A genetic map of human metabolism across the allele frequency spectrum.

IF 29 1区生物学 Q1 GENETICS & HEREDITY

Nature genetics Pub Date : 2025-10-03 DOI:10.1038/s41588-025-02355-3

Martijn Zoodsma,Carl Beuchel,Summaira Yasmeen,Leonhard Kohleick,Aakash Nepal,Mine Koprulu,Florian Kronenberg,Manuel Mayr,Alice Williamson,Maik Pietzner,Claudia Langenberg

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引用次数: 0

Abstract

Genetic studies of human metabolism have been limited in scale and allelic breadth. Here we provide a data-driven map of the genetic regulation of circulating small molecules and lipoprotein characteristics (249 traits) measured using proton nuclear magnetic resonance spectroscopy across the allele frequency spectrum in ~450,000 individuals. Trans-ancestral meta-analyses identify 29,824 locus-metabolite associations mapping to 753 regions with effects largely consistent between men and women and large ancestral groups represented in UK Biobank. We observe and classify extreme genetic pleiotropy, identify regulators of lipid metabolism, and assign effector genes at >100 loci through rare-to-common allelic series. We propose roles for genes less established in metabolic control (for example, SIDT2), genes characterized by phenotypic heterogeneity (for example, APOA1) and genes with specific disease relevance (for example, VEGFA). Our study demonstrates the value of broad, large-scale metabolomic phenotyping to identify and characterize regulators of human metabolism.

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跨等位基因频谱的人类代谢遗传图谱。

人类代谢的遗传研究在规模和等位基因广度上受到限制。在这里，我们提供了一个数据驱动的循环小分子和脂蛋白特征（249个特征）的遗传调控图，使用质子核磁共振波谱测量了约45万个体的等位基因频谱。跨祖先荟萃分析确定了29,824个位点-代谢物关联，映射到753个区域，其影响在男性和女性以及UK Biobank中代表的大型祖先群体之间基本一致。我们观察并分类了极端遗传多效性，确定了脂质代谢的调节因子，并通过罕见到常见的等位基因序列在100个位点上分配了效应基因。我们提出了在代谢控制中较少建立的基因（例如SIDT2），以表型异质性为特征的基因（例如APOA1）和与特定疾病相关的基因（例如VEGFA）的作用。我们的研究证明了广泛、大规模的代谢组学表型在识别和表征人类代谢调节因子方面的价值。

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来源期刊

Nature genetics 生物-遗传学

CiteScore

43.00

自引率

2.60%

发文量

241

审稿时长

3 months

期刊介绍： Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution