An autoimmune disease risk variant has atransmaster regulatory effect mediated by IRF1 under immune stimulation

Functional mechanisms remain unknown for most genetic loci associated to complex human traits and diseases. In this study, we first mappedtrans-eQTLs in a data set of primary monocytes stimulated with LPS, and discovered that a risk variant for autoimmune disease, rs17622517 in an intron ofC5ORF56, affects the expression of the transcription factorIRF120 kb away. The cis-regulatory effect onIRF1is active under early immune stimulus, with a large number oftrans-eQTL effects across the genome under late LPS response. Using CRISPRi silencing, we showed that the SNP locus indeed functions as anIRF1enhancer with widespread transcriptional effects. Genome editing by CRISPR further indicated that rs17622517 is indeed a causal variant in this locus, and recapitulated the LPS-specifictrans-eQTL signal. Our results suggest that this common genetic variant affects inter-individual response to immune stimuli via regulation ofIRF1. For this autoimmune GWAS locus, our work provides evidence of the causal variant, demonstrates a condition-specific enhancer effect, identifiesIRF1as the likely causal gene incis, and indicates that overactivation of the downstream immune-related pathway may be the cellular mechanism increasing disease risk. This work not only provides rare experimental validation of a master-regulatorytrans-eQTL, but also demonstrates the power of eQTL mapping to build mechanistic hypotheses amenable for experimental follow-up using the CRISPR toolkit.