Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

Marta F. Nabais; Simon M. Laws; Tian Lin; Costanza L. Vallerga; Nicola J. Armstrong; Ian P. Blair; John B. Kwok; Karen A. Mather; George D. Mellick; Perminder S. Sachdev; Leanne Wallace; Anjali K. Henders; Ramona A. J. Zwamborn; Paul J. Hop; Katie Lunnon; Ehsan Pishva; Janou A. Y. Roubroeks; Hilkka Soininen; Magda Tsolaki; Patrizia Mecocci; Simon Lovestone; Iwona Kloszewska; Bruno Vellas; Sarah Furlong; Fleur C. Garton; Robert D. Henderson; Susan Mathers; Pamela A. McCombe; Merrilee Needham; Shyuan T. Ngo; Garth Nicholson; Roger Pamphlett; Dominic B. Rowe; Frederik J. Steyn; Kelly L. Williams; Tim J. Anderson; Steven R. Bentley; John Dalrymple-Alford; Javed Fowder; Jacob Gratten; Glenda Halliday; Ian B. Hickie; Martin Kennedy; Simon J. G. Lewis; Grant W. Montgomery; John Pearson; Toni L. Pitcher; Peter Silburn; Futao Zhang; Peter M. Visscher; Jian Yang; Anna J. Stevenson; Robert F. Hillary; Riccardo E. Marioni; Sarah E. Harris; Ian J. Deary; Ashley R. Jones; Aleksey Shatunov; Alfredo Iacoangeli; Wouter van Rheenen; Leonard H. van den Berg; Pamela J. Shaw; Cristopher E. Shaw; Karen E. Morrison; Ammar Al-Chalabi; Jan H. Veldink; Eilis Hannon; Jonathan Mill; Naomi R. Wray; Allan F. McRae; Australian Imaging Biomarkers Life

doi:10.1186/s13059-021-02275-5

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Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

Journal article

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Peer reviewed

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

Marta F. Nabais, Simon M. Laws, Tian Lin, Costanza L. Vallerga, Nicola J. Armstrong, Ian P. Blair, John B. Kwok, Karen A. Mather, George D. Mellick, Perminder S. Sachdev, …

Genome biology, Vol.22(1), pp.90-90

26/03/2021

DOI: https://doi.org/10.1186/s13059-021-02275-5

Handle:

https://hdl.handle.net/10523/24929

Abstract

Biotechnology & Applied Microbiology

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

Background People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Results We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. Conclusions We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.

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Record Identifier: 9926514928901891
Title: Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders
Creators: Marta F. Nabais
Simon M. Laws
Tian Lin
Costanza L. Vallerga
Nicola J. Armstrong
Ian P. Blair
John B. Kwok
Karen A. Mather
George D. Mellick
Perminder S. Sachdev
Leanne Wallace
Anjali K. Henders
Ramona A. J. Zwamborn
Paul J. Hop
Katie Lunnon
Ehsan Pishva
Janou A. Y. Roubroeks
Hilkka Soininen
Magda Tsolaki
Patrizia Mecocci
Simon Lovestone
Iwona Kloszewska
Bruno Vellas
Sarah Furlong
Fleur C. Garton
Robert D. Henderson
Susan Mathers
Pamela A. McCombe
Merrilee Needham
Shyuan T. Ngo
Garth Nicholson
Roger Pamphlett
Dominic B. Rowe
Frederik J. Steyn
Kelly L. Williams
Tim J. Anderson
Steven R. Bentley
John Dalrymple-Alford
Javed Fowder
Jacob Gratten
Glenda Halliday
Ian B. Hickie
Martin Kennedy
Simon J. G. Lewis
Grant W. Montgomery
John Pearson
Toni L. Pitcher
Peter Silburn
Futao Zhang
Peter M. Visscher
Jian Yang
Anna J. Stevenson
Robert F. Hillary
Riccardo E. Marioni
Sarah E. Harris
Ian J. Deary
Ashley R. Jones
Aleksey Shatunov
Alfredo Iacoangeli
Wouter van Rheenen
Leonard H. van den Berg
Pamela J. Shaw
Cristopher E. Shaw
Karen E. Morrison
Ammar Al-Chalabi
Jan H. Veldink
Eilis Hannon
Jonathan Mill
Naomi R. Wray
Allan F. McRae
Australian Imaging Biomarkers Life
Publication Details: Genome biology, Vol.22(1), pp.90-90
Academic Unit: Office of the Dean (UOC); Pathology and Molecular Medicine (UOC); Medicine (UOC)
Publisher: Springer Nature
Grant note: ES/L008238/1 / Economic and Social Research Council; UK Research & Innovation (UKRI); Economic & Social Research Council (ESRC) Health-Holland, Top Sector Life Sciences Health National Institute of Biomedical Imaging and Bioengineering; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Biomedical Imaging & Bioengineering (NIBIB) Eli Lilly and Company; Eli Lilly Fujirebio Araclon Biotech 401162 / (NHMRC)/Australian Research Council Strategic Award; Australian Research Council CereSpir, Inc. Lundbeck; Lundbeck Corporation Austin Health EFPIA National Health and Medical Research Council (NHMRC); National Health & Medical Research Council (NHMRC) of Australia W81XWH-12-2-0012 / DOD ADNI (Department of Defense); United States Department of Defense Johnson & Johnson Pharmaceutical Research & Development LLC.; Johnson & Johnson; Johnson & Johnson USA Jim and Mary Carney Charitable Trust (Whangarei, New Zealand) U01 AG024904 / Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) FP6 2004-LIFESCIHEALTH-5 / SMEs as part of InnoMed (Innovative Medicines in Europe) - European Union of the Sixth Framework program; European Union (EU); Marie Curie Actions Biogen Piramal Imaging Servier Eisai Inc.; Eisai Co Ltd 1078901; 1113400; 1078037; 1103418; 1107258; 1127440 / National Health and Medical Research Council (NHMRC); National Health & Medical Research Council (NHMRC) of Australia ForeFront, a large collaborative research group; General Electric Alzheimer's Association IXICO Ltd. F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc. CogState Ltd.; CogState Limited Mater Foundation Pfizer Inc.; Pfizer National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London Janssen Alzheimer Immunotherapy Research & Development, LLC. Commonwealth Scientific Industrial and research Organization (CSIRO) 1084560 / Australian National Health and Medical Research Council; National Health & Medical Research Council (NHMRC) of Australia Transition Therapeutics National Institute on Aging; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) 733051071 / Netherlands, ZONMW; Netherlands Organization for Health Research and Development Alzheimer's Drug Discovery Foundation Novartis Pharmaceuticals Corporation; Novartis Science and Industry Endowment Fund (SIEF) MR/L501529/1; MR/R024804/1 / United Kingdom, Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 1083187; 1173790; 1078901; 1113400; 1132524; 1095127; 1060992 / NHMRC; National Health & Medical Research Council (NHMRC) of Australia 259867 / European Community's Health Seventh Framework Programme (FP7/2007-2013) CE10001021 / ARC (Centre of Excellence in Cognition and its Disorders Memory Program) Wellcome Trust 20100104 / Cooperative Research Centre (CRC) for Mental Health; Australian Government; Department of Industry, Innovation and Science; Cooperative Research Centres (CRC) Programme BioClinica, Inc. Motor Neurone Disease Research Institute of Australia Ice Bucket Challenge grant; Motor Neurone Disease Australia Cogstate; CogState Limited GE Healthcare; General Electric Meso Scale Diagnostics, LLC. 1173790; 1151854; 1113400; 1084560; 1083187; 1060992 / National Health and Medical Research Council of Australia; National Health & Medical Research Council (NHMRC) of Australia NIHR202421 / National Institute for Health Research; National Institutes of Health Research (NIHR) National Ageing Research Institute (NARI) AbbVie EuroImmun University of Otago Research Grant 1405325 / NHMRC Project; National Health & Medical Research Council (NHMRC) of Australia Merck Co., Inc.; Merck & Company National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre Lumosity Canadian Institutes of Health Research; Canadian Institutes of Health Research (CIHR) Motor Neurone Disease Association DP160102400; FT180100186 / Australian Research Council (ARC); Australian Research Council MND Association NeuroRx Research Takeda Pharmaceutical Company; Takeda Pharmaceutical Company Ltd Bristol-Myers Squibb Company; Bristol-Myers Squibb EU Joint Programme -Neurodegenerative Disease Research (JPND) 772376 - EScORIAL / European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program; European Research Council (ERC) Edith Cowan University (ECU) 633413 / Horizon 2020 Programme (H2020-PHC-2014-two-stage) Neurotrack Technologies Dementia Collaborative Research Centres program (DCRC2); Australian Government; Department of Industry, Innovation and Science; Cooperative Research Centres (CRC) Programme Elan Pharmaceuticals, Inc. 1151854 / Australian National Health and Medical Research (NHMRC) Council; National Health & Medical Research Council (NHMRC) of Australia Centre for Research Excellence from the Australian National Health and Medical Research Council (NHMRC); National Health & Medical Research Council (NHMRC) of Australia Mental Health Research institute (MHRI)
Date published ; e-published: 26/03/2021
Language: English
Resource Type ; Subtype: Journal article