Genes that cause severe liver disease in children also influence risk and severity of common liver conditions in adults

Background and aimsRare, pathogenic variants can cause severe liver disease, requiring transplantation in childhood, but it is unclear how common variants in the same genes affect adults. Here, we aimed to establish population-level genetic evidence for whether monogenic diseases are associated with liver injury in adulthood. MethodsWe identified 99 genes where pathological mutations cause significant liver disease in children. For each, we used data from over 1.8 million adults to identify associations with biomarkers of liver injury. Observations were validated in multiple cohorts of adults with clinical liver disease and transcriptomics. Finally, we illustrated the importance of the JAG1-NOTCH pathway on the ductular reaction using immunohistochemistry. ResultsMost genes (56% (55/99)) had at least moderate evidence of association with liver-related traits at a population level. We identified 82 genome-wide (p<5x10-8) associations with markers of liver injury in 41% (41/99) of genes. Loss of function variants in these genes had a ten-fold greater effect on liver enzymes and well-established variants in PNPLA3 had a three-fold greater effect. Variants in ABCC2, ASL, BCS1L, HFE, and SERPINA1 were linked with presence of clinical liver disease in adults. Aggregated effects of 35 variants as polygenic risk score (PRS) was associated with 0.6% lower prevalence of MASLD between highest and lowest PRS groups. Transcriptional expression of 30% of genes was associated with severity of MASLD. Expression of JAG1-NOTCH2 pathway was associated with severity of PSC. JAG1 and NOTCH2 were expressed in injured bile ducts but not adjacent unaffected ducts. ConclusionsOnset and severity of liver disease in adulthood is influenced by genes that also cause severe monogenic liver disease in children.