Cross-Phenotype GWAS Supports Shared Genetic Susceptibility to Systemic Sclerosis and Primary Biliary Cholangitis

Objective An increased risk of primary biliary cholangitis (PBC) has been reported in patients with systemic sclerosis (SSc). Our study aims to investigate the shared genetic susceptibility between the two disorders and to define candidate causal genes using cross-phenotype GWAS meta-analysis. Methods We performed cross-phenotype GWAS meta-analysis and colocalization analysis for SSc and PBC. We performed both genome-wide and locus-based analysis, including tissue and pathway enrichment analyses, fine-mapping, colocalization analyses with expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets, and phenome-wide association studies (PheWAS). Finally, we used an integrative approach to prioritize candidate causal genes from the novel loci. Results We detected a strong genetic correlation between SSc and PBC (rg = 0.84, p = 1.7 × 10 -6 ). In the cross-phenotype GWAS meta-analysis, we identified 44 non-HLA loci that reached genome-wide significance (p < 5 × 10 -8 ). Evidence of shared causal variants between SSc and PBC was found for nine loci, five of which were novel. Integrating multiple sources of evidence, we prioritized CD40, ERAP1, PLD4, SPPL3 , and CCDC113 as novel candidate causal genes. The CD40 risk locus colocalized with trans-pQTLs of multiple plasma proteins involved in B cell function. Conclusion Our study supports a strong shared genetic susceptibility between SSc and PBC. Through cross-phenotype analyses, we have prioritized several novel candidate causal genes and pathways for these disorders. Key messages What is already known on this topic Systemic sclerosis (SSc) and primary biliary cholangitis (PBC) are autoimmune disorders that exhibit overlapping clinical and histological features. The prevalence of PBC is higher in patients with SSc compared to the general population. Multiple susceptibility genomic loci have been identified for SSc and PBC through genome-wide association studies (GWAS). What this study adds There is a strong genetic correlation between SSc and PBC, comparable in magnitude to the genetic correlation between SSc and systemic lupus erythematosus (SLE). This shared genetic susceptibility aligns with the observed increased relative risk of developing PBC and SLE in individuals with SSc. Using cross-phenotype GWAS and colocalization analysis, we have discovered nine genomic loci that account for the shared genetic etiology. Five of the nine loci were novel. Using an integrative approach, we have prioritized five novel candidate causal genes: CD40, ERAP1, PLD4, SPPL3 and CCDC113 . The CD40 risk allele for SSc and PBC is paradoxically associated with reduced CD40 levels. Causal inference analyses indicate that this reduction in CD40 levels, due to CD40 locus polymorphism, leads to an increase in various plasma proteins involved in B cell activation, including the CD40 ligand. How this study might affect research, practice or policy Mechanistic studies are needed to confirm the candidate causal genes prioritized by our in silico analyses. Our study advocates for heightened awareness among rheumatologists regarding the possibility of concurrent PBC in patients with SSc.