Monogenic liver disease is caused by rare, pathogenic mutations. Exome and genome sequencing frequently identifies variants of unknown significance in these genes. It is not clear whether such non-pathogenic variants confer increased risk of liver injury beyond childhood. Here, we found that these variants increase the severity of liver damage and may act as a ‘second hit’.

We identified 77 monogenic paediatric liver diseases. For each gene, we searched for evidence of a liver phenotype in individuals not known to have genetic disease using population-based datasets. We identified genome-wide significant associations (p<5x10^-8) between variants (e.g. single nucleotide polymorphisms) and liver biochemistry (ALT, bilirubin, GGT, ALP) in n=1,654,950 participants from the Common Metabolic Disease Portal and n=394,841 from UK BioBank using GeneBass.

We found 89 genome-wide associations for biomarkers of liver injury in otherwise apparently healthy individuals across genes from 44/77 (57%) monogenic disorders. For example, common variants in ABCB11 (the cause of PFIC type 2) were associated with GGT (p=2.0x10^-33) and ALT (p=8.4x10^-39). Similarly, common polymorphisms in JAG1 (that do not cause Alagille’s syndrome) were associated with GGT (p=2.3x10^-9) and ALT (p=5.9x10^-10).

Significant associations were found most frequently for 5/7 (71%) of cholestatic disorders and 5/7 (71%) bile acid metabolism disorders, compared to 3/8 (38%) of congenital fibrotic disorders.

In addition to affecting liver enzymes, serum lipid profile (e.g. total cholesterol) was affected by genes from 23/44 (52%).

Common variants in genes that cause rare monogenic liver disease also confer a risk of liver injury later in life. Understanding the mechanisms of these genes provides an opportunity for recognition and treatment of common liver diseases.