically investigate the gene regulatory mechanisms underpinning schizophrenia risk through integrating data from functional genomics (including 30 ChIP-Seq experiments) and position weight matrix (PWM). We identify 132 risk single nucleotide polymorphisms (SNPs) that disrupt transcription factor binding and we find that 97 of the 132 TF binding-disrupting SNPs are associated with gene expression in human brain tissues. We validate the regulatory effect of some TF binding-disrupting SNPs with reporter gene assays (9 SNPs) and allele-specific expression analysis (10 SNPs). Our study reveals gene regulatory mechanisms affected by schizophrenia risk SNPs (including widespread disruption of POLR2A and CTCF binding) and identifies target genes for mechanistic studies and drug development. Our results can be accessed and visualized at SZDB database (
http://www.szdb.org/
).
We know a large number of risk SNPs for schizophrenia, but little about how these SNPs contribute to the disorder. Here, the authors use functional genomics to identify risk SNPs that disrupt transcription factor binding and validate the regulatory effects of the transcription factor binding-disrupting SNPs.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/44
/ 38/39
/ 38/91
/ 45/77
/ Alleles
/ Binding
/ Brain
/ Genetic Predisposition to Disease - genetics
/ Genome-wide association studies
/ Genome-Wide Association Study
/ Genomics
/ Humanities and Social Sciences
/ Humans
/ Loci
/ Polymorphism, Single Nucleotide - genetics
/ Regulatory mechanisms (biology)
/ Risk
/ Science
/ Single-nucleotide polymorphism
/ Weight
