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BMC Medicine
Published in: BMC Medicine 1/2017

Open Access 01-12-2017 | Research article

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

Authors: Xinyi Lin, Ives Yubin Lim, Yonghui Wu, Ai Ling Teh, Li Chen, Izzuddin M. Aris, Shu E. Soh, Mya Thway Tint, Julia L. MacIsaac, Alexander M. Morin, Fabian Yap, Kok Hian Tan, Seang Mei Saw, Michael S. Kobor, Michael J. Meaney, Keith M. Godfrey, Yap Seng Chong, Joanna D. Holbrook, Yung Seng Lee, Peter D. Gluckman, Neerja Karnani, on behalf of the GUSTO study group

Published in: BMC Medicine | Issue 1/2017

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Abstract

Background

Obesity 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.

Methods

In 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.

Results

Eleven 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.

Conclusions

This 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 Registration

This 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.
Appendix
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Metadata
Title
Developmental pathways to adiposity begin before birth and are influenced by genotype, prenatal environment and epigenome
Authors
Xinyi Lin
Ives Yubin Lim
Yonghui Wu
Ai Ling Teh
Li Chen
Izzuddin M. Aris
Shu E. Soh
Mya Thway Tint
Julia L. MacIsaac
Alexander M. Morin
Fabian Yap
Kok Hian Tan
Seang Mei Saw
Michael S. Kobor
Michael J. Meaney
Keith M. Godfrey
Yap Seng Chong
Joanna D. Holbrook
Yung Seng Lee
Peter D. Gluckman
Neerja Karnani
on behalf of the GUSTO study group
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2017
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-017-0800-1

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