title: Association of DNA methylation in the brain with age in older persons is confounded by common neuropathologies.
abstract: DNA methylation plays a crucial role in the regulation of gene expression, cell differentiation and development. Previous studies have reported age-related alterations of methylation levels in the human brain across the lifespan, but little is known about whether the observed association with age is confounded by common neuropathologies among older persons. Using genome-wide DNA methylation data from 740 postmortem brains, we interrogated 420,132 CpG sites across the genome in a cohort of individuals with ages from 66 to 108 years old, a range of ages at which many neuropathologic indices become quite common. We compared the association of DNA methylation prior to and following adjustment for common neuropathologies using a series of linear regression models. In the simplest model adjusting for technical factors including batch effect and bisulfite conversion rate, we found 8156 CpGs associated with age. The number of CpGs associated with age dropped by more than 10% following adjustment for sex. Notably, after adjusting for common neuropathologies, the total number of CpGs associated with age was reduced by approximately 40%, compared to the sex-adjusted model. These data illustrate that the association of methylation changes in the brain with age is inflated if one does not account for age-related brain pathologies. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. Electronic address: jingyun_yang@rush.edu.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gaiteri
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Departments of Neurology & Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Gyan P
authors.initials: GP
authors.lastname: Srivastava
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Departments of Neurology & Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Sue E
authors.initials: SE
authors.lastname: Leurgans
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; Department of Pathology, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Departments of Neurology & Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000145:classification / Q000235:genetics / Q000378:metabolism; D001344:Autopsy; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002544:Cerebral Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D016631:Lewy Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016014:Linear Models; D008297:Male; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D012737:Sex Factors; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000682:Amyloid; D001057:Apolipoproteins E
keywords: Age; CpG; Epigenetics; Methylation; Neuropathology