Fig. 6: Genetic insights into metabolite-disease associations.

a Manhattan plot showing the association results from main MR analyses of metabolite-disease pairs with colocalization evidence. Metabolites are labeled on the x-axis, with color coding to distinguish different categories. Statistical analysis was performed using the Wald ratio method for single-instrument cases and the IVW method when multiple instruments were available. For each metabolite category, the four most significant diseases that remained robust in sensitivity analyses and were not significant in reverse MR are labeled. The −log₁₀(P) values are presented on the y-axis, which is capped at 15. Significance thresholds are marked by a blue dashed line at P < 0.05 and a red dashed line indicating corrections for multiple testing (FDR–corrected Q < 0.05, equivalent to P < 2.09 × 10⁻⁵). Arrows reflect the impact on disease risk per unit increase in metabolic trait, with upward arrows indicating increased risk and downward arrows suggesting decreased risk. Source data are available in Supplementary Data 26. b Forest plots depicting results for metabolite-disease pairs of interest. Odds ratio estimates (central points), 95% confidence intervals (error bars) and two-sided P values were derived from two-sample MR analysis using the IVW method. An asterisk (*) indicates one standard deviation of the log-normalized value of the metabolic traits. Source data are provided in Supplementary Data 26. c Stacked regional plots illustrating the colocalization (PP.H4 > 0.8) of metabolite-disease pairs. Colocalization analysis was performed using coloc R package with Bayesian approach. A two-color gradient displays LD (R²) with the candidate causal variant pinpointed through colocalization analysis. Blue represents metabolic traits, while red indicates clinical diseases. P-values shown are two-sided and not adjusted for multiple comparisons. Source data are provided in Supplementary Data 25. See abbreviations in Supplementary Data 2 and 5.