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 3734 lymphoblastoid cell line samples, identifying four robust loci that replicated in an independent multi-ethnic dataset of 682 individuals. The trans-eQTL signal at the ubiquitin specific peptidase 18 (USP18) locus colocalised with a GWAS signal for systemic lupus erythematosus (SLE). USP18 is a known negative regulator of interferon signalling and 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, 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.

Fig. 1. Overview of the MetaLCL study.

A Overview of the study design and participating cohorts. B Significant trans-eQTLs detected in the meta-analysis. The upper scatter plot shows the number of trans-eQTL target genes detected at each trans-eQTL locus with p < 5 x 10⁻⁸. Six trans-eQTL loci with the most target genes have been labelled with the name of the closest cis gene. The lower scatter plot shows all significant loci for each tested gene at the more stringent p < 1 × 10⁻¹¹ threshold. Cis associations are located on the diagonal while putative trans associations are located off diagonal. The points represent two-sided p-values from inverse-variance weighted meta-analysis. Source data are provided as a Source Data file.

Fig. 2. SLE GWAS association at the USP18 locus is a trans-eQTL for interferon response genes.

A Regional association plot for the SLE GWAS with POEMColoc imputed summary statistics and regional association plot for the lead trans-eQTL gene (HERC5) at the USP18 locus. The trans-eQTL lead and GWAS lead variants (rs4819670) are identical and in high LD with a missense variant (rs3180408) in the USP18 gene. The points represent two-sided p-values from inverse-variance weighted meta-analysis. The original regional association plot for the SLE GWAS is shown on Supplementary Fig. 4. B Volcano plot of the trans-eQTL target genes. Genes with FDR < 5% are highlighted in red. C USP18 down-regulates type I interferon signalling by restricting the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. Source data are provided as a Source Data file.

Fig. 3. Role of interferon signalling in SLE pathogenesis.

A Upstream regulators of interferon response genes (IFNA* contains multi-gene interferon-alpha gene cluster). B Downstream transcriptional targets of the interferon signalling (HLA* marks the HLA region). The increased gene expression is marked in red, while reduced gene expression is marked in blue. The visualisation illustrates the effect on USP18 target genes in relation to the SLE risk allele. DE - differential gene expression in SLE cases versus controls; GWAS - GWAS hits for SLE, ChEMBL, phase III - SLE phase III clinical trials from ChEMBL, PID - genes causing primary immunodeficiency from Genomics England. Source data are provided as a Source Data file.