Epistasis Blog

From the Computational Genetics Laboratory at the University of Pennsylvania (www.epistasis.org)

Sunday, June 17, 2018

Leveraging epigenomics and contactomics data to investigate SNP pairs in GWAS

Our new paper on the incorporation of expert knowledge about epigenomics and chromatin looping for modeling epistasis has been published in Human Genetics.

Manduchi E, Williams SM, Chesi A, Johnson ME, Wells AD, Grant SFA, Moore JH. Leveraging epigenomics and contactomics data to investigate SNP pairs in GWAS. Hum Genet. 2018 May;137(5):413-425. [PubMed]


Although Genome Wide Association Studies (GWAS) have led to many valuable insights into the genetic bases of common diseases over the past decade, the issue of missing heritability has surfaced, as the discovered main effect genetic variants found to date do not account for much of a trait's predicted genetic component. We present a workflow, integrating epigenomics and topologically associating domain data, aimed at discovering trait-associated SNP pairs from GWAS where neither SNP achieved independent genome-wide significance. Each analyzed SNP pair consists of one SNP in a putative active enhancer and another SNP in a putative physically interacting gene promoter in a trait-relevant tissue. As a proof-of-principle case study, we used this approach to identify focused collections of SNP pairs that we analyzed in three independent Type 2 diabetes (T2D) GWAS. This approach led us to discover 35 significant SNP pairs, encompassing both novel signals and signals for which we have found orthogonal support from other sources. Nine of these pairs are consistent with eQTL results, two are consistent with our own capture C experiments, and seven involve signals supported by recent T2D literature.