title: Genome wide association study identifies KCNMA1 contributing to human obesity.
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.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden. hong.jiao@ki.se
authors.forename: Hong
authors.initials: H
authors.lastname: Jiao
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
authors.forename: Johan
authors.initials: J
authors.lastname: Hoffstedt
authors.forename: David
authors.initials: D
authors.lastname: Brodin
authors.forename: Beatrice
authors.initials: B
authors.lastname: Dubern
authors.forename: Sébastien
authors.initials: S
authors.lastname: Czernichow
authors.forename: Ferdinand
authors.initials: F
authors.lastname: van't Hooft
authors.forename: Tomas
authors.initials: T
authors.lastname: Axelsson
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Thorkild I A
authors.initials: TI
authors.lastname: Sørensen
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Karin
authors.initials: K
authors.lastname: Dahlman-Wright
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Karine
authors.initials: K
authors.lastname: Clement
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dahlman
mesh_terms: D000483:Alleles; D015992:Body Mass Index; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005858:Germany; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013548:Sweden
chemical_list: C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits