Characterizing genetic and environmental influences on variable DNA methylation using monozygotic and dizygotic twins

摘要

Variation in DNA methylation is being increasingly associated with health and disease outcomes. Although DNA methylation is hypothesized to be a mechanism by which both genetic and non-genetic factors can influence the regulation of gene expression, little is known about the extent to which DNA methylation at specific sites is influenced by heritable as well as environmental factors. We quantified DNA methylation in whole blood at age 18 in a birth cohort of 1,464 individuals comprising 426 monozygotic (MZ) and 306 same-sex dizygotic (DZ) twin pairs. Site-specific levels of DNA methylation were more strongly correlated across the genome between MZ than DZ twins. Structural equation models revealed that although the average contribution of additive genetic influences on DNA methylation across the genome was relatively low, it was notably elevated at the highly variable sites characterized by intermediate levels of DNAm that are most relevant for epigenetic epidemiology. Sites at which variable DNA methylation was most influenced by genetic factors were significantly enriched for DNA methylation quantitative trait loci (mQTL) effects, and overlapped with sites where inter-individual variation correlates across tissues. Finally, we show that DNA methylation at sites robustly associated with environmental exposures such as tobacco smoking and obesity is also influenced by additive genetic effects, highlighting the need to control for genetic background in analyses of exposure-associated DNA methylation differences. Estimates of the contribution of genetic and environmental influences to DNA methylation at all sites profiled in this study are available as a resource for the research community ( http://www.epigenomicslab.com/online-data-resources ). Author summary The study of monozygotic (MZ) and dizygotic (DZ) twins provides an opportunity for exploring the extent to which heritable and environmental factors contribute to phenotypic variation in human populations. We exploit the twin study design to explore the factors influencing epigenetic variation between individuals, focussing on DNA methylation, the best-characterized and most stable epigenetic modification. We find that site-specific levels of DNA methylation are more strongly correlated across the genome between MZ than DZ twins. 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 DNAm, which are most relevant for epigenetic epidemiology. Sites at which variable DNA methylation is strongly influenced by genetic factors are enriched for DNA methylation quantitative trait loci (mQTL) effects, and overlap with sites where inter-individual variation correlates across tissues. Importantly, we show that DNA methylation at sites robustly associated with environmental exposures such as smoking and obesity is also influenced by genetic effects, highlighting the need to control for genetic background in analyses of exposure-associated DNA methylation differences. Finally, we present a searchable database cataloguing the genetic and environmental contributions to variable DNA methylation across the genome ( http://www.epigenomicslab.com/online-data-resources ).