The effect of genotype and in utero environment on inter-individual 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 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 uteroenvironments, 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.

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