Genetic architecture of plasma metabolome in 254,825 individuals.

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-09-19 DOI:10.1038/s41467-025-62126-w

Yi-Xuan Qiang,Yi-Xuan Wang,Xiao-Yu He,Yue-Ting Deng,Yi-Jun Ge,Bang-Sheng Wu,You Jia,Jian-Feng Feng,Wei Cheng,Jin-Tai Yu

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Abstract

Circulating metabolites are crucial to biological processes underlying health and diseases, yet their genetic determinants remain incompletely understood. Here, we investigate the genetic architecture of nuclear magnetic resonance-based metabolomics, analyzing 249 metabolic measures and 64 biologically plausible ratios in 254,825 participants. We conduct a genome-wide association study (GWAS) identifying 24,438 independent variant-metabolite associations across 427 loci, with effect sizes highly concordant with 19 previous studies. Fine-mapping pinpoints 3610 putative causal associations, 785 of which are novel. Additionally, we utilize whole exome sequencing data and uncover 2948 gene-metabolite associations through aggregate testing, underscoring the importance of rare coding variants overlooked in GWAS. Integrating our findings with disease genetics reveals potential causal associations, such as between acetate levels and the risk of atrial fibrillation and flutter. Collectively, this study delineates the complex genetic architecture of the plasma metabolome, offering a valuable resource for future investigations into disease mechanisms and therapeutic strategies.

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254,825人血浆代谢组遗传结构分析。

循环代谢物对健康和疾病背后的生物过程至关重要，但其遗传决定因素仍未完全了解。在这里，我们研究了基于核磁共振代谢组学的遗传结构，分析了254,825名参与者的249种代谢测量和64种生物学上合理的比率。我们进行了一项全基因组关联研究（GWAS），在427个基因座中鉴定了24,438个独立的变异代谢物关联，其效应量与之前的19项研究高度一致。精细绘图精确地指出了3610个假定的因果关系，其中785个是新的。此外，我们利用全外显子组测序数据，通过聚合测试发现了2948个基因代谢物关联，强调了GWAS中被忽视的罕见编码变异的重要性。将我们的研究结果与疾病遗传学相结合，揭示了潜在的因果关系，例如醋酸盐水平与心房颤动和扑动风险之间的关系。总的来说，这项研究描绘了血浆代谢组的复杂遗传结构，为未来研究疾病机制和治疗策略提供了宝贵的资源。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.