Multi‐ancestral GWAS identifies shared and Asian‐specific loci for SLE and links type III interferon signaling and lysosomal function to the disease

Objectives Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with differences in prevalence and severity among ancestral groups. This study aims to identify novel genetic components either shared or distinct between Asian and European populations. Methods Both trans-ancestral and ancestry-specific meta-analyses of genome-wide association studies (GWAS) for SLE were performed, involving 30,604 participants of European, Chinese or Thai origin. Using public epigenomic data and expression quantitative trait loci, fine-mapping analyses were conducted to identify putative causal variants and genes for the newly identified loci. Performance of polygenic risk scores (PRS) for the Thai cohort was evaluated comparing different training data. Results We identified ten novel SLE susceptibility loci, four of which were found by Asian-specific meta-analyses. A 1bp deletion upstream of IFNLR1 was found associated with SLE, with the risk allele correlated with increased expression of IFNLR1. This gene encodes interferon lambda receptor 1, pointing to the role of type III interferon signaling in SLE. An intronic variant in SLC29A3 was found associated with SLE only in Asians. The putative risk variant may modulate SLC29A3 expression in a monocyte-specific manner. SLC29A3 encodes a lysosomal nucleoside transporter, and subsequent analyses suggest reduced lysosomal function and phagocytosis might be the mechanism underlying this association. In addition, trans-ancestral meta-analysis was proved to be valuable in risk prediction for individuals without ancestry-matched data. Conclusion Multi-ancestral GWAS identified both shared and Asian-specific loci for SLE, and functional annotation pointed to the involvement of increased type III interferon signaling and reduced lysosomal function in SLE.