Mendelian randomization identifies 1400 metabolites that may be pathogenic candidates for non-alcoholic fatty liver disease

The observational association between circulating metabolites and non-alcoholic fatty liver disease (NAFLD) has been somewhat demonstrated. However, it is unclear whether there is a causal relationship for this association. In this study, we used a two-sample bidirectional MR analysis approach to assess the association between 1,400 blood metabolites and NAFLD. Causality was estimated using the inverse variance weighted (IVW) method, and sensitivity analyses were applied after performing false discovery rate (FDR) correction to assess heterogeneity and pleiotropy. In addition, we performed linkage disequilibrium regression (LDSC) analysis, confounder analysis and metabolic pathway analysis. Corrected for FDR, we identified seven metabolites suggestively associated with NAFLD, including imidazole lactate levels (OR = 0.90,95% CI = 0.85–0.95, P  = 0.0004), cysteine-glutathione disulfide levels (OR = 0.80, 95%CI = 0.72–0.89, P  = 0.0001), 3-indoleglyoxylic acid levels(OR = 0.87,95%CI = 0.80–0.94, P  = 0.0009), lithocholate sulfate (1) levels (OR = 1.18,95%CI = 1.07–1.30, P  = 0.006), bilirubin degradation product, C17H18N2O4 (2) levels (OR = 1.14,95%CI = 1.07–1.21, P  = 4.02E-05), bilirubin degradation product, C17H18N2O4 (3) levels (OR = 1.13, 95%CI = 1.06–1.21, P  = 0.0001), and biliverdin levels (OR = 1.12, 95% CI = 1.05–1.18, P  = 0.023). This study provides evidence support for the causal effect of seven metabolites on NAFLD, and provides new perspectives for combining genomics and metabolomics to explore the biological mechanisms of NAFLD.