Birthweight influences liver structure, function and disease risk: Evidence of a causal association.

Aim: Low birthweight is an issue during pregnancy associated with an increased risk of developing liver disease later in life. Previous Mendelian randomisation (MR) studies which explored this issue have not isolated the direct impact of the foetus on birthweight. In the present study, MR was used to assess whether direct foetal effects on birthweight were causally associated with liver structure, function and disease risk independent of intrauterine effects.

Materials and methods: We extracted single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) about direct foetal-affected birthweight (321 223 cases) to conduct univariable and multivariable MR analyses to explore the relationships between birthweight and 4 liver structure measures, 9 liver function measures and 18 liver diseases. A two-step MR analysis was used to further assess and quantify the mediating effects of the mediators.

Results: When isolating direct foetal effects, genetically predicted lower birthweight was associated with a higher risk of non-alcoholic fatty liver disease (NAFLD) (odds ratios [OR], 95% confidence interval [CI]: 1.61, 1.29-2.02, p < 0.001), higher magnetic resonance imaging [MRI] proton density fat fraction (PDFF) and higher serum gamma glutamyltransferase (GGT). Two-step MR identified two candidate mediators that partially mediate the direct foetal effect of lower birthweight on NAFLD, including fasting insulin (proportion mediated: 22.29%) and triglycerides (6.50%).

Conclusions: Our MR analysis reveals a direct causal association between lower birthweight and liver MRI PDFF, as well as the development of NAFLD, which persisted even after accounting for the potential influence of maternal factors. In addition, we identified fasting insulin and triglycerides as mediators linking birthweight and hepatic outcomes, providing insights for early clinical interventions.