Epigenetics of Disease: Translating GWAS Variants To Function

The epigenome works with transcription factors to produce the proper pattern of gene expression at the proper developmental time-point for the proper cell type and state. This layer of control is dysregulated is disease. By comparing the epigenomic landscapes of normal and diseased cells, we can find differences that may be responsible for pathology.

Genome-wide association studies (GWAS) are increasingly revealing disease-associated mutations in regions of the genome that promote or enhance other genes' activity through epigenetic modification. For example, using a combination of GWAS and epigenomic mapping technologies, a mutation associated with heart disease was found to lie in an enhancer active in cardiac tissue (Gupta et al. 2017). In addition, disease-associated genetic variants in multiple sclerosis have been found in control regions that are active in regulatory cells of the immune system, helping to pinpoint the likely origins of this autoimmune disease (Farh et al. 2015).

Such discoveries enable the development of mechanistic hypotheses for the diseases in question: they help translate GWAS variants into functional information. This is increasingly becoming a major focus of the program.


  1. Epigenome maps of disease states
    We participate in a NIAID-funded collaboration with Yale University devoted to the genomics and epigenomics of NFkB-mediated gene regulation in multiple sclerosis. We are also actively mapping epigenomic contributors to cancer, and represent one of five U.S.-based mapping centers participating in Encode 4.
  2. Interpreting GWAS hits in the non-coding genome
    We develop computational models to interpret functions of noncoding variants.
    See computational tool development for details.

Key Papers

Gupta RM, et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell. 2017.

Warren CR, et al. Induced pluripotent stem cell differentiation enables functional validation of GWAS variants in metabolic disease. Cell Stem Cell. 2017.

Choi J, Clement K, et al. DUSP9 modulates DNA hypomethylation in female mouse pluripotent stem cells. Cell Stem Cell. 2017.

Wang X, et al. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures. eLife. 2016.

Kang S, Tsai LT, et al. Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis. Nature Cell Biology. 2014.

Zhu J, Adli M, et al. Genome-wide chromatin state transitions associated with developmental and environmental cues.  Cell.  2013.

Claussnitzer M, Dankel SN, et al. FTO obesity variant circuitry and adipocyte browning in humans. New England Journal of Medicine. 2015.

Farh KK, Marson A, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015.