title: Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants.
abstract: BACKGROUND
  Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity.
  
  
  RESULTS
  a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency > or =10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13 x 10(-7), corrected p = 0.0494; odds ratio (OR)(CT) 1.67, 95% confidence interval (CI) 1.22-2.27; OR(TT) 2.76, 95% CI 1.88-4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium.
  
  
  CONCLUSIONS
  Our GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings.
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany. anke.hinney@uni-due.de
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
authors.forename: Thuy Trang
authors.initials: TT
authors.lastname: Nguyen
authors.forename: André
authors.initials: A
authors.lastname: Scherag
authors.forename: Susann
authors.initials: S
authors.lastname: Friedel
authors.forename: Günter
authors.initials: G
authors.lastname: Brönner
authors.forename: Timo Dirk
authors.initials: TD
authors.lastname: Müller
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Winfried
authors.initials: W
authors.lastname: Rief
authors.forename: Helmut
authors.initials: H
authors.lastname: Schäfer
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000293:Adolescent; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D002648:Child; D015894:Genome, Human; D006801:Humans; D009765:Obesity / Q000235:genetics*; D009929:Organ Size; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human