Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks

Richard C. Pelikan, Jennifer A. Kelly, Yao Fu, Caleb A. Lareau, Kandice L. Tessneer, Graham B. Wiley, Mandi M. Wiley, Stuart B. Glenn, John B. Harley, Joel M. Guthridge, Judith A. James, Martin J. Aryee, Courtney Montgomery and Patrick M. Gaffney ()
Additional contact information
Richard C. Pelikan: Oklahoma Medical Research Foundation
Jennifer A. Kelly: Oklahoma Medical Research Foundation
Yao Fu: Oklahoma Medical Research Foundation
Caleb A. Lareau: Harvard T.H. Chan School of Public Health
Kandice L. Tessneer: Oklahoma Medical Research Foundation
Graham B. Wiley: Oklahoma Medical Research Foundation
Mandi M. Wiley: Oklahoma Medical Research Foundation
Stuart B. Glenn: Oklahoma Medical Research Foundation
John B. Harley: Cincinnati Children’s Hospital
Joel M. Guthridge: Oklahoma Medical Research Foundation
Judith A. James: Oklahoma Medical Research Foundation
Martin J. Aryee: Harvard T.H. Chan School of Public Health
Courtney Montgomery: Oklahoma Medical Research Foundation
Patrick M. Gaffney: Oklahoma Medical Research Foundation

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Genetic variants can confer risk to complex genetic diseases by modulating gene expression through changes to the epigenome. To assess the degree to which genetic variants influence epigenome activity, we integrate epigenetic and genotypic data from lupus patient lymphoblastoid cell lines to identify variants that induce allelic imbalance in the magnitude of histone post-translational modifications, referred to herein as histone quantitative trait loci (hQTLs). We demonstrate 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. We show that the epigenome regulates HLA class II genes differently in individuals who carry HLA-DR3 or HLA-DR15 haplotypes, resulting in differential 3D chromatin conformation and gene expression. Finally, we identify significant expression QTL (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.

Date: 2018
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DOI: 10.1038/s41467-018-05328-9

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