Assessing potential causality between blood metabolites and primary sclerosing cholangitis using two-sample Mendelian randomization

Abstract

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with a poorly understood aetiology. An observational study by Molinaro et al. have suggested an association between blood circulating metabolites and PSC, however, causal inference is limited by confounding and reverse causation. The aim of this study was to assess potential causal effects of blood circulating metabolites on PSC risk using Mendelian randomization (MR), and to compare the findings to the associations found in the observational study. Atwo-sample MR framework was applied using summary statistics from genome-wide association studies (GWAS) of PSC-associated metabolites and PSC. Instrumental variables (IVs) were selected based on genome-wide significance and linkage disequilibrium pruning. Causal effects were estimated using the inverse variance weighted method, with sensitivity analysis performed to assess heterogeneity and horizontal pleiotropy. MR analysis were conducted for seven metabolites previously associated with PSC and seven control metabolites with no association. Overall, the selected IVs explained only a small proportion of variance in metabolite levels, as reflected by low F-statistics, indicating weak instrument strength and a potential bias of causal effect estimates towards the null. No evidence of a causal effect was detected for either PSC-associated metabolites nor the control metabolites. Sensitivity analysis indicated moderate heterogeneity with little evidence of horizontal pleiotropy. These findings suggest that currently available IVs for the blood circulating metabolites are insufficient to robustly assess causality in PSC. While no causal effects were detected, this study highlights important limitations in metabolite-based MR and underscores the need for larger and more powerful metabolite GWAS to enable reliable causal inference.