Abstract
Schizophrenia genome-wide association studies have identified >150 regions of the genome associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. To explore the mechanism of non-coding regulatory elements in schizophrenia, we performed ATAC-seq on adult prefrontal cortex brain samples from 135 individuals with schizophrenia and 137 controls, and identified 118,152 ATAC-seq peaks. These accessible chromatin regions in the brain are highly enriched for schizophrenia SNP heritability. Accessible chromatin regions that overlap evolutionarily conserved regions exhibit an even higher heritability enrichment, indicating that sequence conservation can further refine functional risk variants. We identify few differences in chromatin accessibility between cases and controls, in contrast to thousands of age-related differential accessible chromatin regions. Altogether, we characterize chromatin accessibility in the human prefrontal cortex, the effect of schizophrenia and age on chromatin accessibility, and provide evidence that our dataset will allow for fine mapping of risk variants.
Highlights
Schizophrenia genome-wide association studies have identified >150 regions of the genome associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder
We found that regions of open chromatin in adult DLPFC were strongly enriched for genetic variation relevant for schizophrenia (Fig. 2a): the 1.2% of single-nucleotide polymorphisms (SNPs) (n = 125,762) located in ATAC-seq peaks explained 8.55% of the SNP heritability of schizophrenia (7.1-fold enrichment, P value = 0.015)
It appears that there are many chromatin interactions involving regions of shared genetic effect between schizophrenia, DLPFC gene expression, and open chromatin. While these data provide important functional context for the schizophrenia GWAS associations, more sophisticated functional analysis will be needed to dissect the specific mechanisms leading to schizophrenia risk. Groups such as the Psychiatric Genomics Consortium have generated some of the largest genome-wide association (GWA) data for schizophrenia to date[1]
Summary
Schizophrenia genome-wide association studies have identified >150 regions of the genome associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. Identifying actionable genes has proven complex, with a few exceptions such as rare exon variants in SETD1A7 and copy number variation in single genes like NRXN1 and C48,9 These studies provide strong evidence that genetic risk for schizophrenia results from the concerted effects of many genes. Our overall goal was to comprehensively identify active gene regulatory elements in a brain region relevant to schizophrenia, and to quantify how genetic variation alters function such as single-nucleotide polymorphisms (SNPs) that alter chromatin accessibility (i.e., chromatin QTL (cQTL)). We use these data to parse genetic risk for schizophrenia from large GWA. This is the largest study of chromatin accessibility in schizophrenia and among the largest for any human disease
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