Characterizing genetic and environmental influences on variable DNA methylation using monozygotic and dizygotic twins
Public Library of Science (PLoS)
© 2018 Hannon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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/hidden-link/).
The E-Risk Study is funded by the Medical Research Council (G1002190). Additional support was provided by the National Institute of Child Health and Human Development (HD077482), a Distinguished Investigator Award from the American Asthma Foundation to Dr. Mill, and by the Jacobs Foundation. Dr. Arseneault is a Mental Health Leadership Fellow for the U.K. Economic and Social Research Council. Some of the work reported here used a high-performance computing facility partially supported by grant 2016-IDG-1013 from the North Carolina Biotechnology Center.
This is the author accepted manuscript.The final version is available from Public Library of Science via the DOI in this record
Vol. 14 (8), article e1007544