The effect of genotype and in utero environment on inter-individual variation in neonate DNA methylomes
- Ai Ling Teh1,
- Hong Pan1,
- Li Chen2,
- Mei-Lyn Ong1,
- Shaillay Dogra1,
- Johnny Wong1,
- Julia L MacIsaac3,
- Sarah M Mah3,
- Lisa M McEwen3,
- Seang-Mei Saw4,
- Keith M Godfrey5,
- Yap-Seng Chong4,
- Kenneth Kwek6,
- Chee-Keong Kwoh7,
- Shu-E Soh4,
- Mary FF Chong1,
- Sheila Barton5,
- Neerja Karnani1,
- Clara Y Cheong1,
- Jan Paul Buschdorf1,
- Walter Stunkel1,
- Michael S Kobor3,
- Michael J Meaney8,
- Peter D Gluckman9 and
- Joanna D Holbrook1,10
- 1 Singapore Institute of Clinical Sciences (SICS);
- 2 Sinapore Institute of Clinical Sciences (SICS);
- 3 University of British Columbia;
- 4 National University of Singapore;
- 5 MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre;
- 6 KK Women's and Children's Hospital;
- 7 Nanyang Technology University (NTU);
- 8 McGill University;
- 9 University of Auckland
- ↵* Corresponding author; email: joanna_holbrook{at}sics.a-star.edu.sg
Abstract
Integrating the genotype with epigenetic marks holds the promise of better understanding the biology that underlies the complex interactions of inherited and environmental components that define the developmental origins of a range of disorders. The quality of the in utero environment significantly influences health over the lifecourse. Epigenetics and in particular DNA methylation marks have been postulated as a mechanism for enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, inter-individual variation in methylation can also be a consequence of DNA sequence polymorphisms that result in methylation quantitative trait loci (methQTLs) and, potentially, the interaction between fixed genetic variation and environmental influences. We surveyed the genotypes and DNA methylomes of 237 neonates and found 1423 punctuate regions of the methylome that were highly variable across individuals, termed variably methylated regions (VMRs), against a backdrop of homogeneity. MethQTLs were readily detected in neonatal methylomes and genotype alone best explained about 25% of the VMRs. We found that the best explanation for 75% of VMRs was the interaction of genotype with different in utero environments, including maternal smoking, maternal depression, maternal BMI, infant birth weight, gestational age and birth order. Our study sheds new light on the complex relationship between biological inheritance as represented by genotype and individual prenatal experience and suggests the importance of considering both fixed genetic variation and environmental factors in interpreting epigenetic variation.
- Received December 21, 2013.
- Accepted April 3, 2014.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 3.0 Unported), as described at http://creativecommons.org/licenses/by/3.0/.
