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Int J Biochem Cell Biol. 2015 Oct;67:58-64. doi: 10.1016/j.biocel.2015.05.009. Epub 2015 May 21.

Association of DNA methylation in the brain with age in older persons is confounded by common neuropathologies.

Author information

1
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.
2
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
3
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.
4
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.
5
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.

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.

KEYWORDS:

Age; CpG; Epigenetics; Methylation; Neuropathology

PMID:
26003740
PMCID:
PMC4564337
DOI:
10.1016/j.biocel.2015.05.009
[Indexed for MEDLINE]
Free PMC Article

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