Cross-Phenotype GWAS Supports Shared Genetic Susceptibility to Systemic Sclerosis and Primary Biliary Cholangitis
Authors: Luo Yiming , Khan Atlas , Liu Lili , Lee Cue Hyunkyu , Perreault Gabriel J , Pomenti Sydney F , Gourh Pravitt , Kiryluk Krzysztof , Bernstein Elana J 
Published: July 2024

AbstractObjectiveAn 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.MethodsWe 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.ResultsWe 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 prioritizedCD40, ERAP1, PLD4, SPPL3, andCCDC113as novel candidate causal genes. TheCD40risk locus colocalized with trans-pQTLs of multiple plasma proteins involved in B cell function.ConclusionOur 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 messagesWhat is already known on this topicSystemic 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 addsThere 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, SPPL3andCCDC113.TheCD40risk allele for SSc and PBC is paradoxically associated with reduced CD40 levels. Causal inference analyses indicate that this reduction in CD40 levels, due toCD40locus 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 policyMechanistic studies are needed to confirm the candidate causal genes prioritized by ourin silicoanalyses.Our study advocates for heightened awareness among rheumatologists regarding the possibility of concurrent PBC in patients with SSc.