To assess the degree to which genetic variants influence epigenome activity, we are integrating epigenetic and genotypic data to identify variants that induce allelic imbalance in the magnitude of histone post-translational modifications, referred to herein as enhancer histone quantitative trait loci (hQTLs).
We have demonstrated that enhancer hQTLs are enriched on autoimmune disease risk haplotypes and disproportionately influence gene expression variability compared with non-hQTL variants in strong linkage disequilibrium. In addition, we identified significant eQTL x hQTL interactions that reveal substructure within eQTL gene expression, suggesting potential implications for functional genomic studies that leverage eQTL data for subject selection and stratification.
Lastly, our hQTL approach is shedding new light on the HLA Class II region; a region with the most reproducibly significant GWAS associations with autoimmune diseases, but arguably the least understood. Our findings suggest that the epigenome differentially regulates the two prominent SLE risk haplotypes, HLA-DR3 and HLA-DR15, resulting in different 3D chromatin conformations and gene expression (see featured figure).
Our latest discoveries are featured in Pelikan, et al. 2018 Nat Comm. https://www.nature.com/articles/s41467-018-05328-9