Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Jun 28:4:51.
doi: 10.1186/1755-8794-4-51.

Genome wide association study identifies KCNMA1 contributing to human obesity

Hong Jiao  1 , Peter Arner, Johan Hoffstedt, David Brodin, Beatrice Dubern, Sébastien Czernichow, Ferdinand van't Hooft, Tomas Axelsson, Oluf Pedersen, Torben Hansen, Thorkild I A Sørensen, Johannes Hebebrand, Juha Kere, Karin Dahlman-Wright, Anders Hamsten, Karine Clement, Ingrid Dahlman
Affiliations

Genome wide association study identifies KCNMA1 contributing to human obesity

Hong Jiao et al. BMC Med Genomics. .

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(-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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Strategy for Genome wide association analysis. *Phenotypes of studied cohorts with cohort number within parenthesis. **Number of SNPs taken forward for genotyping and analysis in subsequent cohorts.
Figure 2
Figure 2
Meta-analysis of association between (A) KCNMA1 rs2116830*G, and (B) BDNF rs988712*G with obesity in six cohorts. For meta-analysis results were pooled using the inverse variance method. Combined OR and C.I. were calculated using the random effects estimate method implemented in R.
Figure 3
Figure 3
KCNMA1 expression in adipose tissue in relation to obesity. RNA expression in (A) intact adipose tissue and (B) isolated fat cells of lean (n = 5 women, 2 men) and obese (n = 6 women and n = 1 man) subjects. Relative KCNMA1 expression = 2(Ct KCNMA1 calibrator- Ct KCNMA1 sample)/ 2(Ct 18S calibrator- Ct 18S sample). Two group comparisons were performed with Student's t-test. Values are mean ± SD. *** P< 0.0001; * P< 0.05
See this image and copyright information in PMC

References

    1. Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, Wichmann HE, Meitinger T, Hunter D, Hu FB. et al.A common genetic variant is associated with adult and childhood obesity. Science. 2006;312(5771):279–283. doi: 10.1126/science.1124779. - DOI - PubMed
    1. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW. et al.A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316(5826):889–894. doi: 10.1126/science.1141634. - DOI - PMC - PubMed
    1. Hinney A, Nguyen TT, Scherag A, Friedel S, Bronner G, Muller TD, Grallert H, Illig T, Wichmann HE, Rief W. et al.Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One. 2007;2(12):e1361. doi: 10.1371/journal.pone.0001361. - DOI - PMC - PubMed
    1. Liu YJ, Liu XG, Wang L, Dina C, Yan H, Liu JF, Levy S, Papasian CJ, Drees BM, Hamilton JJ. et al.Genome-wide association scans identified CTNNBL1 as a novel gene for obesity. Hum Mol Genet. 2008;17(12):1803–1813. doi: 10.1093/hmg/ddn072. - DOI - PMC - PubMed
    1. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS. et al.Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008;40(6):768–775. doi: 10.1038/ng.140. - DOI - PMC - PubMed

Publication types

Substances

LinkOut - more resources