Genetic and environmental influences interact with age and sex in shaping the human methylome

Genetic and environmental influences interact with age and sex in shaping the human methylome

Of the many established epigenetic marks and mechanisms, DNA methylation is thought to contribute to stable long-term gene expression regulation and tissue differentiation, and is ideally suited for genome-wide assessment in large human epidemiological studies. A growing body of literature illustrates that traits and diseases are associated with DNA methylation variation. DNA methylation differences between individuals may result from differences in environmental exposures, stochastic variation and genetic influences.

Increasing evidence suggests that genetically induced epigenetic variation between individuals contributes to human disease susceptibility. Methylation differences have been observed between the sexes and across age, suggesting that epigenetic regulation may also be involved in the widely observed age and sex differences in life history traits and the aetiology of complex diseases.

It is well-known that genetically identical model organisms such as cloned animals, isogenic plants and inbred mice exhibit epigenetic and phenotypic differences. These organisms and human identical twins offer insight into the impact of environmental and stochastic influences on the epigenome.

The overall contribution of genetic and environmental differences, from conception onwards, to variation in DNA methylation between humans may be estimated by contrasting the correlation between DNA methylation levels of monozygotic (MZ) and dizygotic (DZ) twins, who share 100% and 50% of segregating genetic variants that contribute to methylation differences, respectively (the classical twin design).

Based on previous twin studies, the average heritability of methylation level on cytosine-guanine dinucleotides (CpGs) across the genome has been estimated between 5% and 19% for different tissues, but it is unknown what part can be explained by common genetic variation and to what extent the impact of genetic and environmental influences on DNA methylation depends on sex and age.

Studies of humans and rats have described sex-specific effects of prenatal dietary exposures on DNA methylation and sex-specific epigenetic effects of in utero exposure to an endocrine disruptor have been described in mice. Some studies indicated that certain epigenetic marks including DNA methylation diverge in twin pairs with ageing, suggesting amplification of environmental or stochastic effects on DNA methylation across the lifespan, although evidence for such effects is not always observed.

A study of neonatal MZ twins reported that twin pairs may show trajectories of divergent, convergent or longitudinally stable methylation patterns after birth. Examples of sites where the relationships between age and DNA methylation depends on genotype and sex-specific methylation quantitative trait loci (QTL) have also been reported.

In the current study, authors analyze data from a large cohort of twins and family members in whom DNA methylation was measured across the genome (Illumina 450k array) in whole blood. They establish an accurate catalogue of between-individual variation in DNA methylation due to environmental effects, total genetic effects and the effects of common genetic variants.

Authors examine differences in epigenetic regulation between the sexes and across age, and test for interactions of genomic effects and environmental effects on methylation with sex and age. Subsequently, they relate their catalogue to previously published loci where DNA methylation is sensitive to smoking, and loci that are epigenetically associated with metabolic phenotypes, including serum metabolite levels, lipid levels and body mass index (BMI).

Researchers demonstrate that (1) many smoking-associated CpGs show epigenetic drift (changes in methylation due to deregulated maintenance) with aging; (2) DNA methylation connected to complex traits is characterized by genetically and environmentally induced variation between individuals; and (3) the importance of the environment increases with age at many sites.

These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation.