USP18modulates lupus risk via negative regulation of interferon response

Abstract

AbstractAlthough 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 performedtransexpression 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. One of these loci was 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). In our analysis, the SLE risk allele increased the expression of 50 interferon-inducible genes, suggesting that the risk allele impairs USP18’s ability to effectively limit the interferon response. Intriguingly, mosttrans-eQTL targets of USP18 lacked independentcisassociations with SLE, cautioning against the use oftrans-eQTL evidence alone for causal gene prioritisation.