Identification of MMEL1 as a novel therapeutic target for primary sclerosing cholangitis: Integrating Mendelian randomization and transcriptome landscapes

Primary sclerosing cholangitis (PSC) is a kind of cholestatic liver disease without effective targeted therapies, and its pathogenesis remains largely unclear. We performed genome-wide Mendelian randomization analysis to identify therapeutic targets PSC risk. Summary statistics for PSC were obtained from 2 datasets: the International PSC Study Group (2871 cases and 12,019 controls) and the FinnGen cohort (1483 cases and 361,641 controls). Cis-expression quantitative trait loci for druggable genes were extracted from the eQTLGen Consortium and Genotype-Tissue Expression Version 8 database and applied as genetic instrumental variables. Colocalization analysis was performed to estimate the probability that single nucleotide polymorphisms associated with PSC and eQTLs shared causal locus. Six drug targets (APOM, BTN3A2, HLA-DRA, membrane metalloendopeptidase like 1 [MMEL1], NEU1, and RXRB) presented significant Mendelian randomization results in 2 independent datasets. MMEL1, of which eQTLs resourced from blood, liver, transverse colon, and intestine, was all found to have strong evidence for colocalization with PSC. Genetically proxied inhibition of MMEL1 was also detected to attenuate the risk of immune bowel diseases and ulcerative colitis. A transcriptome-wide associated study presented consistent inference, as shown above. Our study highlighted 1 candidate druggable target (MMEL1 for PSC development and prognosis).