Systematic Localization of Common Disease-Associated Variation in Regulatory DNA

TLDR

Genome‑wide association studies have identified many noncoding variants associated with common diseases and traits. We found that disease‑associated noncoding variants cluster in DNase I hypersensitive sites, many of which are fetal‑active and enriched for gestational traits, and that these sites target distant genes, disrupt transcription factor motifs, alter chromatin states, and form regulatory networks; additionally, weakly associated variants show tissue‑selective DHS enrichment and enabled de novo identification of pathogenic cell types for Crohn’s disease, multiple sclerosis, and an ECG trait, underscoring the pervasive role of regulatory DNA variation in common disease.

Abstract

Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure-related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn's disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.