RT Journal Article SR Electronic T1 An autoimmune disease risk variant has a trans master regulatory effect mediated by IRF1 under immune stimulation JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.02.21.959734 DO 10.1101/2020.02.21.959734 A1 Margot Brandt A1 Sarah Kim-Hellmuth A1 Marcello Ziosi A1 Alper Gokden A1 Aaron Wolman A1 Nora Lam A1 Yocelyn Recinos A1 Veit Hornung A1 Johannes Schumacher A1 Tuuli Lappalainen YR 2020 UL http://biorxiv.org/content/early/2020/02/24/2020.02.21.959734.abstract AB Functional mechanisms remain unknown for most genetic loci associated to complex human traits and diseases. In this study, we first mapped trans-eQTLs in a data set of primary monocytes stimulated with LPS, and discovered that a risk variant for autoimmune disease, rs17622517 in an intron of C5ORF56, affects the expression of the transcription factor IRF1 20 kb away. The cis-regulatory effect on IRF1 is active under early immune stimulus, with a large number of trans-eQTL effects across the genome under late LPS response. Using CRISPRi silencing, we showed that the SNP locus indeed functions as an IRF1 enhancer with widespread transcriptional effects. Genome editing by CRISPR further indicated that rs17622517 is indeed a causal variant in this locus, and recapitulated the LPS-specific trans-eQTL signal. Our results suggest that this common genetic variant affects inter-individual response to immune stimuli via regulation of IRF1. For this autoimmune GWAS locus, our work provides evidence of the causal variant, demonstrates a condition-specific enhancer effect, identifies IRF1 as the likely causal gene in cis, 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-regulatory trans-eQTL, but also demonstrates the power of eQTL mapping to build mechanistic hypotheses amenable for experimental follow-up using the CRISPR toolkit.