Background and aims Rare, pathogenic variants in multiple genes can cause severe liver disease, requiring transplantation in childhood, but it is unclear whether common variants in the same genes confer risk of liver disease in adults. Here, we aimed to establish whether ‘monogenic’ liver diseases are associated with a spectrum of liver phenotypes in adulthood.

Methods We identified 99 genes where pathological mutations cause significant liver disease in children. For each, we used population-level data from over 1.5 million adults to identify associations with biomarkers of liver injury (e.g. ALT). These observations were validated using six external cohorts of adults with clinical liver disease and transcriptomics. Finally, we illustrated the importance of the JAG1-NOTCH pathway on the ductular reaction in adult liver disease using immunohistochemistry and transcriptomics.

Results We identified 89 genome-wide (p<5x10-8) associations with biomarkers of liver injury in 46% (45/99) of genes. Variants in ABCC2, ADK, ASL, BCS1L, HFE, and SERPINA1 were also linked with presence of clinical liver disease in adults. For example, rs2862926C>T encoding p.Ile1324= in ABCC2 (which causes Dubin-Johnson syndrome) was associated with lower ALT (p=7.1x10-12) and lower risk of MASLD (p-FDR=0.03). Transcriptional expression of 30% of genes was associated with severity of MASLD. p.Pro871Arg in JAG1 causes a subtle form of Alagille syndrome with higher bilirubin (9.7x10-10) and hypertension (p=4.2x10-14). JAG1 and NOTCH2 were expressed in injured bile ducts but not adjacent unaffected ducts and transcriptional expression of JAG1 correlated with fibrosis stage in primary sclerosing cholangitis.

Conclusions Pathways affected by severe childhood liver disease also influence risk and severity of liver disease in adulthood.

KZ is an employee of Gilead Sciences Inc. JX was an employee of Gilead Sciences Inc. at the time the research was conducted.

AS, SPD, YHO, and JPM: NIHR BRC Birmingham. JPM is supported by grants from 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). JM: Czech Science Foundation (25-15821S), PRIMUS/21/SCI/006 project funded by Charles University Grant Agency, MSCA Fellowships CZ - Charles University CZ.02.01.01/00/22_010/0002902

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)

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Yes

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↵* Joint first authors

↵† Affiliation at the time research was conducted.

Funding: AS, SPD, YHO, and JPM: NIHR BRC Birmingham.

JPM is supported by grants from 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).

JM: Czech Science Foundation (25-15821S), PRIMUS/21/SCI/006 project funded by Charles University Grant Agency, MSCA Fellowships CZ - Charles University CZ.02.01.01/00/22_010/0002902

Conflicts of interest: KZ is an employee of Gilead Sciences Inc. JX was an employee of Gilead Sciences Inc. at the time the research was conducted.

All raw data is publicly available and code used is available at: https://github.com/jmann01/MonogenicLiver.