Abstract
BackgroundCerebral 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.ResultsIn 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.ConclusionsIn 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.
Highlights
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
An age acceleration increase by 1 year was associated with an increase of WMH burden by ~1 grade (0.007 on the log scale) (Table 4)
We examined the association of selected SNPs in each locus with WMH burden in middle-aged to elderly individuals from population-based cohorts of the NeuroCHARGE consortium, including 17,936 participants of European ancestry and 1943 African-Americans [17]
Summary
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. White matter hyperintensities (WMH) on brain magnetic resonance imaging (MRI) are typical markers of small vessel disease and are associated with an increased risk of stroke, cognitive and functional impairment, dementia, and death [1]. Using whole blood DNA methylation array data from 656 subjects aged 19 to 101, Hannum et al developed a predictor of age based on 71 CpG sites [6]. Using 82 publicly available DNA methylation array data sets comprising 51 healthy tissues and cell types across a range of chronologic ages, Horvath developed a multi-tissue predictor of age based on 353 CpG sites [7]. The deviation of the DNA methylationpredicted age from the chronologic age, defined as “age acceleration”, is used as an index of “biological” aging
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