Genome-wide characterization of circulating metabolic biomarkers reveals substantial pleiotropy and novel disease pathways

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study of 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 predominantly population-based cohorts. We discover over 400 independent loci and assign likely causal genes at two-thirds of these using detailed manual curation of highly plausible biological candidates. We highlight the importance of sample- and participant characteristics, such as fasting status and sample type, that can have significant impact on genetic associations, revealing direct and indirect associations on glucose and phenylalanine. 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 for the first time the metabolic associations of an understudied phenotype, 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 acetoacetate and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.