Developmental pathways to adiposity begin before birth and are influenced by genotype, prenatal environment and epigenome

Abstract

BackgroundObesity is an escalating health problem worldwide, and hence the causes underlying its development are of primary importance to public health. There is growing evidence that suboptimal intrauterine environment can perturb the metabolic programing of the growing fetus, thereby increasing the risk of developing obesity in later life. However, the link between early exposures in the womb, genetic susceptibility, and perturbed epigenome on metabolic health is not well understood. In this study, we shed more light on this aspect by performing a comprehensive analysis on the effects of variation in prenatal environment, neonatal methylome, and genotype on birth weight and adiposity in early childhood.MethodsIn a prospective mother-offspring cohort (N = 987), we interrogated the effects of 30 variables that influence the prenatal environment, umbilical cord DNA methylation, and genotype on offspring weight and adiposity, over the period from birth to 48 months. This is an interim analysis on an ongoing cohort study.ResultsEleven of 30 prenatal environments, including maternal adiposity, smoking, blood glucose and plasma unsaturated fatty acid levels, were associated with birth weight. Polygenic risk scores derived from genetic association studies on adult adiposity were also associated with birth weight and child adiposity, indicating an overlap between the genetic pathways influencing metabolic health in early and later life. Neonatal methylation markers from seven gene loci (ANK3, CDKN2B, CACNA1G, IGDCC4, P4HA3, ZNF423 and MIRLET7BHG) were significantly associated with birth weight, with a subset of these in genes previously implicated in metabolic pathways in humans and in animal models. Methylation levels at three of seven birth weight-linked loci showed significant association with prenatal environment, but none were affected by polygenic risk score. Six of these birth weight-linked loci continued to show a longitudinal association with offspring size and/or adiposity in early childhood.ConclusionsThis study provides further evidence that developmental pathways to adiposity begin before birth and are influenced by environmental, genetic and epigenetic factors. These pathways can have a lasting effect on offspring size, adiposity and future metabolic outcomes, and offer new opportunities for risk stratification and prevention of obesity.Clinical Trial RegistrationThis birth cohort is a prospective observational study, designed to study the developmental origins of health and disease, and was retrospectively registered on 1 July 2010 under the identifier NCT01174875.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0800-1) contains supplementary material, which is available to authorized users.

Relationships of maternal body mass index and plasma biomarkers with childhood body mass index and adiposity at 6 years: The Children of SCOPE study

“…Our analyses found a strong relationship between maternal and childhood obesity, although a limitation is that we were not able to examine the child's obesity polygenic risk score (PRS) as an explanation for the finding, but other studies suggest that genetic influences, reflected in PRS, are unlikely to have anything more than a modest influence on the association. 49 The measures of body composition utilized in this study have limitations. BMI, which was used to define obesity in the mothers, is an indirect measure fat mass.…”

Weight-related quality of life in obese, pregnant women in South Africa

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Gene-methylation interactions: Discovering region-wise DNA methylation levels that modify SNP-associated disease risk

“…Further, White et al 23 performed a multi-step analysis of several data sources (genetic, methylation and transcription) to unravel the association of genes with neurological disorders. In another work, several linear regression models were tested to identify associations between methylation levels at CpG sites and child's birth weight 24 , and subsequently to test for association between the top CpGs and genotypes. A few studies searched for an association between a specific genotype and the methylation level at a chosen CpG from a neighboring region [25][26][27] .…”