Genetic variants influence how environment affects DNA methylation

Identical twins share the same genetic sequence and much of their early environment, but differences in their epigenetics may reveal how genes and environment interact.

Genetic association studies look for a link between genetic variants and the diseases we develop or drugs we respond to. Some variants may make us particularly susceptible to environmental factors, such as smoking, but it can be challenging to isolate and distinguish genetic and environmental interactions. By measuring epigenetic variation across the genomes of almost 1000 sets of identical twins, researchers have found loci associated with increased epigenetic variability. Within these variable twin pairs, methylation differences are assumed to arise from different environmental exposures (given that the genomes remain identical between twins), providing a readout of a gene-environment effect.

'Most human traits and diseases are influenced by both genetics and environment, but capturing how these two factors interact can be very challenging,' said Jordana Bell, professor in epigenomics at King's College London (KCL) and senior author on the study published in Genome Biology. 'Here, by using genetically identical twins, we're able to generate replicable evidence of gene-environment interactions'.

The researchers used DNA methylation epigenetic marker to look for differences between identical twins in the TwinsUK cohort. Searching for correlations between 5.1 million genetic variants and over 260,000 DNA methylation sites, they found 1656 sites of variable DNA methylation associated with unique genetic variants. About 38 percent of these associations replicated in a second cohort of 655 sets of twins in the Netherlands, identifying a core set of loci linked to variable methylation.

Because monozygotic twins share the same DNA, differences in methylation within a twin pair must arise from non-genetic influences. If particular genetic variants are associated with greater methylation variability between twins, they may indicate loci where genetic background modifies sensitivity to environmental exposures. However, the environmental variables captured in this analysis are somewhat limited. Five of the seven 'environment' measures correspond to immune cell-type counts in the blood samples, which account for most of the associations observed. Two more generalised environmental variables – BMI and smoking – each associate with a single replicable DNA methylation site and genetic variant.

Speaking about the aims of the study, Xiaopu Zhang, PhD student at KCL and first author said: 'Understanding gene-environment interactions may allow us to better stratify and prioritise individuals for interventions. It's not about predicting who will get a disease, but about identifying who could benefit most from certain interventions or healthy habits'.

The challenge remains to understand the biology of these associations. The researchers exploited existing association studies to correlate these genetic and epigenetic variants with diseases, but the wide array of conditions are challenging to interpret. More broadly, DNA methylation may be a secondary or indirect marker rather than a direct contributor to differing biology. Future work may incorporate richer environmental data in twin studies, potentially revealing additional gene-environment interactions and clarifying whether methylation differences are drivers of biological change or simply markers of underlying processes.