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.

中文翻译：

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全基因组关联和孟德尔随机化分析优先考虑具有生物活性的代谢物，对常见疾病具有假定的因果关系

生物活性代谢物是许多途径和疾病病理生理学的核心，但许多生物活性代谢物仍未表征。在这里，我们在两个大型队列（组合N≈9,300）中使用非靶向LC-MS血浆代谢组学对生物活性代谢物进行了定量，并利用了全基因组关联分析和孟德尔随机化来揭示在生物活性代谢中发挥作用的遗传基因座，并优先考虑代谢物的功能，从而深度表征。我们确定了118个与2319个不同代谢物特征水平相关的位点，这些特征在整个队列中复制并在荟萃分析中达到了全研究的意义。在这些基因座中，以前未知39个与血液代谢产物有关。包含SLCO1B1和UGT1A的基因座高度多效性，占所有关联的> 40％。孟德尔随机抽样的两个样本发现31种代谢物特征对至少五种常见疾病的46种因果关系。其中15个，包括白三烯D4，对冠心病和原发性硬化性胆管炎都有保护作用。我们使用16年的随访健康记录进一步评估了基线代谢物特征与突发性冠心病之间的关联。这项研究表征了生物活性代谢物特征的遗传景观及其对疾病的假定因果关系。我们使用16年的随访健康记录进一步评估了基线代谢物特征与突发性冠心病之间的关联。这项研究表征了生物活性代谢物特征的遗传景观及其对疾病的假定因果关系。我们使用16年的随访健康记录进一步评估了基线代谢物特征与突发性冠心病之间的关联。这项研究表征了生物活性代谢物特征的遗传景观及其对疾病的假定因果关系。