What do age, sex, environment, and genomics have in common? Well, aside from taking your mind to the wrong place, they also interact to shape your methylome. There’s no denying that genome and epigenome share many intimate associations (cue dim lighting). We’ve seen that epigenetic modification can precede mutation in cancer and evolution. Then, of course, genetic variation in the right place can deprive the epigenome of its much needed substrate, like in the case of SNPs or even CpG SNPs.
One challenge to understanding the associations of the epigenome lies in knowing whether your differential methylation is a product of the genome, your factor of interest, or something entirely different.
In order to tackle the complex associations between genome and epigenome, a talented team primarily from the Vrije Universiteit (VU) Amsterdam (in the Netherlands) has examined how SNPs, age, sex, and environmental exposure shape the CpGenome.
The team analyzed 450k array data collected at the Netherlands Twin Register in whole blood samples from twins and some of their family members. By taking advantage of monozygotic (and largely genetically identical) twins the team was able to shed some light on the role of environmental exposures and stochastic events.
Moreover, by taking the classical twin design and comparing the profiles of monozygotic twins to dizygotic (fraternal) twins, which only shares half of their genetic content, the team could also tease out how much the genetic and environmental effects in total contribute to individual differences in methylation level from conception onwards.
The study included men and women of a broad age range (17-79 years), which made it possible to examine (statistical) interactions of age and sex with genetic and environmental influences on the methylome. This particular analysis was done because the researchers wanted to know if the amount of variation in DNA methylation levels between people change with age or differ between men and women? If so, is it the genetic part of the variance or the environmentally induced part that differs?
By examining the CpGenome of 769 monozygotic and 424 dizygotic twin pairs they found that:
DNA Methylation is Heritable
- Additive genetic effects and unique environmental effects accounted for most of the variation in DNA methylation levels, while common environmental influences shared by twins and non-additive genetic influences had a smaller effect.
- The total heritability (h2) of methylation levels was 0.19 (s.d=0.20) on average (across all genome-wide sites), and the proportion of total heritability explained by all common genotyped SNPs (h2SNPs/h2) was 0.37 on average.
- Sites where the methylation level was highly heritable more often showed intermediate methylation levels and more variable methylation levels compared to sites with a low heritability.
Environment, Sex, and Age Interact with DNA Methylation
- Unique environmental influences and/or stochastic effects explained on average 81 % of the variance in methylation levels, if you average over all genome-wide sites (this proportion is smaller for the more variable methylation sites).
- Unique environmental influences were found to be a more important determinant of sex-specific and age-specific methylation variation between individuals than genetic influences.
- There’s a significant interaction between sex and genetic or environmental effects that is evident at 2,667 sites methylation sites (0.7%). At 59% of these sites, the heritability was lower in women. It was usually the amount of unique environmental variance that differed between the sexes.
- There is also a significant interaction between age and genetic or environmental effects on DNA methylation that is evident at 10.4% of all sites: At most of these locations, the unique environmental variance and total variance of DNA methylation between individuals gets bigger with age, and the proportion of variance explained by genetic influences (heritability) gets smaller. This finding could mean that effects of environmental influences on the methylome accumulate during the lifespan, and that individuals (including monozygotic twins) differ in the extent to which they are not exposed or react to these influences.
- Sites where the environmental variance changed with age showed significant overlap with DHSs of several types of fetal cells, embryonic stem cells and IPS cells.
- The above pattern was observed for DNA methylation level at cg22178392 in the TNIP1 gene, which was previously found to be associated with serum LDL cholesterol level in blood and adipose tissue: The higher the age of people, the larger the variation in methylation level between them due to unique environmental influences. The heritability of DNA methylation at this site decreases from 0.54 at age 25 to 0.39 at age 50 in blood.
- The variation in methylation level at cg12803068 in MYO1G, associated with smoking, was largely explained by genetic influences, but the unique environmental variance increased with age. The heritability of this site decreased from 0.91 at age 25 to 0.71 at age 50.
- At 65 sites where the environmental variance changed with age and where methylation level was previously reported to be associated with smoking status, data from monozygotic twins stratified by smoking status (“smoking-discordant” and “smoking-concordant” twin pairs) confirmed the role of smoking in the increasing environmental variance with increasing age at these sites.
Smoking is just one of the many potential environmental influences on the human methylome. It also remains to be examined what exactly the relevance of the findings are for our health. Lead author Jenny van Dongen shares, “One of the exciting findings from our study is that the degree of DNA methylation is regulated by the genome itself. So to some extent the genome regulates its own expression regardless of environment. And we now understand that the extent to which the genome regulates its expression differs markedly in different locations of the genome.”
She further shares her vision that this “…catalogue of genetic and environmental influences on DNA methylation along the genome that can be used by other researchers to get insight into the causes of (sex- and age-specific) variation in DNA methylation at (putative) disease loci. Our catalogue may hold valuable information on locations in the genome where methylation variation between people reflects disease-relevant environmental exposures or genetic variation.”
Ultimately, this research will help provide a much needed base-point for disentangling what is truly responsible for the differential methylation prevalent in human population.
Go learn more about what twins can reveal about the intimate relationship of the genome and epigenome over at Nature Communications, April 2016
***EpiGenie would like to thank Jenny van Dongen for providing the content of this write-up***