Genome-wide characterization of circulating metabolic biomarkers
Genome-wide characterization of circulating metabolic biomarkers
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循环代谢生物标志物的全基因组表征
DOI：
10.1038/s41586-024-07148-y
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发表时间：
2024-03-06
期刊：
影响因子：
64.8
通讯作者：
Kettunen，Johannes
中科院分区：
文献类型：
--
作者：
Karjalainen，Minna K.;Karthikeyan，Savita;Kettunen，Johannes
使用高通量代谢组学平台的全基因组关联分析导致了对人类代谢生物学的新见解，，，，，-。对全身代谢遗传决定因素的详细了解对于揭示遗传途径如何影响生物机制和复杂疾病至关重要，，-。在这里，我们提出了一项全基因组关联研究，通过核磁共振波谱对来自33个队列的136,016名参与者的233个循环代谢特征进行了量化。我们确定了400多个独立的基因座，并在其中三分之二的基因座上分配了可能的因果基因。我们强调了样本和参与者特征的重要性，这些特征可以对遗传关联产生重大影响。我们使用脂蛋白和脂质相关变异的详细代谢谱来更好地表征已知的脂质位点和新的位点如何在颗粒水平上影响脂蛋白代谢。我们展示了综合表型分子数据的转化效用，表征了妊娠期肝内胆汁淤积的代谢关联。最后，我们观察到多种代谢途径存在大量的遗传多效性，并说明在孟德尔随机化分析中谨慎选择工具的重要性，揭示了丙酮与高血压之间的假定因果关系。我们的公开结果为社区研究代谢在不同疾病中的作用提供了基础资源。
Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism, , , , , –. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases, , –. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.