Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity

Abstract

Natural Killer (NK) cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect NK gene expression is poorly understood. We performed expression quantitative trait locus (eQTL) mapping of negatively selected NK cells from a population of healthy Europeans (n=245). We find a significant subset of genes demonstrate eQTL specific to NK cells and these are highly informative of human disease, in particular autoimmunity. An NK cell transcriptome-wide association study (TWAS) across five common autoimmune diseases identified further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor (KIR) Region, GNLY and MC1R. Our findings provide new insights into the unique biology of NK cells, demonstrating markedly different eQTL from other immune cells, with implications for disease mechanisms.

Genome-wide association study of leprosy in Malawi and Mali

“…Integrating data describing chromatin state [16] and eQTL mapping [17][18][19][20][21]38] in a range of tissues we identify robust evidence of regulatory activity at the leprosy-associated locus. One of the credible set SNPs we identify in the leprosy GWAS, rs2274351:T, is located in an active promoter at the 5' ends of two genes (ACTR1A and SUFU).…”

“…range of primary immune cells; monocytes [17], B cells [18], NK cells [19], neutrophils [20], CD4 + T cells and CD8 + T cells [21]. In keeping with the observation that a credible set SNP for the leprosy association overlaps with an active promoter 5' to ACTR1A, among eQTL mapping data in primary immune cells (Fig 3A ), there is evidence for colocalisation between the leprosy risk locus and an eQTL for ACTR1A expression in CD4 + T cells (posterior probability of colocalisation, PP4 = 0.94).…”

ACTR1Ahas pleiotropic effects on risk of leprosy, inflammatory bowel disease and atopy

“…Coloc adopts a Bayesian approach to compare evidence for independent or shared association signals for two traits at a given genetic locus. We tested for colocalization between leprosy susceptibility at the chr10q24.32 locus and previously-published eQTL mapping studies in naïve and stimulated primary immune cells from individuals of European ancestry (Fairfax et al, 2014; Fairfax et al, 2012; Gilchrist et al, 2021; Kasela et al, 2017; Naranbhai et al, 2015); NK cells (n = 245), B cells (n = 283), monocytes (n = 414), CD4 + T cells (n = 293), CD8 + T cells (n = 283), neutrophils (n = 101), LPS-stimulated monocytes (2 hours, n = 261; 24 hours, n = 322) and IFN γ -stimulated monocytes (n = 267). We considered evidence for colocalization for each gene within a 250kb window of the peak leprosy association (rs2015583).…”

“…In keeping with the observation that the human genetics of leprosy risk is characterized by considerable heterogeneity of effect between populations, there is no evidence for leprosy association (p < 0.05) in Chinese populations (8,156 cases, 15,610 controls) A leprosy risk locus modifies ACTR1A expression in CD4 + T cells Trait-associated genetic variation identified by GWAS are highly enriched for regulatory variation. To explore whether leprosy-associated genetic variation at chr10q24.32 modifies leprosy risk through its effect on gene expression, we investigated whether the leprosy risk locus colocalizes with expression quantitative trait loci (eQTL) in a range of primary immune cells; monocytes (Fairfax et al, 2014), B cells (Fairfax et al, 2012), NK cells (Gilchrist et al, 2021), neutrophils (Naranbhai et al, 2015), CD4 + T cells and CD8+ T cells (Kasela et al, 2017). These data demonstrate colocalization of the leprosy risk locus at chr10q24.32 with an eQTL for ACTR1A expression in CD4 + T cells (posterior probability of colocalization, P P 4 = 0.94), but not gene expression in other cell types (Fig.…”

“…Coloc adopts a Bayesian approach to compare evidence for independent or shared association signals for two traits at a given genetic locus. We tested for colocalization between leprosy susceptibility at the chr10q24.32 locus and previously-published eQTL mapping studies in naïve and stimulated primary immune cells from individuals of European ancestry (Fairfax et al, 2014;Fairfax et al, 2012;Gilchrist et al, 2021;Kasela et al, 2017;Naranbhai et al, 2015); NK cells (n = 245), B cells (n = 283), monocytes…”