GWAS for Systemic Sclerosis Identified six novel susceptibility loci including penetrating Fcγ-Receptor Region

Abstract We conducted a Japanese GWAS for systemic sclerosis (SSc) comprising 1,428 cases and 112,599 controls, the largest Asian GWAS for SSc ever, and identified three novel signals. The lead SNP in FCGR/FCRL region had a strong effect size (OR 2.05, P = 4.9×10 −11 ). The complete LD SNP, rs10917688, was found in a cis-regulatory element and a part of binding motifs for IRF8. IRF8 was a significant locus in the European GWAS and rs10917688 showed an association only in the presence of the risk allele of IRF8 in Japanese. rs10917688 was marked with H3K4me1 in primary B cells, and the heritability was enriched in active histone marks of primary B cells. A meta-analysis with the latest European GWAS found additional 30 significant loci including three novel signals. PRS constructed with the effect sizes of the meta-analysis indicated potential portability of genetic associations beyond populations (AUC: 0.593). The fitting of PRS was improved by further prioritizing the top 5% SNPs of IRF8 biding sites in B cells, underscoring common genetic architecture across populations and critical roles of B cells and IRF8 for SSc development.