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Twin Study Distinguishes Methylation Profiles Responding to Genetic, Environmental Factors

NEW YORK (GenomeWeb) – Using DNA methylation profiles for hundreds of age-matched individuals from identical and non-identical twin pairs, researchers from the UK and the US were able to tease apart some of the epigenetic alterations that reflect genetic factors, environmental factors, or both.

"Our study provides a useful framework for interpreting the results of epigenetic epidemiological studies and shows that epigenetic differences are a potential mechanism linking genetic variation to gene regulation," University of Exeter Medical School complex disease epigenetics researcher Eilis Hannon said in a statement.

Hannon is first author on a study published online today in PLOS Genetics that compared DNA methylation in identical and non-identical twin pairs. Based on quantified, array-based DNA methylation profiles for individuals from hundreds of identical or non-identical twin pairs, she and her co-authors identified parts of the genome where genetic factors were most likely to affect DNA methylation levels — sites that tended to overlap with methylation quantitative trait loci and variably-methylated sites that were consistent between tissues in a given individual.

"While the average contribution of additive genetic influences on DNA methylation is relatively low, it is notably elevated at sites that are highly variable and have intermediate levels of [DNA methylation], which are most relevant for epigenetic epidemiology," Hannon and her colleagues wrote.

Some additive genetic effects were also documented in parts of the genome where DNA methylation has been linked to environmental factors, the authors noted, prompting them to call for care when assessing the epigenetic effects of such exposures.

"DNA methylation at sites robustly associated with environmental exposures such as tobacco smoking and obesity is also influenced by additive genetic effects," they wrote, "highlighting the need to control for genetic background in analyses of exposure-associated DNA methylation differences."

The team's analyses centered on participants from a UK birth cohort assembled for the Environmental Risk (E-Risk) Longitudinal Twin Study, encompassing more than 2,200 individuals born in 1994 or 1995.

Using Illumina Infinium HumanMethylation450 BeadChip arrays, the researchers profiled DNA methylation in whole blood samples from 1,464 twins who were enrolled in E-Risk and had reached the age of 18, including individuals from 426 monozygotic twin pairs and 306 same-sex dizygotic twin pairs.

The team went on to quantify DNA methylation at almost 421,000 autosomal variants in these individuals, using the data to explore methylation variability and the extent to which methylation at sites across the genome reflects genetic and non-genetic factors.

"These results highlight how both heritable and environmental factors can influence the way in which genes are expressed and function, with important implications for studies of health and disease," senior author Jonathan Mill, a complex disease epigenetics researcher at the University of Exeter, said in a statement.

In addition to identifying clusters of methylation marks influenced by genetic factors, for example, the team found that both environmental and genetic contributors could impact those methylation marks that vary with age or blood cell type.

"Although the largest contributor to inter-individual variation in DNA methylation across all tested sites was found to be non-shared environmental factors, which also captures measurement error, our findings highlight the importance of genetic influences on DNA methylation," the authors wrote. "Genetic influences appear to be especially important in mediating levels of DNA methylation at highly variable DNA methylation sites and those that are characterized by high levels of co-variation across tissues, suggesting that concerns relating to tissue-specific effects may be less relevant for genetic studies of DNA methylation."