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Clin Epigenetics. 2019 Sep 2;11(1):130. doi: 10.1186/s13148-019-0729-7.

Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer's disease.

Author information

1
Turku Bioscience Centre, University of Turku and Åbo Akademi University, FIN-20520, Turku, Finland.
2
Turku Doctoral Programme of Molecular Medicine, University of Turku, FI-20014, Turku, Finland.
3
Department of Computer Science, Aalto University School of Science, FI-00076, Helsinki, Finland.
4
Institute of Gerontology and Aging Research Network-Jönköping (ARN-J), School of Health and Welfare, Jönköping University, SE-55111, Jönköping, Sweden.
5
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177, Stockholm, Sweden.
6
Drug Research Doctoral Program, University of Turku, FI-20014, Turku, Finland.
7
Turku PET Centre, University of Turku, FI-20520, Turku, Finland.
8
Institute for Molecular Medicine Finland, University of Helsinki, FI-00014, Helsinki, Finland.
9
Turku Brain and Mind Center, FinnBrain Birth Cohort Study, Institute of Clinical Medicine, University of Turku, FI-20014, Turku, Finland.
10
Department of Psychiatry, University of Turku and Turku University Hospital, FI-20014, Turku, Finland.
11
Department of Pathology/Neuropathology, Turku University Hospital, University of Turku, FI-20014, Turku, Finland.
12
Department of Psychology, University of Southern California, Los Angeles, CA, 90089, USA.
13
Department of Public Health, University of Helsinki, FI-00271, Helsinki, Finland.
14
Division of Clinical Neurosciences, Turku University Hospital, FI-20014, Turku, Finland.
15
Turku Bioscience Centre, University of Turku and Åbo Akademi University, FIN-20520, Turku, Finland. riikka.lund@utu.fi.

Abstract

BACKGROUND:

Alzheimer's disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs.

RESULTS:

Comparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value ≤ 0.05. Several of the affected genes are primarily associated with neuronal functions and pathologies and do not display disease-associated differences in gene expression in blood. The DNA methylation mark in ADARB2 gene was found to be differentially methylated also in the anterior hippocampus, including entorhinal cortex, of non-twin cases and controls. Targeted bisulfite pyrosequencing of the DNA methylation mark in ADARB2 gene in 62 Finnish and Swedish twin pairs revealed that, in addition to the disease status, DNA methylation of this region is influenced by gender, age, zygosity, APOE genotype, and smoking. Further analysis of 120 Swedish twin pairs indicated that this specific DNA methylation mark is not predictive for Alzheimer's disease and becomes differentially methylated after disease onset.

CONCLUSIONS:

DNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer's disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels.

KEYWORDS:

Alzheimer’s disease; DNA methylome; Hippocampus; Peripheral blood; Twin pair

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