title: Type 2 diabetes risk alleles are associated with reduced size at birth.
abstract: OBJECTIVE
  Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.
  
  
  METHODS
  We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.
  
  
  RESULTS
  We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11-31], P = 2 x 10(-5), and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39-120) lighter at birth than the 8% carrying none (P(trend) = 5 x 10(-7)). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus.
  
  
  CONCLUSIONS
  Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
authors.affiliation: Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Bennett
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.forename: Beverley
authors.initials: B
authors.lastname: Shields
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Groves
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Hana
authors.initials: H
authors.lastname: Lango
authors.forename: John R B
authors.initials: JR
authors.lastname: Perry
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Aimo
authors.initials: A
authors.lastname: Ruokonen
authors.forename: Elina
authors.initials: E
authors.lastname: Hyppönen
authors.forename: Chris
authors.initials: C
authors.lastname: Power
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: David P
authors.initials: DP
authors.lastname: Strachan
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D001724:Birth Weight; D002874:Chromosome Mapping; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics; D012359:tRNA Methyltransferases
chemical_list: C078492:HHEX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human