The identification of blood-derived response eQTLs reveals complex effects of regulatory variants on inflammatory and infectious disease risk

Abstract

Hundreds of risk loci for immune mediated inflammatory and infectious diseases have been identified by genome-wide association studies (GWAS). Yet, what causal variants and genes in risk loci underpin the observed associations remains poorly understood for most. The identification of colocalized cis-expression Quantitative Trait Loci (cis-eQTLs) is a promising way to identify candidate causative genes. The catalogue of cis-eQTLs of the immune system is likely incomplete as many cis-eQTLs may be context-specific. We built a large cohort of 406 healthy individuals and expanded the immune cis-regulome through their whole blood transcriptome obtained after stimulation with specific toll-like receptor (TLR) agonists and T-cell receptor (TCR) antagonist. We report three mechanisms that may explain why an eQTL could only be revealed after immune stimulation. More than half of the cis-eQTLs detected in this study would have been overlooked without specific immune stimulations. We then mined this new catalogue of response (r) eQTLs, with public GWAS summary statistics of three diseases through a colocalization approach: inflammatory bowel diseases, rheumatoid arthritis and COVID-19 disease. We identified reQTL-specific colocalizations for risk loci for which no matching eQTL were reported before, revealing interesting new candidate causal genes.