Genetic and environmental influences interact with age and sex in shaping the human methylome
Jenny van Dongen, Michel G. Nivard, Gonneke Willemsen, Jouke-Jan Hottenga, Quinta Helmer, Conor V. Dolan, Erik A. Ehli, Gareth E. Davies, Maarten van Iterson, Charles E. Breeze, Stephan Beck, BIOS Consortium, H. Eka Suchiman, Rick Jansen, Joyce B. van Meurs, Bastiaan T. Heijmans, P. Eline Slagboom & Dorret I. Boomsma
Nature Communications 7, Article number: 11115 (2016)
DNA methylation Epigenomics
Received: 10 June 2015 Accepted: 23 February 2016 Published online: 07 April 2016
Estimates of DNA methylation heritability from the GRM-based approach in 2,603 individuals. From inside to outside: the most inner circular diagram displays the average methylation level at each site, the second band shows the total heritability of DNA methylation level, the third band shows the SNP heritability of DNA methylation level, and the most outer circle shows the chromosome ideograms. Colours range from dark blue (0%) to dark red (100%).
The methylome is subject to genetic and environmental effects. Their impact may depend on sex and age, resulting in sex- and age-related physiological variation and disease susceptibility. Here we estimate the total heritability of DNA methylation levels in whole blood and estimate the variance explained by common single nucleotide polymorphisms at 411,169 sites in 2,603 individuals from twin families, to establish a catalogue of between-individual variation in DNA methylation. Heritability estimates vary across the genome (mean=19%) and interaction analyses reveal thousands of sites with sex-specific heritability as well as sites where the environmental variance increases with age. Integration with previously published data illustrates the impact of genome and environment across the lifespan at methylation sites associated with metabolic traits, smoking and ageing. These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation.
We thank the twins and their family members who participate in the studies of the Netherlands Twin Register. This study was funded by: BBRMI-NL-financed BIOS Consortium (NWO 184.021.007), and Genetics of Mental Illness, a lifespan approach to the genetics of childhood and adult neuropsychiatric disorders and comorbid conditions (ERC-230374). JvD is supported by ACTION. ACTION receives funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768. MV is supported by Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB. CB was supported by EpiTrain (EU-FP7 316758).
Jenny van Dongen & Michel G. Nivard
These authors contributed equally to this work.
Bastiaan T. Heijmans, P. Eline Slagboom & Dorret I. Boomsma
These authors jointly supervised this work.
Department of Biological Psychology, VU Amsterdam, Van der Boechorststraat 1, 1081BT Amsterdam, The Netherlands
Jenny van Dongen, Michel G. Nivard, Gonneke Willemsen, Jouke-Jan Hottenga, Quinta Helmer, Conor V. Dolan, René Pool & Dorret I. Boomsma
Avera Institute for Human Genetics, 3720 W. 69th Street, Sioux Falls, South Dakota 57108, USA
Erik A. Ehli & Gareth E. Davies
Department of Molecular Epidemiology, Leiden University Medical Center, Postzone S5-P, Postbus 9600, 2300 RC Leiden, The Netherlands
Maarten van Iterson, Marian Beekman, Joris Deelen, Ruud van der Breggen, Nico Lakenberg, Matthijs Moed, René Luijk, H. Eka Suchiman, Bastiaan T. Heijmans & P. Eline Slagboom
UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK
Charles E. Breeze & Stephan Beck
Department of Psychiatry, VU University Medical Center, A.J. Ernststraat 1187, 1081 HL Amsterdam, The Netherlands
Department of Internal Medicine, Erasmus Medical Center, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
André G. Uitterlinden, P. Mila Jhamai, Michael Verbiest, Marijn Verkerk, Jeroen van Rooij & Joyce B. van Meurs
Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Peter A.C.’t Hoen, Martijn Vermaat & Michiel van Galen
Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands
Marleen M.J. van Greevenbroek, Coen D.A. Stehouwer, Carla J.H. van der Kallen & Casper G. Schalkwijk
Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands
Cisca Wijmenga, Sasha Zhernakova, Ettje F. Tigchelaar, Dasha V. Zhernakova, Patrick Deelen, Marc Jan Bonder & Lude Franke
Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Diana van Heemst
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
Jan H. Veldink & Leonard H. van den Berg
Department of Genetic Epidemiology, ErasmusMC, 3000 CA Rotterdam, The Netherlands
Cornelia M. van Duijn & Aaron Isaacs
Department of Epidemiology, ErasmusMC, 3000 CA Rotterdam, The Netherlands
Bert A. Hofman
Sequence Analysis Support Core, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Hailiang Mei, Peter van’t Hof & Wibowo Arindrarto
SURFsara, 1090 GP Amsterdam, The Netherlands
Jan Bot & Irene Nooren
Genomics Coordination Center, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Freerk van Dijk & Morris A. Swertz
Medical Statistics Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Szymon M. Kielbasa & Erik W. van Zwet
Peter A.C.’t Hoen, René Pool, Marleen M.J. van Greevenbroek, Coen D.A. Stehouwer, Carla J.H. van der Kallen, Casper G. Schalkwijk, Cisca Wijmenga, Sasha Zhernakova, Ettje F. Tigchelaar, Marian Beekman, Joris Deelen, Diana van Heemst, Jan H. Veldink, Leonard H. van den Berg, Cornelia M. van Duijn, Bert A. Hofman, André G. Uitterlinden, P. Mila Jhamai, Michael Verbiest, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Hailiang Mei, Jan Bot, Dasha V. Zhernakova, Peter van’t Hof, Patrick Deelen, Irene Nooren, Matthijs Moed, Martijn Vermaat, René Luijk, Marc Jan Bonder, Freerk van Dijk, Michiel van Galen, Wibowo Arindrarto, Szymon M. Kielbasa, Morris A. Swertz, Erik W. van Zwet, Aaron Isaacs & Lude Franke
J.v.D. and M.G.N. contributed equally. B.T.H., G.W., P.E.S. and D.I.B. jointly supervised research. J.v.D., B.T.H., M.G.N., G.W., P.E.S. and D.I.B. conceived and designed the experiments. E.A.E., G.E.D., the BIOS Consortium, H.E.S., and J.B.v.M. performed the experiments. J.v.D., M.G.N. and C.B. performed statistical analysis. J.v.D., B.T.H., M.G.N., J.J.H., Q.H., C.V.D., E.A.E., M.V.I. and the BIOS consortium analysed the data. M.G.N., C.V.D., M.v.I., C.B., S.B. and the BIOS consortium contributed reagents/materials/analysis tools. J.v.D., B.T.H., M.G.N., G.W., E.A.E., G.E.D., R.J., J.B.v.M., P.E.S. and D.I.B. wrote the paper. B.T.H., P.E.S. and D.I.B. contributed equally.
The authors declare no competing financial interests.
Correspondence to Jenny van Dongen.