Cerebral white matter hyperintensities on MRI and acceleration of epigenetic aging: the atherosclerosis risk in communities study

Abhay Raina, Xiaoping Zhao, Megan L. Grove, Jan Bressler, Rebecca F. Gottesman, Weihua Guan, James S. Pankow, Eric Boerwinkle, Thomas H. Mosley, Myriam Fornage

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Background: Cerebral white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) are part of the spectrum of brain vascular injury accompanying aging and are associated with a substantial risk of stroke and dementia. We investigated the association of cerebral WMH burden on MRI with a DNA methylation-based biomarker of aging, termed DNA methylation age acceleration, which represents the deviation of the DNA methylation-predicted age from the chronologic age. Results: In this cross-sectional observational study of 713 African-American participants of the Atherosclerosis Risk in Communities study, aged 51–73 years, estimates of predicted age were obtained based on two algorithms (Hannum et al. and Horvath) from DNA methylation measured using the Illumina HM450 array on genomic DNA extracted from blood. Age acceleration, calculated as the residual values from the regression of each of the predicted age measures onto the chronologic age, was significantly associated with WMH burden after accounting for chronologic age and sex, body mass index, systolic blood pressure, hypertension, diabetes, current smoking, and blood cell composition, and results were similar for either Hannum et al.- or Horvath-derived estimates (P = 0.016 and 0.026). An age acceleration increase by 1 year was associated with an increase of WMH burden by ~1 grade. To shed light on possible biological mechanisms underlying this association, we conducted a genome-wide association study of age acceleration and identified four loci harboring genes implicated in hemostasis, cell proliferation, protein degradation, and histone methylation. However, none of these loci were associated with WMH burden. Conclusions: In this population-based study of middle-aged to older African-American adults, we report an association between accelerated epigenetic aging and increased WMH burden, independent of known risk factors, including chronologic age. Additional studies are needed to clarify whether DNA methylation age reflects biological mechanisms implicated in the aging of the cerebral white matter.

Original languageEnglish (US)
Article number21
JournalClinical epigenetics
Issue number1
StatePublished - Feb 14 2017

Bibliographical note

Publisher Copyright:
© 2017, The Author(s).


  • Aging
  • Cerebrovascular disease
  • DNA methylation
  • Epigenetic age acceleration
  • Epigenetic clock
  • White matter hyperintensities


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