Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1,2,3,4,5,6,7. This detailed knowledge of the genetic... Show moreGenome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1,2,3,4,5,6,7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8,9,10,11. 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. Show less
Per- and polyfluoroalkyl substances (PFAS) are widely used and persistent chemicals, leading to ubiquitous exposure. Although high PFAS levels have been associated with an adverse cardiovascular... Show morePer- and polyfluoroalkyl substances (PFAS) are widely used and persistent chemicals, leading to ubiquitous exposure. Although high PFAS levels have been associated with an adverse cardiovascular risk profile, the distribution of levels and relations with cardio-metabolic risk markers in the general population have not been fully characterized. We assessed the association between blood levels of perfluorooctaneic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) and a range of lipoproteins and metabolites as well as clinical lipid measurements. We used data from participants of the Netherlands Epidemiology of Obesity study (NEO) (n = 584) and the Rhineland Study (n = 1962), jointly spanning an age range of 30 to 89 years. PFAS were measured with the Metabolon HD4 platform, and lipoprotein and metabolite profiles were measured using Nightingale's nuclear magnetic resonance-spectroscopy platform, and mainly comprised lipoprotein markers. Using linear regression analyses, we quantified age-, sex-, and education-adjusted associations of PFOA, PFOS, and PFHxS with clinical lipid measurements and 224 lipoproteins and metabolites. Higher levels of PFAS, particularly PFOS and PFHxS, were associated with higher concentrations of total lipid, cholesterol and phospholipid content in most HDL, IDL, LDL, and VLDL subclasses. The effect sizes were age-dependent for the majority of the associations, with the deleterious effects of PFAS being generally stronger in people below compared to those above median age. Our observation that in the general population even low PFAS concentrations are associated with an unfavorable lipid profile, calls for further critical regulation of PFAS substances. Show less
