Abstract
A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the Add-NeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage. (C) 2020 The Authors. Published by Elsevier Inc.
| Original language | English |
|---|---|
| Pages (from-to) | 26-45 |
| Number of pages | 20 |
| Journal | Neurobiology of Aging |
| Volume | 95 |
| DOIs | |
| Publication status | Published - Nov 2020 |
Keywords
- ALGORITHM
- Alzheimer's disease (AD)
- BIOMARKERS
- Biomarker
- Blood
- DEMENTIA
- DISCOVERY
- DNA methylation
- HOXB6
- MESSENGER-RNA EXPRESSION
- METHYLATION
- MILD COGNITIVE IMPAIRMENT
- Mild cognitive impairment (MCI)
- OXYTOCIN
- PACKAGE
- PATTERN
- RISK
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In: Neurobiology of Aging, Vol. 95, 11.2020, p. 26-45.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene
AU - Roubroeks, Janou A. Y.
AU - Smith, Adam R.
AU - Smith, Rebecca G.
AU - Pishva, Ehsan
AU - Ibrahim, Zina
AU - Sattlecker, Martina
AU - Hannon, Eilis J.
AU - Kloszewska, Iwona
AU - Mecocci, Patrizia
AU - Soininen, Hilkka
AU - Tsolaki, Magda
AU - Vellas, Bruno
AU - Wahlund, Lars-Olof
AU - Aarsland, Dag
AU - Proitsi, Petroula
AU - Hodges, Angela
AU - Lovestone, Simon
AU - Newhouse, Stephen J.
AU - Dobson, Richard J. B.
AU - Mill, Jonathan
AU - van den Hove, Daniel L. A.
AU - Lunnon, Katie
N1 - Funding Information: Support for the current study was provided by a major project grant from the Alzheimer's Society, United Kingdom ( AS-PG-14–038 ) to KL, a project grant from the Medical Research Council (MRC), United Kingdom ( MR/N027973/1 ) to KL as part of the Joint Programme—Neurodegenerative Disease Research (JPND) initiative for the EPI-AD consortium, an NIH, United States, R01 grant ( AG036039 ) to JM, an Equipment Grant from Alzheimer's Research UK (ART-EG2010A-2) to JM, a PhD studentship from the GW4 MRC BioMed DTP (United Kingdom) for JAYR, and an Alzheimer's Research UK South West Network Centre pump priming award to JAYR. Funding Information: We thank the AddNeuroMed cohort and the participants who made this research possible. The AddNeuroMed data are from a public-private partnership supported by EFPIA companies and SMEs as part of InnoMed (Innovative Medicines in Europe), an Integrated Project funded by the European Union of the Sixth Framework program priority FP6 2004-LIFESCIHEALTH-5. Clinical leads responsible for data collection are Iwona K?oszewska (Lodz), Simon Lovestone (London), Patrizia Mecocci (Perugia), Hilkka Soininen (Kuopio), Magda Tsolaki (Thessaloniki), and Bruno Vellas (Toulouse); the imaging leads are Andy Simmons (London), Lars-Olad Wahlund (Stockholm), and Christian Spenger (Zurich); and the bioinformatics leads are Richard Dobson (London) and Stephen Newhouse (London). This work was further supported by The National Institute for Health Research at the University College London Hospitals Biomedical Research Centre, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, and Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome Trust. Support for the current study was provided by a major project grant from the Alzheimer's Society, United Kingdom (AS-PG-14?038) to KL, a project grant from the Medical Research Council (MRC), United Kingdom (MR/N027973/1) to KL as part of the Joint Programme?Neurodegenerative Disease Research (JPND) initiative for the EPI-AD consortium, an NIH, United States, R01 grant (AG036039) to JM, an Equipment Grant from Alzheimer's Research UK (ART-EG2010A-2) to JM, a PhD studentship from the GW4 MRC BioMed DTP (United Kingdom) for JAYR, and an Alzheimer's Research UK South West Network Centre pump priming award to JAYR. Funding Information: We thank the AddNeuroMed cohort and the participants who made this research possible. The AddNeuroMed data are from a public-private partnership supported by EFPIA companies and SMEs as part of InnoMed (Innovative Medicines in Europe), an Integrated Project funded by the European Union of the Sixth Framework program priority FP6 2004-LIFESCIHEALTH-5. Clinical leads responsible for data collection are Iwona Kłoszewska (Lodz), Simon Lovestone (London), Patrizia Mecocci (Perugia), Hilkka Soininen (Kuopio), Magda Tsolaki (Thessaloniki), and Bruno Vellas (Toulouse); the imaging leads are Andy Simmons (London), Lars-Olad Wahlund (Stockholm), and Christian Spenger (Zurich); and the bioinformatics leads are Richard Dobson (London) and Stephen Newhouse (London). This work was further supported by The National Institute for Health Research at the University College London Hospitals Biomedical Research Centre, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, and Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome Trust. Publisher Copyright: © 2020 The Author(s)
PY - 2020/11
Y1 - 2020/11
N2 - A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the Add-NeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage. (C) 2020 The Authors. Published by Elsevier Inc.
AB - A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the Add-NeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage. (C) 2020 The Authors. Published by Elsevier Inc.
KW - ALGORITHM
KW - Alzheimer's disease (AD)
KW - BIOMARKERS
KW - Biomarker
KW - Blood
KW - DEMENTIA
KW - DISCOVERY
KW - DNA methylation
KW - HOXB6
KW - MESSENGER-RNA EXPRESSION
KW - METHYLATION
KW - MILD COGNITIVE IMPAIRMENT
KW - Mild cognitive impairment (MCI)
KW - OXYTOCIN
KW - PACKAGE
KW - PATTERN
KW - RISK
U2 - 10.1016/j.neurobiolaging.2020.06.023
DO - 10.1016/j.neurobiolaging.2020.06.023
M3 - Article
C2 - 32745807
SN - 0197-4580
VL - 95
SP - 26
EP - 45
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -