Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Nat Genet. 2020 Feb;52(2):167-176. doi: 10.1038/s41588-019-0567-8. Epub 2020 Jan 20.
The kidneys integrate information from continuous systemic processes related to the absorption, distribution, metabolism and excretion (ADME) of metabolites. To identify underlying molecular mechanisms, we performed genome-wide association studies of the urinary concentrations of 1,172 metabolites among 1,627 patients with reduced kidney function. The 240 unique metabolite-locus associations (metabolite quantitative trait loci, mQTLs) that were identified and replicated highlight novel candidate substrates for transport proteins. The identified genes are enriched in ADME-relevant tissues and cell types, and they reveal novel candidates for biotransformation and detoxification reactions. Fine mapping of mQTLs and integration with single-cell gene expression permitted the prioritization of causal genes, functional variants and target cell types. The combination of mQTLs with genetic and health information from 450,000 UK Biobank participants illuminated metabolic mediators, and hence, novel urinary biomarkers of disease risk. This comprehensive resource of genetic targets and their substrates is informative for ADME processes in humans and is relevant to basic science, clinical medicine and pharmaceutical research.
肾脏整合了与代谢物吸收、分布、代谢和排泄 (ADME) 相关的连续系统过程的信息。为了确定潜在的分子机制，我们对 1627 名肾功能降低患者的 1172 种代谢物的尿液浓度进行了全基因组关联研究。鉴定和复制的 240 个独特的代谢物 - 基因座关联 (代谢物数量性状基因座，mQTL) 突出了运输蛋白的新型候选底物。鉴定的基因在 ADME 相关组织和细胞类型中富集，并揭示了生物转化和解毒反应的新候选基因。mQTL 的精细映射和与单细胞基因表达的整合允许对因果基因、功能变体和靶细胞类型进行优先级排序。mQTL 与来自 450,000 名英国生物库参与者的遗传和健康信息的结合揭示了代谢调节剂，从而揭示了疾病风险的新型尿液生物标志物。该遗传靶标及其底物的综合资源为人类 ADME 过程提供了信息，并与基础科学、临床医学和药物研究相关。
