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Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer’s disease-related dysregulation
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 se...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916110/ https://www.ncbi.nlm.nih.gov/pubmed/31843015 http://dx.doi.org/10.1186/s13148-019-0787-x |
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author | Haertle, Larissa Müller, Tobias Lardenoije, Roy Maierhofer, Anna Dittrich, Marcus Riemens, Renzo J. M. Stora, Samantha Roche, Mathilde Leber, Markus Riedel-Heller, Steffi Wagner, Michael Scherer, Martin Ravel, Aimé Mircher, Clotilde Cieuta-Walti, Cecile Durand, Sophie van de Hove, Daniel L. A. Hoffmann, Per Ramirez, Alfredo Haaf, Thomas El Hajj, Nady Mégarbané, André |
author_facet | Haertle, Larissa Müller, Tobias Lardenoije, Roy Maierhofer, Anna Dittrich, Marcus Riemens, Renzo J. M. Stora, Samantha Roche, Mathilde Leber, Markus Riedel-Heller, Steffi Wagner, Michael Scherer, Martin Ravel, Aimé Mircher, Clotilde Cieuta-Walti, Cecile Durand, Sophie van de Hove, Daniel L. A. Hoffmann, Per Ramirez, Alfredo Haaf, Thomas El Hajj, Nady Mégarbané, André |
author_sort | Haertle, Larissa |
collection | PubMed |
description | 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. 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. 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. 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. |
format | Online Article Text |
id | pubmed-6916110 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-69161102019-12-30 Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer’s disease-related dysregulation Haertle, Larissa Müller, Tobias Lardenoije, Roy Maierhofer, Anna Dittrich, Marcus Riemens, Renzo J. M. Stora, Samantha Roche, Mathilde Leber, Markus Riedel-Heller, Steffi Wagner, Michael Scherer, Martin Ravel, Aimé Mircher, Clotilde Cieuta-Walti, Cecile Durand, Sophie van de Hove, Daniel L. A. Hoffmann, Per Ramirez, Alfredo Haaf, Thomas El Hajj, Nady Mégarbané, André Clin Epigenetics Research 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. 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. 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. 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. BioMed Central 2019-12-16 /pmc/articles/PMC6916110/ /pubmed/31843015 http://dx.doi.org/10.1186/s13148-019-0787-x Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Haertle, Larissa Müller, Tobias Lardenoije, Roy Maierhofer, Anna Dittrich, Marcus Riemens, Renzo J. M. Stora, Samantha Roche, Mathilde Leber, Markus Riedel-Heller, Steffi Wagner, Michael Scherer, Martin Ravel, Aimé Mircher, Clotilde Cieuta-Walti, Cecile Durand, Sophie van de Hove, Daniel L. A. Hoffmann, Per Ramirez, Alfredo Haaf, Thomas El Hajj, Nady Mégarbané, André Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer’s disease-related dysregulation |
title | Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer’s disease-related dysregulation |
title_full | Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer’s disease-related dysregulation |
title_fullStr | Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer’s disease-related dysregulation |
title_full_unstemmed | Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer’s disease-related dysregulation |
title_short | Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer’s disease-related dysregulation |
title_sort | methylomic profiling in trisomy 21 identifies cognition- and alzheimer’s disease-related dysregulation |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916110/ https://www.ncbi.nlm.nih.gov/pubmed/31843015 http://dx.doi.org/10.1186/s13148-019-0787-x |
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