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

Background and aims Rare, 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.

We 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.

Most 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.

Onset and severity of liver disease in adulthood is influenced by genes that also cause severe monogenic liver disease in children. Competing Interest Statement KZ is an employee of Gilead Sciences Inc. JX was an employee of Gilead Sciences Inc. at the time the research was conducted. Funding Statement AS, SPD, YHO, and JPM: NIHR BRC Birmingham. JPM is supported by grants from Birmingham Health Partners, NIHR ACL (CL-2022-09-005), Royal Society (RG\R1\241312), BSPGHAN-Guts (BSPGHAN2023_01), ESPGHAN, Royal College Physicians Dame Sheila Sherlock Bursary, and Little Princess Trust (CCLGA 2024 10 Mann). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All liver tissue was obtained following informed consent, under the "Liver Inflammation" study (Research Ethics Committee approval reference - NHS Health Research Authority and Health and Care Research Wales (HCRW): 18/WA/0214; IRAS reference: 223072) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Data Availability All raw data is publicly available and code used is available at: https://github.com/jmann01/MonogenicLiver.