Genome wide association and Mendelian randomization analysis prioritizes bioactive metabolites with putative causal effects on common diseases

Bioactive metabolites are central to numerous pathways and disease pathophysiology, yet many bioactive metabolites are still uncharacterized. Here, we quantified bioactive metabolites using untargeted LC-MS plasma metabolomics in two large cohorts (combined N≈9,300) and utilized genome-wide association analysis and Mendelian randomization to uncover genetic loci with roles in bioactive metabolism and prioritize metabolite features for more in-depth characterization. We identified 118 loci associated with levels of 2,319 distinct metabolite features which replicated across cohorts and reached study-wide significance in meta-analysis. Of these loci, 39 were previously not known to be associated with blood metabolites. Loci harboring SLCO1B1 and UGT1A were highly pleiotropic, accounting for >40% of all associations. Two-sample Mendelian randomization found 46 causal effects of 31 metabolite features on at least one of five common diseases. Of these, 15, including leukotriene D4, had protective effects on both coronary heart disease and primary sclerosing cholangitis. We further assessed the association between baseline metabolite features and incident coronary heart disease using 16 years of follow-up health records. This study characterizes the genetic landscape of bioactive metabolite features and their putative causal effects on disease.