Trans-eQTL mapping prioritises USP18 as a negative regulator of interferon response at a lupus risk locus

Abstract

Although genome-wide association studies have provided valuable insights into the genetic basis of complex traits and diseases, translating these findings to causal genes and their downstream mechanisms remains challenging. We performed trans expression quantitative trait locus (trans-eQTL) meta-analysis in 3,734 lymphoblastoid cell line samples, identifying four robust loci that replicated in an independent multi-ethnic dataset of 682 individuals. We prioritised a missense variant in the ubiquitin specific peptidase 18 (USP18) gene that is a known negative regulator of interferon signalling and has previously been associated with increased risk of systemic lupus erythematosus (SLE). The SLE risk allele increased the expression of 50 interferon-inducible genes, suggesting that the risk allele impairs USP18s ability to effectively limit the interferon response. Intriguingly, the USP18 trans-eQTL signal would not have been discovered in a meta-analysis of up to 43,301 whole blood samples, reaffirming the importance of capturing context-specific genetic effects for GWAS interpretation.