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Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer's disease-related dysregulation.
- Source :
-
Clinical epigenetics [Clin Epigenetics] 2019 Dec 16; Vol. 11 (1), pp. 195. Date of Electronic Publication: 2019 Dec 16. - Publication Year :
- 2019
-
Abstract
- Background: Trisomy 21 (T21) is associated with intellectual disability that ranges from mild to profound with an average intellectual quotient of around 50. Furthermore, T21 patients have a high risk of developing Alzheimer's disease (AD) early in life, characterized by the presence of senile plaques of amyloid protein and neurofibrillary tangles, leading to neuronal loss and cognitive decline. We postulate that epigenetic factors contribute to the observed variability in intellectual disability, as well as at the level of neurodegeneration seen in T21 individuals.<br />Materials and Methods: A genome-wide DNA methylation study was performed using Illumina Infinium® MethylationEPIC BeadChips on whole blood DNA of 3 male T21 patients with low IQ, 8 T21 patients with high IQ (4 males and 4 females), and 21 age- and sex-matched control samples (12 males and 9 females) in order to determine whether DNA methylation alterations could help explain variation in cognitive impairment between individuals with T21. In view of the increased risk of developing AD in T21 individuals, we additionally investigated the T21-associated sites in published blood DNA methylation data from the AgeCoDe cohort (German study on Ageing, Cognition, and Dementia). AgeCoDe represents a prospective longitudinal study including non-demented individuals at baseline of which a part develops AD dementia at follow-up.<br />Results: Two thousand seven hundred sixteen differentially methylated sites and regions discriminating T21 and healthy individuals were identified. In the T21 high and low IQ comparison, a single CpG located in the promoter of PELI1 was differentially methylated after multiple testing adjustment. For the same contrast, 69 differentially methylated regions were identified. Performing a targeted association analysis for the significant T21-associated CpG sites in the AgeCoDe cohort, we found that 9 showed significant methylation differences related to AD dementia, including one in the ADAM10 gene. This gene has previously been shown to play a role in the prevention of amyloid plaque formation in the brain.<br />Conclusion: The differentially methylated regions may help understand the interaction between methylation alterations and cognitive function. In addition, ADAM10 might be a valuable blood-based biomarker for at least the early detection of AD.
- Subjects :
- Adult
Alzheimer Disease diagnosis
Cognition
Early Diagnosis
Epigenesis, Genetic
Female
Genome-Wide Association Study
Germany
Humans
Longitudinal Studies
Male
Prospective Studies
Young Adult
ADAM10 Protein genetics
Alzheimer Disease genetics
Amyloid Precursor Protein Secretases genetics
DNA Methylation
Down Syndrome genetics
Epigenomics methods
Membrane Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1868-7083
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical epigenetics
- Publication Type :
- Academic Journal
- Accession number :
- 31843015
- Full Text :
- https://doi.org/10.1186/s13148-019-0787-x