title: Genome-wide population-based association study of extremely overweight young adults--the GOYA study.
abstract: BACKGROUND
  Thirty-two common variants associated with body mass index (BMI) have been identified in genome-wide association studies, explaining ∼1.45% of BMI variation in general population cohorts. We performed a genome-wide association study in a sample of young adults enriched for extremely overweight individuals. We aimed to identify new loci associated with BMI and to ascertain whether using an extreme sampling design would identify the variants known to be associated with BMI in general populations.
  
  
  RESULTS
  From two large Danish cohorts we selected all extremely overweight young men and women (n = 2,633), and equal numbers of population-based controls (n = 2,740, drawn randomly from the same populations as the extremes, representing ∼212,000 individuals). We followed up novel (at the time of the study) association signals (p<0.001) from the discovery cohort in a genome-wide study of 5,846 Europeans, before attempting to replicate the most strongly associated 28 SNPs in an independent sample of Danish individuals (n = 20,917) and a population-based cohort of 15-year-old British adolescents (n = 2,418). Our discovery analysis identified SNPs at three loci known to be associated with BMI with genome-wide confidence (P<5×10(-8); FTO, MC4R and FAIM2). We also found strong evidence of association at the known TMEM18, GNPDA2, SEC16B, TFAP2B, SH2B1 and KCTD15 loci (p<0.001), and nominal association (p<0.05) at a further 8 loci known to be associated with BMI. However, meta-analyses of our discovery and replication cohorts identified no novel associations.
  
  
  CONCLUSIONS
  Our results indicate that the detectable genetic variation associated with extreme overweight is very similar to that previously found for general BMI. This suggests that population-based study designs with enriched sampling of individuals with the extreme phenotype may be an efficient method for identifying common variants that influence quantitative traits and a valid alternative to genotyping all individuals in large population-based studies, which may require tens of thousands of subjects to achieve similar power.
authors.affiliation: MRC CAiTE centre, University of Bristol, Bristol, United Kingdom. paternoster@bristol.ac.uk
authors.forename: Lavinia
authors.initials: L
authors.lastname: Paternoster
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.forename: Ellen Aagaard
authors.initials: EA
authors.lastname: Nohr
authors.forename: Claus
authors.initials: C
authors.lastname: Holst
authors.forename: Valerie
authors.initials: V
authors.lastname: Gaborieau
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Anette Prior
authors.initials: AP
authors.lastname: Gjesing
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Witte
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.forename: Allan
authors.initials: A
authors.lastname: Linneberg
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.forename: Anelli
authors.initials: A
authors.lastname: Sandbaek
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Elliott
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.forename: Beate
authors.initials: B
authors.lastname: St Pourcain
authors.forename: George
authors.initials: G
authors.lastname: McMahon
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.forename: Jörg
authors.initials: J
authors.lastname: Hager
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Thorkild I A
authors.initials: TI
authors.lastname: Sørensen
mesh_terms: D000293:Adolescent; D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D015992:Body Mass Index; D004268:DNA-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D050177:Overweight / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015221:Potassium Channels / Q000235:genetics; D011506:Proteins / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000235:genetics; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C400427:FAIM2 protein, human; C552182:KCTD15 protein, human; C470072:MC4R protein, human; D008565:Membrane Proteins; D015221:Potassium Channels; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; C443860:SEC16B protein, human; C530715:TMEM18 protein, human; D050656:Transcription Factor AP-2; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human