Garrod’s concept of ‘chemical individuality’ has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant–metabolite associations (P < 1.25 × 10⁻¹¹) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant–metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.

加罗德的“化学个体性”概念有助于理解人类疾病的分子起源。无针对性的高通量代谢组学技术提供了大规模人类新陈代谢的深入快照。我们使用在 19,994 名个体中检测的 913 种代谢物研究了人类血浆代谢组的遗传结构，并在 330 个基因组区域内鉴定了 2,599 个变异-代谢物关联 ( P < 1.25 × 10 ^-11 )，其中包含罕见变异（次要等位基因频率 ≤ 1%）解释了9.4%的关联。通过对每个区域的代谢物进行联合建模，我们确定了 423 个区域性的、共同调节的变异代谢物簇，称为遗传影响的代谢型。我们为这些受遗传影响的代谢型中的 62.4% 分配了因果基因，为基本代谢物生理学和临床相关性提供了新的见解，包括代谢物引导发现潜在的药物不良反应（ DPYD和SRD5A2 ）。我们展示了代谢引起基因的先天性错误的强烈富集，其中非致病性变异携带者的代谢物关联和临床表型的例子与先天性代谢错误的特征相匹配。对代谢物特异性遗传评分的系统表型随访揭示了多种潜在的病因学关系。