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Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels.

ABSTRACT: Metabolites are small molecules involved in cellular metabolism, which can be detected in biological samples using metabolomic techniques. Here we present the results of genome-wide association and meta-analyses for variation in the blood serum levels of 129 metabolites as measured by the Biocrates metabolomic platform. In a discovery sample of 7,478 individuals of European descent, we find 4,068 genome- and metabolome-wide significant (Z-test, P < 1.09 × 10(-9)) associations between single-nucleotide polymorphisms (SNPs) and metabolites, involving 59 independent SNPs and 85 metabolites. Five of the fifty-nine independent SNPs are new for serum metabolite levels, and were followed-up for replication in an independent sample (N = 1,182). The novel SNPs are located in or near genes encoding metabolite transporter proteins or enzymes (SLC22A16, ARG1, AGPS and ACSL1) that have demonstrated biomedical or pharmaceutical importance. The further characterization of genetic influences on metabolic phenotypes is important for progress in biological and medical research.

SUBMITTER: Draisma HHM

PROVIDER: S-EPMC4745136 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels.

Draisma Harmen H M HHM Pool René R Kobl Michael M Jansen Rick R Petersen Ann-Kristin AK Vaarhorst Anika A M AAM Yet Idil I Haller Toomas T Demirkan Ayşe A Esko Tõnu T Zhu Gu G Böhringer Stefan S Beekman Marian M van Klinken Jan Bert JB Römisch-Margl Werner W Prehn Cornelia C Adamski Jerzy J de Craen Anton J M AJM van Leeuwen Elisabeth M EM Amin Najaf N Dharuri Harish H Westra Harm-Jan HJ Franke Lude L de Geus Eco J C EJC Hottenga Jouke Jan JJ Willemsen Gonneke G Henders Anjali K AK Montgomery Grant W GW Nyholt Dale R DR Whitfield John B JB Penninx Brenda W BW Spector Tim D TD Metspalu Andres A Slagboom P Eline PE van Dijk Ko Willems KW 't Hoen Peter A C PAC Strauch Konstantin K Martin Nicholas G NG van Ommen Gert-Jan B GB Illig Thomas T Bell Jordana T JT Mangino Massimo M Suhre Karsten K McCarthy Mark I MI Gieger Christian C Isaacs Aaron A van Duijn Cornelia M CM Boomsma Dorret I DI

Nature communications 20150612

Metabolites are small molecules involved in cellular metabolism, which can be detected in biological samples using metabolomic techniques. Here we present the results of genome-wide association and meta-analyses for variation in the blood serum levels of 129 metabolites as measured by the Biocrates metabolomic platform. In a discovery sample of 7,478 individuals of European descent, we find 4,068 genome- and metabolome-wide significant (Z-test, P < 1.09 × 10(-9)) associations between single-nucl ...[more]

PMID: 26068415

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Project description:BACKGROUND: Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity. METHODS: We performed a GWA analysis in 164 morbidly obese subjects (BMI:body mass index>40 kg/m2) and 163 Swedish subjects (>45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P<0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n=4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for14 adults. RESULTS: Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830*G and BDNF rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830*G with P=2.82×10(-10) and an odds ratio (OR) based on cases vs controls of 1.26 [95% C.I. 1.12-1.41] and for BDNF rs988712*G with P=5.2×10(-17) and an OR of 1.36 [95% C.I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P=0.0001) and fat cell (P=0.04) expression of KCNMA1 was increased in obesity. CONCLUSIONS: We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.

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Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels.

Publications

Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels.

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