Abstract 15265: Exome-wide Association Study of the Human Metabolome in a Community-based Cohort

Introduction: Because metabolites are hypothesized to play key roles as markers and effectors of cardio-metabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We hypothesize that the study of low frequency and rare variants of potential functional significance will refine our understanding of the genetic determinants of human metabolism. Methods: We analyzed the association between 217 plasma metabolites and exome variants captured on the Illumina HumanExome Beadchip in 2,076 Framingham Heart Study (FHS) participants. Of the >240,000 variants on the exome array, we restricted our analysis to the subset of 92,633 variants that were polymorphic and nonsynonymous, nonsense, or located in a splice site. We performed association analyses that relate each single variant to each metabolite, as well as gene-based burden tests that evaluate the aggregate effects of all variants within a gene. Statistical analyses accounted for number of SNPs or genes (...