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.
Highlights
Genetic variants can confer risk to complex genetic diseases by modulating gene expression through changes to the epigenome
Genetic variants can induce epigenetic “footprints”—manifested as allele-specific imbalances in the magnitude of histone post-translational modifications (PTMs) (histone quantitative trait loci)— that identify functional states of enhancer elements[7]. These hQTLs can disrupt transcription factor binding motifs leading to enhancer dysfunction that is heritable from parent to offspring[8,9]. These results suggest that a priori knowledge of epigenome alterations induced by hQTLs could focus analysis of disease risk haplotypes on enhancer elements most likely to harbor diseasemodifying variants, even within the context of strong linkage disequilibrium (LD)
Following realignment of Chromatin immunoprecipitation (ChIP)-seq reads using WASP to control for reference genome alignment bias[7], the 315,210 single nucleotide polymorphisms (SNPs) were tested for allelic imbalance on histone PTMs using the combined haplotype test (CHT)[8]
Summary
Genetic variants can confer risk to complex genetic diseases by modulating gene expression through changes to the epigenome. The epigenome coordinates information flow in three-dimensional (3D) space through chromatin loops that facilitate long-range engagement of enhancers with promoters of genes whose expression sustains or modulates the cell state[4] From this framework, it follows that DNA mutations and polymorphisms have the potential to modify cellular phenotypes by inducing changes in the epigenome circuitry and how it processes information, for complex genetic diseases. Genetic variants can induce epigenetic “footprints”—manifested as allele-specific imbalances in the magnitude of histone PTMs (histone quantitative trait loci (hQTLs))— that identify functional states of enhancer elements[7] These hQTLs can disrupt transcription factor binding motifs leading to enhancer dysfunction that is heritable from parent to offspring[8,9]. We identify statistically significant physical interactions between eQTLs and hQTLs, in LD, that modify eQTL-based gene expression and explain, in part, gene expression variability of eQTL data, suggesting potential implications for functional genomic studies that leverage eQTL data for subject selection and stratification
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