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JAMA Neurol. 2015 Jan;72(1):15-24. doi: 10.1001/jamaneurol.2014.3049.

Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease.

Author information

1
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
2
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts4Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departme.
3
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois7Department of Preventive Medicine, Rush University Medical Center, Chicago, Illinois.
4
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois8Department of Pathology, Rush University Medical Center, Chicago, Illinois.
5
Epigenomics Program, Broad Institute, Cambridge Center, Cambridge, Massachusetts10Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts.

Abstract

IMPORTANCE:

Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown.

OBJECTIVE:

To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies.

DESIGN, SETTING, AND PARTICIPANTS:

Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old.

EXPOSURES:

DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay.

MAIN OUTCOMES AND MEASURES:

Pathological diagnosis of AD by National Institute on Aging-Reagan criteria following a standard postmortem examination.

RESULTS:

Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and paired helical filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with paired helical filament tau tangle density, and the expression of BIN1 was associated with Aβ load.

CONCLUSIONS AND RELEVANCE:

Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.

PMID:
25365775
PMCID:
PMC4344367
DOI:
10.1001/jamaneurol.2014.3049
[Indexed for MEDLINE]
Free PMC Article

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