Early life affects late-life health through determining DNA methylation across the lifespan: A twin study
Shuai Li,
Zhoufeng Ye,
Karen A. Mather,
Tuong L. Nguyen,
Gillian S. Dite,
Nicola J. Armstrong,
Ee Ming Wong,
Anbupalam Thalamuthu,
Graham G. Giles,
Jeffrey M. Craig,
Richard Saffery,
Melissa C. Southey,
Qihua Tan,
Perminder S. Sachdev,
John L. Hopper
Affiliations
Shuai Li
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia; Correspond to Dr Shuai Li, Address: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Carlton, Victoria 3053, Australia.
Zhoufeng Ye
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
Karen A. Mather
Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia
Tuong L. Nguyen
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
Gillian S. Dite
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia; Genetic Technologies Ltd, Fitzroy, Victoria, Australia
Nicola J. Armstrong
Mathematics and Statistics, Curtin University, Western Australia, Australia
Ee Ming Wong
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia; Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia
Anbupalam Thalamuthu
Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia
Graham G. Giles
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
Jeffrey M. Craig
The Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Victoria, Australia; Murdoch Children's Research Institute, Parkville, Victoria, Australia
Richard Saffery
Murdoch Children's Research Institute, Parkville, Victoria, Australia
Melissa C. Southey
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia; Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
Qihua Tan
Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark
Perminder S. Sachdev
Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, New South Wales, Australia
John L. Hopper
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
Summary: Background: Previous findings for the genetic and environmental contributions to DNA methylation variation were for limited age ranges only. We investigated the lifespan contributions and their implications for human health for the first time. Methods: 1,720 monozygotic twin (MZ) pairs and 1,107 dizygotic twin (DZ) pairs aged 0-92 years were included. Familial correlations (i.e., correlations between twins) for 353,681 methylation sites were estimated and modelled as a function of twin pair cohabitation history. Findings: The methylome average familial correlation was around zero at birth (MZ pair: -0.01; DZ pair: -0.04), increased with the time of twins living together during childhood at rates of 0.16 (95%CI: 0.12-0.20) for MZ pairs and 0.13 (95%CI: 0.07-0.20) for DZ pairs per decade, and decreased with the time of living apart during adulthood at rates of 0.026 (95%CI: 0.019-0.033) for MZ pairs and 0.027 (95%CI: 0.011-0.043) for DZ pairs per decade. Neither the increasing nor decreasing rate differed by zygosity (both P>0.1), consistent with cohabitation environment shared by twins, rather than genetic factors, influencing the methylation familial correlation changes. Familial correlations for 6.6% (23,386/353,681) sites changed with twin pair cohabitation history. These sites were enriched for high heritability, proximal promoters, and epigenetic/genetic associations with various early-life factors and late-life health conditions. Interpretation: Early life strongly influences DNA methylation variation across the lifespan, and the effects are stronger for heritable sites and sites biologically relevant to the regulation of gene expression. Early life could affect late-life health through influencing DNA methylation. Funding: Victorian Cancer Agency, Cancer Australia, Cure Cancer Foundation.
