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

• Published in: Nature communications Vol. 9; no. 1; pp. 2905 - 14
• Main Authors: Pelikan, Richard C., Kelly, Jennifer A., Fu, Yao, Lareau, Caleb A., Tessneer, Kandice L., Wiley, Graham B., Wiley, Mandi M., Glenn, Stuart B., Harley, John B., Guthridge, Joel M., James, Judith A., Aryee, Martin J., Montgomery, Courtney, Gaffney, Patrick M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.07.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 38/15; 38/22; 38/39; 38/91; 45/15; 631/208/177; 631/208/729/743; 631/337/100/101; 692/699/249/1313; Chromatin; Chromatin - genetics; Conformation; Epigenetics; Female; Gene expression; Gene mapping; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetic variance; Genome-Wide Association Study; Genotype; Genotype & phenotype; Haplotypes; Haplotypes - genetics; Health risks; Histocompatibility antigen HLA; Humanities and Social Sciences; Humans; Linkage disequilibrium; Linkage Disequilibrium - genetics; Lymphoblastoid cell lines; Male; multidisciplinary; Post-translation; Quantitative trait loci; Quantitative Trait Loci - genetics; Risk; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05328-9

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. Disease risk variants can exert their influence on phenotypes by altering epigenome function. Here, Pelikan et al. show that variants inducing allelic imbalance in histone marks in lymphoblastoid cell lines from lupus patients are enriched in autoimmune disease haplotypes and influence gene expression.