title: Genome-wide association study of height-adjusted BMI in childhood identifies functional variant in ADCY3.
abstract: OBJECTIVE
  Genome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that "kg/m(2) " is an index of weight fully adjusted for height, but in general this is not true. The aim here was to assess the contribution of common genetic variation to a adjusted version of that phenotype which appropriately accounts for covariation in height in children.
  
  
  METHODS
  A GWAS of height-adjusted BMI (BMI[x] = weight/height(x) ), calculated to be uncorrelated with height, in 5809 participants (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC) was performed.
  
  
  RESULTS
  GWAS based on BMI[x] yielded marked differences in genomewide results profile. SNPs in ADCY3 (adenylate cyclase 3) were associated at genome-wide significance level (rs11676272 (0.28 kg/m(3.1) change per allele G (0.19, 0.38), P = 6 × 10(-9) ). In contrast, they showed marginal evidence of association with conventional BMI [rs11676272 (0.25 kg/m(2) (0.15, 0.35), P = 6 × 10(-7) )]. Results were replicated in an independent sample, the Generation R study.
  
  
  CONCLUSIONS
  Analysis of BMI[x] showed differences to that of conventional BMI. The association signal at ADCY3 appeared to be driven by a missense variant and it was strongly correlated with expression of this gene. Our work highlights the importance of well understood phenotype use (and the danger of convention) in characterising genetic contributions to complex traits.
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Stergiakouli
authors.forename: Romy
authors.initials: R
authors.lastname: Gaillard
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Tavaré
authors.forename: Nina
authors.initials: N
authors.lastname: Balthasar
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Loos
authors.forename: Hendrik R
authors.initials: HR
authors.lastname: Taal
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Beate
authors.initials: B
authors.lastname: St Pourcain
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Cole
authors.forename: Vincent W V
authors.initials: VW
authors.lastname: Jaddoe
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics*; D000293:Adolescent; D000483:Alleles; D001827:Body Height / Q000235:genetics; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D000262:Adenylyl Cyclases; C421784:adenylate cyclase 3