Genome-wide average DNA methylation is determined in utero

Shuai Li; Ee Ming Wong; Pierre-Antoine Dugué; Allan F McRae; Eunae Kim; Ji-Hoon Eric Joo; Tuong L Nguyen; Jennifer Stone; Gillian S Dite; Nicola J Armstrong; Karen A Mather; Anbupalam Thalamuthu; Margaret J Wright; David Ames; Roger L Milne; Jeffrey M Craig; Richard Saffery; Grant W Montgomery; Yun-Mi Song; Joohon Sung; Timothy D Spector; Perminder S Sachdev; Graham G Giles; Melissa C Southey; John L Hopper

doi:10.1093/ije/dyy028

Genome-wide average DNA methylation is determined in utero

Int J Epidemiol. 2018 Jun 1;47(3):908-916. doi: 10.1093/ije/dyy028.

Authors

Shuai Li¹, Ee Ming Wong^{2

3}, Pierre-Antoine Dugué^{1

4}, Allan F McRae⁵, Eunae Kim⁶, Ji-Hoon Eric Joo^{2

3}, Tuong L Nguyen¹, Jennifer Stone⁷, Gillian S Dite¹, Nicola J Armstrong⁸, Karen A Mather⁹, Anbupalam Thalamuthu⁹, Margaret J Wright⁵, David Ames¹⁰, Roger L Milne^{1

4}, Jeffrey M Craig^{11

12

13}, Richard Saffery^{11

12}, Grant W Montgomery¹⁴, Yun-Mi Song¹⁵, Joohon Sung^{6

16}, Timothy D Spector¹⁷, Perminder S Sachdev⁹, Graham G Giles^{1

4}, Melissa C Southey^{2

3}, John L Hopper^{1

6

16}

Affiliations

¹ Centre for Epidemiology and Biostatistics.
² Genetic Epidemiology Laboratory, University of Melbourne, Parkville, VIC, Australia.
³ Precision Medicine, Monash University, Clayton, VIC, Australia.
⁴ Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia.
⁵ Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
⁶ Complex Disease and Genome Epidemiology Branch, Department of Public Health Science, School of Public Health, Seoul National University, Seoul, Republic of Korea.
⁷ Centre for Genetic Origins of Health and Disease, Curtin University and the University of Western Australia, Perth, WA, Australia.
⁸ Mathematics and Statistics, Murdoch University, Perth, WA, Australia.
⁹ Centre for Healthy Brain Ageing (CHeBA), University of New South Wales, Sydney, NSW, Australia.
¹⁰ National Ageing Research Institute and University of Melbourne Academic Unit for Psychiatry of Old Age, Parkville, VIC, Australia.
¹¹ Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC, Australia.
¹² Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.
¹³ School of Medicine, Deakin University, Geelong, VIC, Australia.
¹⁴ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
¹⁵ Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
¹⁶ Institute of Health and Environment, Seoul National University, Seoul, Republic of Korea.
¹⁷ Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.

Abstract

Background: Investigating the genetic and environmental causes of variation in genome-wide average DNA methylation (GWAM), a global methylation measure from the HumanMethylation450 array, might give a better understanding of genetic and environmental influences on methylation.

Methods: We measured GWAM for 2299 individuals aged 0 to 90 years from seven twin and/or family studies. We estimated familial correlations, modelled correlations with cohabitation history and fitted variance components models for GWAM.

Results: The correlation in GWAM for twin pairs was ∼0.8 at birth, decreased with age during adolescence and was constant at ∼0.4 throughout adulthood, with no evidence that twin pair correlations differed by zygosity. Non-twin first-degree relatives were correlated, from 0.17 [95% confidence interval (CI): 0.05-0.30] to 0.28 (95% CI: 0.08-0.48), except for middle-aged siblings (0.01, 95% CI: -0.10-0.12), and the correlation increased with time living together and decreased with time living apart. Spouse pairs were correlated in all studies, from 0.23 (95% CI: 0.3-0.43) to 0.31 (95% CI: 0.05-0.52), and the correlation increased with time living together. The variance explained by environmental factors shared by twins alone was 90% (95% CI: 74-95%) at birth, decreased in early life and plateaued at 28% (95% CI: 17-39%) in middle age and beyond. There was a cohabitation-related environmental component of variance.

Conclusions: GWAM is determined in utero by prenatal environmental factors, the effects of which persist throughout life. The variation of GWAM is also influenced by environmental factors shared by family members, as well as by individual-specific environmental factors.

Keywords: DNA methylation; Epigenomics; twin study.