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Hans T. Bjornsson, MD, PhD; Martin I. Sigurdsson, MD; M. Daniele Fallin, PhD; Rafael A. Irizarry, PhD; Thor Aspelund, PhD; Hengmi Cui, PhD; Wenqiang Yu, PhD; Michael A. Rongione, BA; Tomas J. Ekström, PhD; Tamara B. Harris, PhD; Lenore J. Launer, PhD; Gudny Eiriksdottir, PhD; Mark F. Leppert, MD; Carmen Sapienza, PhD; Vilmundur Gudnason, MD, PhD; Andrew P. Feinberg, MD, MPH

JAMA. 2008;299(24):2877-2883.

Context  Changes over time in epigenetic marks, which are modifications of DNA such as by DNA methylation, may help explain the late onset of common human diseases. However, changes in methylation or other epigenetic marks over time in a given individual have not yet been investigated.

Objectives  To determine whether there are longitudinal changes in global DNA methylation in individuals and to evaluate whether methylation maintenance demonstrates familial clustering.

Design, Setting, and Participants  We measured global DNA methylation by luminometric methylation assay, a quantitative measurement of genome-wide DNA methylation, on DNA sampled at 2 visits on average 11 years apart in 111 individuals from an Icelandic cohort (1991 and 2002-2005) and on average 16 years apart in 126 individuals from a Utah sample (1982-1985 and 1997-2005).

Main Outcome Measure  Global methylation changes over time.

Results  Twenty-nine percent of Icelandic individuals showed greater than 10% methylation change over time (P < .001). The family-based Utah sample also showed intra-individual changes over time, and further demonstrated familial clustering of methylation change (P = .003). The family showing the greatest global methylation loss also demonstrated the greatest loss of gene-specific methylation by a separate methylation assay.

Conclusion  These data indicate that methylation changes over time and suggest that methylation maintenance may be under genetic control.

Author Affiliations: Departments of Medicine (Drs Bjornsson, Sigurdsson, Cui, Yu, and Feinberg, and Mr Rongione), Epidemiology (Dr Fallin), and Biostatistics (Drs Fallin and Irizarry), and Center for Epigenetics (Drs Bjornsson, Sigurdsson, Fallin, Irizarry, Cui, Yu, and Feinberg and Mr Rongione), Johns Hopkins University, Baltimore, Maryland; Hjartavernd, Reykjavik, Iceland (Drs Aspelund, Eiriksdottir, and Gudnason); Department of Clinical Neuroscience, Karolinska Institute, Karolinska University Hospital-Solna, Stockholm, Sweden (Dr Ekström); Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, Maryland (Drs Harris and Launer); Department of Human Genetics and Eccles Institute of Human Genetics, University of Utah, Salt Lake City (Dr Leppert); and Fels Institute for Cancer Research and Department of Pathology, Temple University Medical School, Philadelphia, Pennsylvania (Dr Sapienza).

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