An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?

• DOI: 10.1371/journal.pgen.1009684
• Publication Date: 2021-07-27T17:30:46Z
• Authors: Margot Brandt; Sarah Kim-Hellmuth; Marcello Ziosi; Alper Gokden; Aaron Wolman; Nora Lam; Yocelyn Recinos; Zharko Daniloski; John A. Morris; Veit Hornung; Johannes Schumacher; Tuuli Lappalainen
• Keywords: IRF1; Genome-wide Association Study; SNP

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, discovered that risk variant autoimmune disease, rs17622517 an intron C5ORF56, affects the expression transcription factor IRF1 20 kb away. The cis-regulatory effect specific is active under early immune stimulus, large number trans-eQTL effects across genome late LPS response. Using CRISPRi silencing, showed perturbation SNP locus downregulates causes widespread transcriptional effects. Genome editing by CRISPR had suggestive recapitulation LPS-specific signal lent support site being functional. Our results suggest common inter-individual response stimuli via regulation IRF1. For GWAS locus, our work provides evidence functional variant, demonstrates condition-specific enhancer effect, identifies as likely causal gene cis, indicates overactivation downstream immune-related pathway may be cellular mechanism increasing disease risk. This not only rare experimental validation master-regulatory trans-eQTL, but also power eQTL mapping build mechanistic hypotheses amenable follow-up using toolkit.