An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene

Janou A. Y. Roubroeks; Adam R. Smith; Rebecca G. Smith; Ehsan Pishva; Zina Ibrahim; Martina Sattlecker; Eilis J. Hannon; Iwona Kloszewska; Patrizia Mecocci; Hilkka Soininen; Magda Tsolaki; Bruno Vellas; Lars-Olof Wahlund; Dag Aarsland; Petroula Proitsi; Angela Hodges; Simon Lovestone; Stephen J. Newhouse; Richard J. B. Dobson; Jonathan Mill; Daniel L. A. van den Hove; Katie Lunnon

doi:10.1016/j.neurobiolaging.2020.06.023

An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene

Janou A. Y. Roubroeks, Adam R. Smith, Rebecca G. Smith, Ehsan Pishva, Zina Ibrahim, Martina Sattlecker, Eilis J. Hannon, Iwona Kloszewska, Patrizia Mecocci, Hilkka Soininen, Magda Tsolaki, Bruno Vellas, Lars-Olof Wahlund, Dag Aarsland, Petroula Proitsi, Angela Hodges, Simon Lovestone, Stephen J. Newhouse, Richard J. B. Dobson, Jonathan MillDaniel L. A. van den Hove, Katie Lunnon^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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	https://doi.org/10.1016/j.neurobiolaging.2020.06.023
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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Roubroeks, J. A. Y., Smith, A. R., Smith, R. G., Pishva, E., Ibrahim, Z., Sattlecker, M., Hannon, E. J., Kloszewska, I., Mecocci, P., Soininen, H., Tsolaki, M., Vellas, B., Wahlund, L-O., Aarsland, D., Proitsi, P., Hodges, A., Lovestone, S., Newhouse, S. J., Dobson, R. J. B., ... Lunnon, K. (2020). An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene. Neurobiology of Aging, 95, 26-45. https://doi.org/10.1016/j.neurobiolaging.2020.06.023

@article{1ac0f82ae5ec4d75a961188d4779c247,

title = "An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene",

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.",

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",

author = "Roubroeks, {Janou A. Y.} and Smith, {Adam R.} and Smith, {Rebecca G.} and Ehsan Pishva and Zina Ibrahim and Martina Sattlecker and Hannon, {Eilis J.} and Iwona Kloszewska and Patrizia Mecocci and Hilkka Soininen and Magda Tsolaki and Bruno Vellas and Lars-Olof Wahlund and Dag Aarsland and Petroula Proitsi and Angela Hodges and Simon Lovestone and Newhouse, {Stephen J.} and Dobson, {Richard J. B.} and Jonathan Mill and {van den Hove}, {Daniel L. A.} and Katie Lunnon",

note = "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 K{\l}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. Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = nov,

doi = "10.1016/j.neurobiolaging.2020.06.023",

language = "English",

volume = "95",

pages = "26--45",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Science",

}

Roubroeks, JAY, Smith, AR, Smith, RG, Pishva, E, Ibrahim, Z, Sattlecker, M, Hannon, EJ, Kloszewska, I, Mecocci, P, Soininen, H, Tsolaki, M, Vellas, B, Wahlund, L-O, Aarsland, D, Proitsi, P, Hodges, A, Lovestone, S, Newhouse, SJ, Dobson, RJB, Mill, J, van den Hove, DLA & Lunnon, K 2020, 'An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene', Neurobiology of Aging, vol. 95, pp. 26-45. https://doi.org/10.1016/j.neurobiolaging.2020.06.023

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 -