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The following is a summary of “Cross-Phenotype Genome-Wide Association Study Supports Shared Genetic Susceptibility to Systemic Sclerosis and Primary Biliary Cholangitis” published in the December 2024 issue of Rheumatology by Luo et al.
Patients with systemic sclerosis (SSc) have an increased risk of developing primary biliary cholangitis (PBC).
Researchers conducted a retrospective study to investigate the shared genetic susceptibility between SSc and PBC and define candidate causal genes using cross-phenotype GWAS meta-analysis.
They performed cross-phenotype GWAS meta-analysis and Bayesian colocalization analysis for SSc and PBC. Genome-wide and locus-based analyses were conducted, including tissue and pathway enrichment, fine-mapping, Bayesian colocalization with expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets, and phenome-wide association studies (PheWAS). An integrative approach was used to prioritize candidate causal genes from novel loci.
The results showed a strong genetic correlation between SSc and PBC (rg = 0.84, P = 1.7 x 10-6). About 44 non-HLA loci reached genome-wide significance (P < 5 x 10-8); 9 loci showed shared causal variants, with 5 being novel. CD40, ERAP1, PLD4, SPPL3, and CCDC113 were prioritized as candidate causal genes. The CD40 locus colocalized with trans-pQTLs of plasma proteins involved in B cell function.
Investigators found strong shared genetic susceptibility between SSc and PBC. Through cross-phenotype analyses, they prioritized novel candidate causal genes and pathways for both disorders.
Source: acrjournals.onlinelibrary.wiley.com/doi/abs/10.1002/art.43081
