Genetic studies have identified thousands of genetic variants that are associated with human diseases. Some of these variants cause disease because they encode mutated proteins, but for many disease-associated genes, the mechanism that links a genetic variant to a disease phenotype are unclear. Many disease-associated genetic variants lie in regions of the genome that regulate gene expression. Such variants may alter gene expression by changing epigenetic modifications or 3-dimensional interactions with other genetic loci. Therefore, identifying genetic variants that influence epigenetic modifications or chromatin structure would help would help elucidate the genetic interactions that underlie complex human diseases.

Richard Pelikan, PhD and Pat Gaffney, MD used a novel approach to survey the genome for genetic variants that influence epigenetic modifications, chromatin topology, and gene expression. In lymphoblastoid cell lines from patients with systemic lupus erythematosus, this approach identified 6,261 genetic variants that influence the magnitude of histone modifications. These variants were designated histone quantitative trail loci (hQTLs). Of these hQTLs, 386 were previously associated with autoimmune disease, and 36% of the disease-associated hQTLs significantly contributed to gene expression variation in their target genes. In addition, the hQTLs interacted with known expression quantitative trait loci (eQTLs) located on different haplotype blocks. Finally, genetic variants in the HLA Class II locus have previously been associated with autoimmune diseases. By comparing the HLA-DR3 and HLA-DR15 risk haplotypes in the HLA Class II locus this study showed that enrichment of hQTLs in the HLA-DR3 haplotype was associated with differences in 3D chromatin conformation and gene expression. These findings provide new insights that can be used to discovery the causes of complex diseases.

This study used samples from the OSCTR Clinical Resources Core, and personnel in the Biostatistics, Epidemiology, and Research Design Core contributed to the manuscript as a co-author. In addition, the first author is an early stage investigator whose professional development has been facilitated by OSCTR resources, and the senior author is an OSCTR mentor.

Reference: Pelikan RC, Kelly JA, Fu Y, Lareau CA, Tessneer KL, Wiley GB, et al. Enhancer histone-QTLs Are Enriched on Autoimmune Risk Haplotypes and Influence Gene Expression Within Chromatin Networks. Nat Commun. 2018 Jul 25;9(1):2905.