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Open Access Research article

Genome wide association study identifies KCNMA1 contributing to human obesity

Hong Jiao12*, Peter Arner3, Johan Hoffstedt3, David Brodin1, Beatrice Dubern4, Sébastien Czernichow4, Ferdinand van't Hooft5, Tomas Axelsson6, Oluf Pedersen78, Torben Hansen78, Thorkild IA Sørensen9, Johannes Hebebrand10, Juha Kere12*, Karin Dahlman-Wright1, Anders Hamsten5, Karine Clement11 and Ingrid Dahlman3

Author Affiliations

1 Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden

2 Clinical Research Centre, Karolinska University Hospital, SE-141 57 Stockholm, Sweden

3 Department of Medicine at Karolinska Institutet and Karolinska University Hospital, SE-141 86 Stockholm, Sweden

4 INSERM, U-557/INRA U-1125, CNAM, UP13, CRNH-IdF, 93017 Bobigny, France; University Paris 13, 93017, Bobigny, France; AP-HP, Avicenne Hospital, 93017 Bobigny, France

5 Cardiovascular Genetics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, SE-17176 Stockholm, Sweden

6 Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

7 Hagedorn Research Institute, Gentofte,, Copenhagen, Denmark

8 Center of Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Denmark

9 Institute for Preventive Medicine, Copenhagen University Hospital, Center for Health and Society, Copenhagen, Denmark

10 Department of Child and Adolescent Psychiatry of the University of Duisburg-Essen, Essen, Germany

11 INSERM, U-872, Nutriomique (team 7) 75006 Paris, France; University Pierre and Marie Curie-Paris 6, Cordeliers Research Center, 75006 Paris, France; AP-HP, Pitié-Salpétrière Hospital, 75013 Paris, France

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BMC Medical Genomics 2011, 4:51  doi:10.1186/1755-8794-4-51

Published: 28 June 2011

Abstract

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 × 10-17and 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.