The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes.
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 the enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, interindividual 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 ∼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.
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609;
Ai Ling
AL
Teh
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609; School of Computer Engineering, Nanyang Technological University (NTU), Singapore 639798;
Hong
H
Pan
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609;
Li
L
Chen
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609;
Mei-Lyn
ML
Ong
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609;
Shaillay
S
Dogra
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609;
Johnny
J
Wong
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4 Canada;
Julia L
JL
MacIsaac
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4 Canada;
Sarah M
SM
Mah
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4 Canada;
Lisa M
LM
McEwen
Saw Swee Hock School of Public Health, NUS, Singapore 117597;
Seang-Mei
SM
Saw
MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, United Kingdom;
Keith M
KM
Godfrey
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609; Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore 119228;
Yap-Seng
YS
Chong
KK Women's and Children's Hospital, Singapore 229899;
Kenneth
K
Kwek
School of Computer Engineering, Nanyang Technological University (NTU), Singapore 639798;
Chee-Keong
CK
Kwoh
Saw Swee Hock School of Public Health, NUS, Singapore 117597; Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore 119228;
Shu-E
SE
Soh
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609; Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore 119228;
Mary F F
MF
Chong
MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, United Kingdom;
Sheila
S
Barton
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609;
Neerja
N
Karnani
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609;
Clara Y
CY
Cheong
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609;
Jan Paul
JP
Buschdorf
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609;
Walter
W
Stünkel
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4 Canada;
Michael S
MS
Kobor
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609; Ludmer Centre for Neuroinformatics and Mental Health, Douglas University Mental Health Institute, McGill University, Montreal, (Quebec) H4H 1R3 Canada;
Michael J
MJ
Meaney
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609; Centre for Human Evolution, Adaptation and Disease, Liggins Institute, University of Auckland, Auckland 1142, New Zealand.
Peter D
PD
Gluckman
Singapore Institute of Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore 117609;
Joanna D
JD
Holbrook
D019295:Computational Biology / Q000379:methods; D018899:CpG Islands; D019175:DNA Methylation; D004777:Environment; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D059647:Gene-Environment Interaction; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D040641:Quantitative Trait Loci; D012307:Risk Factors; D059467:Transcriptome