Because metabolites play key roles as markers and effectors of cardiometabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We recently completed a genome-wide association study (GWAS) of 217 plasma metabolites, including >100 not measured in prior GWAS.⁸ For most analytes, estimated heritability explained >20% of inter-individual variation, and the variation in metabolite levels attributable to heritable factors was greater than that attributable to clinical factors. We identified 31 genetic loci associated with plasma metabolites, including 23 not previously reported. We identified 8 novel associations in loci with disease phenotypes highlighting novel potential biomarkers or pathway participants. In experimental studies, we demonstrated how this information highlighted a novel role for AGXT2 in cholesterol ester and triacylglycerol metabolism (not shown). The analyses in the present proposal markedly expand our prior work by integrating many more individuals/families and metabolites, and will also leverage exome chip data. In addition to allowing us to identify the genetic underpinnings of metabolic signatures, these data provide an opportunity to perform “Mendelian Randomization” studies to assess potential causality.