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Clin Epigenetics. 2019 Nov 27;11(1):164. doi: 10.1186/s13148-019-0755-5.

Alzheimer's disease-associated (hydroxy)methylomic changes in the brain and blood.

Author information

1
School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Maastricht University, P.O. Box 616, 6200, MD, Maastricht, the Netherlands.
2
Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075, Göttingen, Germany.
3
University of Exeter Medical School, University of Exeter, Exeter, UK.
4
Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, 50937, Cologne, Germany.
5
Department of Neurodegeneration and Gerontopsychiatry, University of Bonn, 53127, Bonn, Germany.
6
Department of Bioinformatics-BiGCaT, Maastricht University, Maastricht, The Netherlands.
7
German Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, Germany.
8
Institute of Human Genetics, University of Bonn, 53127, Bonn, Germany.
9
Department of Genomics, Life & Brain Center, University of Bonn, 53127, Bonn, Germany.
10
Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, CH-4058, Basel, Switzerland.
11
Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, 04103, Leipzig, Germany.
12
Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, 50937, Cologne, Germany.
13
Department of Psychiatry and Division of Medical Psychology, University of Bonn, 53105, Bonn, Germany.
14
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
15
Moscow Institute of Physics and Technology, Dolgoprudny, Moscow, Russian Federation.
16
CIC bioGUNE, Bizkaia Technology Park, 801 Building, 48160, Derio, Spain.
17
IKERBASQUE, Basque Foundation for Science, Dolgoprudny, Bilbao, Spain.
18
L.J. Roberts Center for Alzheimer's Research Banner Sun Health Research Institute, Sun City, AZ, USA.
19
Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA.
20
Institute of Psychiatry, King's College London, London, UK.
21
School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Maastricht University, P.O. Box 616, 6200, MD, Maastricht, the Netherlands. d.vandenhove@maastrichtuniversity.nl.
22
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany. d.vandenhove@maastrichtuniversity.nl.

Abstract

BACKGROUND:

Late-onset Alzheimer's disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD.

RESULTS:

We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (- 3.76% 5mC, pŠidák = 1.07E-06), CHRNB1 (+ 1.46% 5hmC, pŠidák = 4.01E-04), RHBDF2 (- 3.45% UC, pŠidák = 4.85E-06), and C3 (- 1.20% UC, pŠidák = 1.57E-03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, pŠidák = 7.14E-04).

CONCLUSIONS:

The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.

KEYWORDS:

Alzheimer’s disease; Blood; Brain; DNA hydroxymethylation; DNA methylation; Epigenetics; Middle temporal gyrus

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