Research Article: Determining Origins and Causes of Childhood Obesity via Mendelian Randomization Analysis

Date Published: March 11, 2008

Publisher: Public Library of Science

Author(s): Eric L Ding, Frank B Hu

Abstract: The authors discuss a new study that investigated the developmental overnutrition hypothesis in a large cohort of British pregnant mothers.

Partial Text: Childhood obesity has become a serious public health problem worldwide. The United States Centers for Disease Control and Prevention estimates that one in three children and adolescents are currently overweight/obese [1]. The adverse complications of childhood obesity on physical health and psychosocial development are tremendous [2]. Moreover, pediatric obesity may substantially increase future burden of cardiovascular disease and other morbidities in adulthood [3,4].

The obesity epidemic not only represents a public health crisis in our current generation, but may also have lasting adverse consequences on the health of future generations. The developmental overnutrition hypothesis proposes that within the pregnant womb of an overweight/obese mother, the developing fetus is exposed to higher in utero levels of glucose and free fatty acids. Such exposure may permanently disrupt or dysregulate appetite control and hormones and impair energy metabolism, thereby increasing offspring adiposity and risk of obesity [5]. This theory suggests that fetal metabolic programming by an adverse in utero environment may lead to obesity in adolescence and young adulthood, spawning a potential vicious cycle of transgenerational transmission of the obesity epidemic from parents to offspring, regardless of offspring genetics or childhood environment.

In this issue of PLoS Medicine, Debbie Lawlor and colleagues investigated the developmental overnutrition hypothesis in a large cohort of British pregnant mothers, analyzing 4,091 sets of mother–father–offspring trios [5]. In their initial analysis comparing parental body mass index with offspring fat mass, they found that the association between parental body mass index and offspring adiposity at ages nine to 11 was stronger among mother–offspring pairs than among father–offspring pairs. This finding suggests that the maternal influence on offspring adiposity extends beyond genetic contributions alone—providing some support to the developmental overnutrition hypothesis. However, such evidence for this hypothesis is indirect, as the findings could be explained by the influence of other maternally predominant factors such as breast-feeding. Therefore, Lawlor and colleagues undertook a second, more sophisticated analysis using a previously established gene of adult and childhood obesity, the FTO gene [6], as an “instrument” of maternal obesity (a marker for the in utero environment) via a Mendelian randomization (MR) analysis.

In transferring genes from parents to offspring, genetic alleles are assigned through a random process at the time of gamete formation (Mendel’s Second Law). The randomly assorted alleles are analogous to randomly allocated treatments in randomized controlled trials. Based on this principle, MR analysis uses genetic variants with known functions as markers of long-term exposure to estimate unconfounded exposure–outcome associations in observational studies [7]. The analysis requires the identification of a genetic variant that robustly predicts the exposure of interest to serve as an instrumental variable for this exposure, also known as the “intermediate phenotype.” Theoretically, such analysis can eliminate all confounding bias because subjects are randomly assigned to different genotypes, thereby enabling one to determine the potential causal relation between exposure and outcome.

The study has considerable strength as a prospective study based on a well-established cohort, with anthropomorphic information from a large number of parental–offspring trios. In addition, objective data on adiposity in offspring were available from dual energy x-ray absorptiometry scans. Although the application of MR analysis in the study has certain advantages in estimating causal associations compared to conventional observational analyses, there are potential limitations [8] that deserve discussion.

Overall, with the unique and large prospective cohort of over 4,000 parental–offspring trios and the integration of genetic data via MR analysis for causal inference, this study presents an important contribution to testing the fetal origin of obesity hypothesis. Not only does this provocative study warrant replication in a different population, but future research should also aim to investigate the fetal origin hypothesis using other direct intermediate measures of in utero “overnutrition,” such as gestational levels of maternal hyperglycemia and free fatty acids. Moreover, it would also be highly informative to investigate the hypothesis via MR using other established or soon-to-be discovered genes responsible for obesity, diabetes, and/or other metabolic disorders. Recent advances in genome-wide association studies have made it possible to identify reproducible genes for these conditions. Larger sample sizes and more robust estimates of the genotype–intermediate phenotype and genotype–outcome associations in future studies would also help provide more precise MR estimates for causal inference.



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