Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions

Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements. To identify genetic variants underlying chromatin variability in humans we mapped quantitative trait loci for three different histone marks (H3K4me3, H3K4me1 and H3K27ac) in lymphoblastoid cell lines (LCL) derived from 76 individuals. These individuals have been extensively genotyped by the 1000 genomes project as part of the Yoruban population (YRI). We integrated previously published RNA and DNase data for these individuals to elucidate the interplay between chromatin variation and gene expression. Additionally we performed chromatin interaction assays (HiC and ChIA-PET) in one individual to investigate the contribution of 3D proximity to genetic regulation.