title: Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable.
abstract: BACKGROUND
  The developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis.
  
  
  RESULTS
  We explored this hypothesis by comparing the associations of maternal and paternal pre-pregnancy body mass index (BMI) with offspring dual energy X-ray absorptiometry (DXA)-determined fat mass measured at 9 to 11 y (4,091 parent-offspring trios) and by using maternal FTO genotype, controlling for offspring FTO genotype, as an instrument for maternal adiposity. Both maternal and paternal BMI were positively associated with offspring fat mass, but the maternal association effect size was larger than that in the paternal association in all models: mean difference in offspring sex- and age-standardised fat mass z-score per 1 standard deviation BMI 0.24 (95% confidence interval [CI]: 0.22 to 0.26) for maternal BMI versus 0.13 (95% CI: 0.11, 0.15) for paternal BMI; p-value for difference in effect < 0.001. The stronger maternal association was robust to sensitivity analyses assuming levels of non-paternity up to 20%. When maternal FTO, controlling for offspring FTO, was used as an instrument for the effect of maternal adiposity, the mean difference in offspring fat mass z-score per 1 standard deviation maternal BMI was -0.08 (95% CI: -0.56 to 0.41), with no strong statistical evidence that this differed from the observational ordinary least squares analyses (p = 0.17).
  
  
  CONCLUSIONS
  Neither our parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9-11 y. Developmental overnutrition related to greater maternal BMI is unlikely to have driven the recent obesity epidemic.
authors.affiliation: Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom. d.a.lawlor@bristol.ac.uk
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: Roger M
authors.initials: RM
authors.lastname: Harbord
authors.forename: Sam
authors.initials: S
authors.lastname: Leary
authors.forename: Andy
authors.initials: A
authors.lastname: Ness
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
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
mesh_terms: D015502:Absorptiometry, Photon; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D002648:Child; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009035:Mothers; D009765:Obesity / Q000209:etiology* / Q000235:genetics; D044343:Overnutrition / Q000150:complications* / Q000453:epidemiology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000453:epidemiology; D011506:Proteins / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human