Assessing the potential causal effects of 1099 plasma metabolites on 2099 binary disease endpoints

Abstract

Metabolites are small molecules that are useful for estimating disease risk and elucidating disease biology. Here, we perform two-sample Mendelian randomization to systematically infer the potential causal effects of 1099 plasma metabolites measured in 6136 Finnish men from the METSIM study on risk of 2099 binary disease endpoints measured in 309,154 Finnish individuals from FinnGen. We find evidence for 282 putative causal effects of 70 metabolites on 183 disease endpoints. We also identify 25 metabolites with potential causal effects across multiple disease domains, including ascorbic acid 2-sulfate affecting 26 disease endpoints in 12 disease domains. Our study suggests that N-acetyl-2-aminooctanoate and glycocholenate sulfate affect risk of atrial fibrillation through two distinct metabolic pathways and that N-methylpipecolate may mediate the putative causal effect of N6,N6-dimethyllysine on anxious personality disorder.

Fig. 1. Summary of the 282 significant potential causal effects of 70 metabolites on 183 disease traits.

a the overall design of univariable MR to test causal effects of 1099 metabolites on 2099 disease traits; b distribution of metabolites by the number of disease traits that they showed significant putative causal effects on; c distribution of metabolites by the number of disease categories that they showed significant putative causal effects on; d distribution of disease traits by the number of their associated putative causal metabolites. Source data are provided as a Source Data file.

Fig. 2. Heat map of the 282 potential causal effects of 70 metabolites on 183 FinnGen disease traits.

The x-axis denotes the 183 disease traits of 20 colored categories (from left to right). The y-axis denotes the 70 metabolites of eight colored biochemical classes (from bottom to top). The bar plots show the number of FinnGen disease traits that each metabolite confers potential causal effects on (on the left) and the number of putative causal metabolites for each disease trait (on the top). The color of cells denotes the direction of potential causal effects (red for positive and blue for negative effects) of metabolites on disease traits. Source data are provided as a Source Data file.

Fig. 3. IV sharing (upper left triangular heat map) and Pearson correlation (lower right triangular heat map) for all pairs of the 70 metabolites.

The color bar on the x-axis and y-axis denotes the biochemical classes of metabolites. In the upper left triangular heat map, each cell denotes the proportion of IVs with metabolite association at P ≤ 10⁻⁵ shared between the pair of metabolites. In the lower right triangular heat map, each cell denotes the IV correlation between the pair of metabolites. The diagonal cells are colored in dark gray to distinguish the upper and lower triangular heat maps. Source data are provided as a Source Data file.

Fig. 4. MR suggests two metabolic pathways for anxious personality disorder.

Genes implicated for the ratio of N6,N6-dimethyllysine, and N-methylpipecolate and for androsterone sulfate are italicized.