Epigenetic landscapes of intracranial aneurysm risk haplotypes implicate enhancer function of endothelial cells and fibroblasts in dysregulated gene expression

Genome-wide association studies have identified many single nucleotide polymorphisms (SNPs) associated with increased risk for intracranial aneurysm (IA). However, how such variants affect gene expression within IA is poorly understood. We used publicly-available ChIP-Seq data to study chromatin landscapes surrounding risk loci to determine whether IA-associated SNPs affect functional elements that regulate gene expression in cell types comprising IA tissue. We mapped 16 significant IA-associated SNPs to linkage disequilibrium (LD) blocks within human genome. Using ChIP-Seq data, we examined these regions for presence of H3K4me1, H3K27ac, and H3K9ac histone marks (typically associated with latent/active enhancers). This analysis was conducted in several cell types that are present in IA tissue (endothelial cells, smooth muscle cells, fibroblasts, macrophages, monocytes, neutrophils, T cells, B cells, NK cells). In cell types with significant histone enrichment, we used HiC data to investigate topologically associated domains (TADs) encompassing the LD blocks to identify genes that may be affected by IA-associated variants. Bioinformatics were performed to determine the biological significance of these genes. Genes within HiC-defined TADs were also compared to differentially expressed genes from RNA-seq/microarray studies of IA tissues. We found that endothelial cells and fibroblasts, rather than smooth muscle or immune cells, have significant enrichment for enhancer marks on IA risk haplotypes (p