Multilevel Exploration of Shared Genetic Architecture Between Primary Biliary Cholangitis and Four Autoimmune Diseases.

introductionPrimary Biliary Cholangitis (PBC) frequently coexists with various autoimmune diseases, such as Multiple Sclerosis (MS), Psoriasis (PS), Rheumatoid Arthritis (RA), and Sjögren's Syndrome (SS). Understanding the genetic associations between these diseases is crucial for providing deeper insights into their shared pathogenic mechanisms and comorbidity patterns.

methodsThis study utilized genome-wide association study summary data of PBC and four autoimmune diseases (MS, PS, RA, and SS). A multi-stage analytical pipeline was employed to systematically investigate the genetic associations between the diseases. The analytical approach consisted of three stages: first, linkage disequilibrium score regression and high-definition likelihood methods were applied to estimate overall genetic correlations between the diseases; second, local genetic correlation analysis was conducted to pinpoint genetic signals in specific chromosomal regions; third, conditional/conjunctional false discovery rate (cond/conjFDR) algorithms were used to quantitatively assess genetic overlap and identify shared susceptibility loci.

resultsGenome-wide analysis revealed significant genetic associations between PBC and the four autoimmune diseases (MS, PS, RA, and SS). Regional analysis showed local genetic correlations across various chromosomal segments. cond/conjFDR analysis confirmed genetic intersections among the diseases and identified several critical genetic polymorphic loci that influence disease susceptibility. DISCUSSION: This study comprehensively delineates the shared genetic architecture underlying PBC and four autoimmune diseases through integrative analyses of multiple genome-wide approaches. The results highlight strong genetic correlations, particularly between PBC and MS, PS, RA, and SS, and identify key shared susceptibility genes, including CLEC16A, CD58, CD86, STAT4, IRF5, TYK2, and TNFAIP3, which collectively mediate immune dysregulation through autophagy, cytokine signaling, and NF-κB pathways. These findings not only extend current understanding of the molecular mechanisms driving autoimmune comorbidity but also provide potential genetic targets for future functional validation and therapeutic exploration.

conclusionThis study provides comprehensive genomic evidence for the genetic connections between PBC and the four autoimmune diseases (MS, PS, RA, and SS), offering valuable insights into the shared pathological mechanisms underlying their comorbidities.