The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

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 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.

Le nouveau paradigme de l’origine développementale de la santé et des maladies (DOHaD)

“…Le séquençage du génome a apporté une connaissance fabuleuse, mais ne nous offre qu'un nombre restreint de marqueurs de prédiction fiables quant à la susceptibilité à certaines maladies chroniques, une application qui n'est pas à la hauteur de l'espoir suscité. Une étude récente estime qu'à la naissance, les interactions gène/environnement liées à des processus épigéné-tiques représentent 75 % de la variabilité phénotypique, alors que le génotype ne rend compte que de 25 % [13]. Et pourtant, les marques épigénétiques ne s'apposent pas au hasard, mais dépendent aussi de la séquence de l'ADN.…”

DOHaD et information épigénétique

“…Des études de cohorte ont montré que, pour ce qui est du risque d'hypertension artérielle à l'âge adulte, le rôle de l'environnement durant les phases précoces du développement (révélé par le poids à la naissance) est comparable, en termes d'ampleur d'effet, à celui de l'environnement à l'âge adulte. D'autre part, le rôle du génotype ne semble pas dépasser 25 % [7] dans les estimations les plus favorables, les 75 % restants étant associés à des interactions entre génotype et environnement, donc à des mécanismes relevant de l'épigéné-tique et imputable au phénomène de DOHaD. Dans ce contexte, ce n'est pas tant le mécanisme épigénétique qui est appréhendé par les sciences humaines et sociales que les conséquences sociales qui pourraient être induites par les connaissances liées au concept DOHaD.…”

Impact of Early Environment on Children's Mental Health: Lessons From DNA Methylation Studies With Monozygotic Twins

“…This idea is supported by a study conducted by Yousefi et al (2013), who found that methylation levels at various sites on the leptin receptor gene were best explained by an interaction between the leptin receptor genotype and maternal smoking behavior. In another study, researchers identified variably methylated regions (VMRs) in a group of neonates and quantified the relative contribution of environmental and genetic factors to methylation at these regions (Teh et al, 2014). They found that 25% of the VMRs were best explained by genotype alone and the other 75% were best explained by the interaction between genotype and environment.…”

“…There is extensive evidence that genetic variation influences DNA methylation profiles (e.g., Chen et al, 2015;Liu et al, 2014;McRae et al, 2014;Teh et al, 2014). For instance, McRae et al (2014) compared similarity in DNA methylation levels in 614 individuals from 117 families.…”

“…For example, individuals exposed to in utero adversity (e.g., maternal stress/depression, malnutrition) or early adversity (e.g., parental violence) may differ environmentally, but also genetically, from those with low levels of early adversity (Teh et al, 2014).…”