Metabolite quantitative traits carry great promise for epidemiological studies, and their genetic background has been addressed using Genome-Wide Association Studies (GWAS). Thus far, the role of less common variants has not been exhaustively studied. Here, we set out a GWAS for metabolite quantitative traits in serum, followed by exome sequence analysis to zoom in on putative causal variants in the associated genes. 1H Nuclear Magnetic Resonance (1H-NMR) spectroscopy experiments yielded successful quantification of 42 unique metabolites in 2,482 individuals from The Erasmus Rucphen Family (ERF) study. Heritability of metabolites were estimated by SOLAR. GWAS was performed by linear mixed models, using HapMap imputations. Based on physical vicinity and pathway analyses, candidate genes were screened for coding region variation using exome sequence data. Heritability estimates for metabolites ranged between 10% and 52%. GWAS replicated three known loci in the metabolome wide significance: CPS1 with glycine ... : Lipids_CH3.gwas2-Hydroxybutyrate.gwasLeucine.gwasIsoleucine.gwasValine.gwas3-Hydroxyisobutyrate.gwasAlpha-ketoisovalerate.gwasEthanol.gwas3-Hydroxybutyrate.gwasLipids_CH2.gwasAlanine.gwasAcetate.gwasMethionine.gwasAcetone.gwasLipids_CH2CO.gwasGlutamate.gwasPyruvate_Oxaloacetate.gwasSuccinate.gwasCarnitine.gwasGlutamine.gwasCitrate.gwasDimethylamine.gwasDimethylglycine.gwasAlpha-ketoglutarate.gwasLysine.gwasOrnithine.gwasTMAO_Betaine.gwas1_5-Anhydrosorbitol.gwasMethanol.gwasGlycine.gwasGlycerol.gwasMyoinositol.gwasBetaine.gwasCreatine.gwasCreatinine.gwasLactate.gwasProline.gwasGlucose.gwasLipids_CH=CH%2ACH2CH2.gwasLipids_CHTyrosine.gwasPhenylalanine.gwasFormate.gwas ...