Causal genetics prioritizes therapeutic targets and blood signatures in primary biliary cholangitis

Primary biliary cholangitis is an autoimmune cholestatic liver disease, but upstream immune programs linking inherited risk to hepatic remodeling and therapeutic targets remain incompletely defined. We developed a cross-tissue causal multi-omics framework integrating PBC GWAS, 731 GWAS-derived immune traits, peripheral blood transcriptomes, and liver bulk and single-cell RNA-seq. Two-sample Mendelian randomization with reverse-causation testing and independent replication identified genetically predicted CD27⁺ unswitched memory B cells as a risk-increasing immune trait for PBC. Liver transcriptomic analyses showed immune and stromal remodeling, while functional mapping prioritized 18 immune-inflammatory genes and supported an 11-gene LASSO blood signature that distinguished PBC from controls. Single-cell analyses localized the causal signal to an expanded hepatic CD27⁺ IgM memory-like B-cell state characterized by terminal, non-proliferative features, adaptive immune activation, T-cell activation programs, and chemokine-centered intercellular communication. Transcription factor activity inference highlighted a CREB1/AP-1-centered regulatory module and nominated pathway inhibitors as hypothesis-generating candidates. Together, these findings provide convergent, but inferential, evidence linking CD27-related genetic susceptibility, a PBC-associated blood transcriptional signature.