title: Cerebral white matter hyperintensities on MRI and acceleration of epigenetic aging: the atherosclerosis risk in communities study.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 1825 Pressler Street, 77030 Houston, TX USA.
authors.forename: Abhay
authors.initials: A
authors.lastname: Raina
authors.affiliation: Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 1825 Pressler Street, 77030 Houston, TX USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Division of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Grove
authors.affiliation: Division of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Bressler
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD USA.
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Gottesman
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Guan
authors.affiliation: Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Division of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Division of Geriatrics, School of Medicine, University of Mississippi Medical Center, Jackson, MS USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Mosley
authors.affiliation: Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 1825 Pressler Street, 77030 Houston, TX USA.|Division of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX USA.
authors.forename: Myriam
authors.identifier: 0000-0003-0677-8158
authors.initials: M
authors.lastname: Fornage
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000375:Aging / Q000208:ethnology / Q000235:genetics*; D000465:Algorithms; D050197:Atherosclerosis / Q000453:epidemiology* / Q000235:genetics; D015992:Body Mass Index; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D066127:White Matter / Q000000981:diagnostic imaging*
keywords: Aging; Cerebrovascular disease; DNA methylation; Epigenetic age acceleration; Epigenetic clock; White matter hyperintensities