Integrative Genetic and Epigenetic Analysis Uncovers Regulatory Mechanisms of Autoimmune Disease

Am J Hum Genet. 2017 Jul 6;101(1):75-86. doi: 10.1016/j.ajhg.2017.06.001.


Genome-wide association studies in autoimmune and inflammatory diseases (AID) have uncovered hundreds of loci mediating risk. These associations are preferentially located in non-coding DNA regions and in particular in tissue-specific DNase I hypersensitivity sites (DHSs). While these analyses clearly demonstrate the overall enrichment of disease risk alleles on gene regulatory regions, they are not designed to identify individual regulatory regions mediating risk or the genes under their control, and thus uncover the specific molecular events driving disease risk. To do so we have departed from standard practice by identifying regulatory regions which replicate across samples and connect them to the genes they control through robust re-analysis of public data. We find significant evidence of regulatory potential in 78/301 (26%) risk loci across nine autoimmune and inflammatory diseases, and we find that individual genes are targeted by these effects in 53/78 (68%) of these. Thus, we are able to generate testable mechanistic hypotheses of the molecular changes that drive disease risk.

Keywords: DNase I hypersensitivity site; fine-mapping; genome-wide association study; non-coding variation.

MeSH terms

  • Alleles
  • Autoimmune Diseases / genetics*
  • Chromosomes, Human, Pair 6 / genetics
  • Deoxyribonuclease I / metabolism
  • Epigenesis, Genetic*
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Inflammation / genetics
  • Organ Specificity / genetics
  • Physical Chromosome Mapping
  • Regulatory Sequences, Nucleic Acid / genetics*
  • Reproducibility of Results
  • Risk Factors


  • Deoxyribonuclease I