Abstract
Chromatin looping between regulatory elements and gene promoters presents a potential mechanism whereby disease risk variants affect their target genes. In this study, we use H3K27ac HiChIP, a method for assaying the active chromatin interactome in two cell lines: keratinocytes and skin lymphoma–derived CD8+ T cells. We integrate public datasets for a lymphoblastoid cell line and primary CD4+ T cells and identify gene targets at risk loci for skin-related disorders. Interacting genes enrich for pathways of known importance in each trait, such as cytokine response (psoriatic arthritis and psoriasis) and replicative senescence (melanoma). We show examples of how our analysis can inform changes in the current understanding of multiple psoriasis-associated risk loci. For example, the variant rs10794648, which is generally assigned to IFNLR1, was linked to GRHL3, a gene essential in skin repair and development, in our dataset. Our findings, therefore, indicate a renewed importance of skin-related factors in the risk of disease.
Highlights
GWASs have uncovered the genetic factors that contribute to disease risk for many complex disorders, including dermatological conditions such as psoriasis (Ps) (Tsoi et al, 2017) or atopic dermatitis (AD) (Paternoster et al, 2015)
HaCaT unstimulated HiChIP interactions originating from GWAS locus
HaCaT IFN-γ stimulated HiChIP interactions originating from GWAS locus b
Summary
GWASs have uncovered the genetic factors that contribute to disease risk for many complex disorders, including dermatological conditions such as psoriasis (Ps) (Tsoi et al, 2017) or atopic dermatitis (AD) (Paternoster et al, 2015). Previous studies have used these techniques to identify causal genes at GWAS loci (Cairns et al, 2016; Dryden et al, 2014; Jager et al, 2015; Martin et al, 2016, 2015; McGovern et al, 2016; Mumbach et al, 2017), uncovering many important mechanisms and pathways involved in various diseases. These studies have, mainly focused on cells derived from blood and immune cells
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