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Research Article

Exploring the Developmental Overnutrition Hypothesis Using Parental–Offspring Associations and FTO as an Instrumental Variable

  • Debbie A Lawlor mail,

    To whom correspondence should be addressed. E-mail: d.a.lawlor@bristol.ac.uk

    Affiliations: Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom, Department of Social Medicine, University of Bristol, Bristol, United Kingdom

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  • Nicholas J Timpson,

    Affiliations: Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

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  • Roger M Harbord,

    Affiliation: Department of Social Medicine, University of Bristol, Bristol, United Kingdom

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  • Sam Leary,

    Affiliation: Department of Oral and Dental Science, University of Bristol, Bristol, United Kingdom

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  • Andy Ness,

    Affiliation: Department of Oral and Dental Science, University of Bristol, Bristol, United Kingdom

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  • Mark I McCarthy,

    Affiliations: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom

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  • Timothy M Frayling,

    Affiliations: Genetics of Complex Traits, Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom, Diabetes Genetics, Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom

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  • Andrew T Hattersley,

    Affiliations: Genetics of Complex Traits, Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom, Diabetes Genetics, Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom

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  • George Davey Smith

    Affiliations: Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom, Department of Social Medicine, University of Bristol, Bristol, United Kingdom

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  • Published: March 11, 2008
  • DOI: 10.1371/journal.pmed.0050033

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RESPONSE TO LAWLOR ET AL: EXPLORING THE DEVELOPMENTAL OVERNUTRITION HYPOTHESIS USING PARENTAL-OFFSPRING ASSOCIATIONS AND FTO AS AN INSTRUMENTAL VARIABLE. PLOS MEDICINE 2008; 5(3):E33

Posted by plosmedicine on 31 Mar 2009 at 00:32 GMT

Author: Rebecca Reynolds
Position: Senior Lecturer Endocrinology and Diabetes Endocrinology Unit Centre for Cardiovascular Sciences
Institution: Queen’s Medical Research Institute, Edinburgh
E-mail: R.Reynolds@ed.ac.uk
Additional Authors: Paul Seed, Lucilla Poston
Submitted Date: November 10, 2008
Published Date: November 14, 2008
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

The ‘developmental overnutrition’ hypothesis proposes overweight and overnutrition during pregnancy lead to permanent changes in offspring energy balance with increased adiposity and greater obesity risk in later life[1]. The consequent intergenerational cycle of obesity may contribute to the obesity epidemic ‘independent’ of further genetic or environmental factors. Certainly maternal obesity prior to pregnancy is associated with fetal macrosomia[2], increased neonatal % body fat[3], and greater adiposity at 7yrs[4] but studies have not been extended to reproductive age offspring.

In their study, Lawlor et al[5] interrogate data from ALSPAC, to test the ‘developmental overnutrition’ hypothesis. Both maternal and paternal self-reported pre-pregnancy BMI was positively associated with offspring fat mass at 9-11yrs. The effect of maternal BMI was greater than paternal BMI, thus lending support for the hypothesis, but the apparent effect size (mean difference in offspring sex- and age-standardised fat mass z-score per 1 standard deviation (SD) maternal BMI:0.24;95%CI:0.22-0.26) was considered too weak to explain the obesity epidemic.

There are several possible influences which might underpin this weak relationship. Importantly, the women do not appear over-nourished. Subjects in this UK cohort were recruited during 1991-92, but the incidence of obesity at the start of pregnancy has risen dramatically in intervening years[6]. Whilst the BMI of the cohort is not given, the mean BMI in this cohort reported elsewhere is 22.9(SD3.7)kg/m2[7]. This implies that only 3% would have a BMI over 30kg/m2 (usual obesity definition), assuming normal distribution. The authors acknowledge that their findings cannot exclude an association between greater maternal pregnancy weight gain and increased offspring adiposity in later life but we suggest that the hypothesis cannot be adequately tested in this lean cohort, as the ‘graded association’ implied cannot be assumed. Assessment of pre-pregnancy and paternal BMI by self report is also unreliable and may detract from accuracy of reported associations, and underestimate the effect due to regression dilution bias.

Lawlor et al examined potential genetic influences on offspring fat and lean mass. To date this is the largest study with both maternal and offspring genotype and objectively measured offspring fat mass. Whilst offspring fat mass was associated with maternal FTO genotype, this association may be explained by offspring FTO genotype. There is a large degree of uncertainty about this conclusion because the confidence interval is too wide to make a definite statement (adjusted regression coefficient:-0.08SD of offspring fat mass/SD maternal BMI,95%CI -0.56-0.41).

In mothers, an increase of 0.09SD (0.33 BMI units) was associated with each additional FTO allele. No results relating to offspring BMI are reported, and offspring FTO status is reported only as a confounder. Several studies have shown strong and highly significant associations between FTO polymorphisms and obesity, but it should be remembered that FTO only accounts for about 1% of BMI genetic variance[8].

We consider that the authors’ conclusion ‘that developmental overnutrition related to greater maternal BMI is unlikely to have driven the recent obesity epidemic’ is overstrong on the basis of this study. Further cohort studies are needed to explore the ‘developmental overnutrition’ hypothesis. Ideally, these should be in the children of overweight and obese women. Body composition of mother and child should be adequately assessed[9], and associations investigated with attention to the many potentially confounding factors, including FTO alleles.

1.Oken E, Gillman MW. (2003) Fetal origins of obesity. Obes Res ;11(4):496-506.
2.Jensen DM, Damm P, Sorensen B, Molsted-Pedersen L, Westergaard JG, Ovesen P et al (2003). Pregnancy outcome and prepregnancy body mass index in 2459 glucose-tolerant Danish women. Am J Obstet Gynecol;189(1):239-44.
3. Sewell MF, Huston-Presley L, Super DM, Catalano P. (2006) Increased neonatal fat mass, not lean body mass, is associated with maternal obesity. Am J Obstet Gynecol;195(4):1100-3.
4. Blair NJ, Thompson JM, Black PN, Becroft DM, Clark PM, Han DY et al. (2007) Risk factors for obesity in 7-year-old European children: the Auckland Birthweight Collaborative Study. Arch Dis Child;92(10):866-71.
5. Lawlor DA, Timpson NJ, Harbord RM, Leary S, Ness A, McCarthy MI et al. (2008) Exploring the developmental overnutrition hypothesis using parental offspring associations and FTO as an instrumental variable. PLoS Med 11;5(3):e33.
6. Heslehurst N, Ells LJ, Simpson H, Batterham A, Wilkinson J, Summerbell CD. (2007) Trends in maternal obesity incidence rates, demographic predictors, and health inequalities in 36,821 women over a 15-year period. BJOG;114(2):187-94.
7. Davey SG, Steer C, Leary S, Ness A. (2007) Is there an intrauterine influence on obesity? Evidence from parent child associations in the Avon Longitudinal Study of Parents and Children (ALSPAC). Arch Dis Child;92(10):876-80.
8. Loos RJ, Bouchard C. (2008) FTO: the first gene contributing to common forms of human obesity. Obes Rev;9(3):246-50.
9. Duggleby SL, Jackson AA, Godfrey KM, Robinson SM, Inskip HM. (2008) Cutoff points for anthropometric indices of adiposity: differential classification in a large population of young women. Br J Nutr 18;1-7.

No competing interests declared.