Genome Biology (Mar 2021)
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 Kłoszewska,
- Bruno Vellas,
- the Australian Imaging Biomarkers and Lifestyle study,
- the Alzheimer’s Disease Neuroimaging Initiative,
- 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
Affiliations
- Marta F. Nabais
- Institute for Molecular Bioscience, The University of Queensland
- Simon M. Laws
- School of Medical and Health Sciences, Edith Cowan University
- Tian Lin
- Institute for Molecular Bioscience, The University of Queensland
- Costanza L. Vallerga
- Institute for Molecular Bioscience, The University of Queensland
- Nicola J. Armstrong
- Murdoch University
- Ian P. Blair
- Australian Centre for Precision Health, University of South Australia Cancer Research Institute, School of Health Sciences, University of South Australia
- John B. Kwok
- Brain and Mind Centre, Sydney Medical School, The University of Sydney
- Karen A. Mather
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- George D. Mellick
- Griffith Institute for Drug Discovery (GRIDD), Griffith University
- Perminder S. Sachdev
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- Leanne Wallace
- Institute for Molecular Bioscience, The University of Queensland
- Anjali K. Henders
- Institute for Molecular Bioscience, The University of Queensland
- Ramona A. J. Zwamborn
- Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht University
- Paul J. Hop
- Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht University
- Katie Lunnon
- University of Exeter Medical School, RILD Building, RD&E Hospital Wonford
- Ehsan Pishva
- University of Exeter Medical School, RILD Building, RD&E Hospital Wonford
- Janou A. Y. Roubroeks
- University of Exeter Medical School, RILD Building, RD&E Hospital Wonford
- Hilkka Soininen
- Institute of Clinical Medicine, Neurology, University of Eastern Finland
- Magda Tsolaki
- 1st Department of Neurology, Memory and Dementia Unit, Aristotle University of Thessaloniki
- Patrizia Mecocci
- Department of Medicine, Institute of Gerontology and Geriatrics, University of Perugia
- Simon Lovestone
- Department of Psychiatry, Warneford Hospital, University of Oxford
- Iwona Kłoszewska
- Medical University of Lodz
- Bruno Vellas
- INSERM U 558, University of Toulouse
- the Australian Imaging Biomarkers and Lifestyle study
- the Alzheimer’s Disease Neuroimaging Initiative
- Sarah Furlong
- Centre for Motor Neuron Disease Research, Macquarie University
- Fleur C. Garton
- Institute for Molecular Bioscience, The University of Queensland
- Robert D. Henderson
- Queensland Brain Institute, The University of Queensland
- Susan Mathers
- Calvary Health Care Bethlehem
- Pamela A. McCombe
- Centre for Clinical Research, The University of Queensland
- Merrilee Needham
- Fiona Stanley Hospital
- Shyuan T. Ngo
- Queensland Brain Institute, The University of Queensland
- Garth Nicholson
- ANZAC Research Institute, Concord Repatriation General Hospital
- Roger Pamphlett
- Discipline of Pathology and Department of Neuropathology, Brain and Mind Centre, The University of Sydney
- Dominic B. Rowe
- Centre for Motor Neuron Disease Research, Macquarie University
- Frederik J. Steyn
- Department of Neurology, Royal Brisbane and Women’s Hospital
- Kelly L. Williams
- Centre for Motor Neuron Disease Research, Macquarie University
- Tim J. Anderson
- New Zealand Brain Research Institute
- Steven R. Bentley
- Eskitis Institute for Drug Discovery, Griffith University
- John Dalrymple-Alford
- New Zealand Brain Research Institute
- Javed Fowder
- Griffith Institute for Drug Discovery (GRIDD), Griffith University
- Jacob Gratten
- Mater Research, Translational Research Institute
- Glenda Halliday
- Brain and Mind Research Centre, Sydney Medical School, The University of Sydney
- Ian B. Hickie
- Brain and Mind Research Centre, Sydney Medical School, The University of Sydney
- Martin Kennedy
- Department of Pathology and Biomedical Science, University of Otago
- Simon J. G. Lewis
- Brain and Mind Research Centre, Sydney Medical School, The University of Sydney
- Grant W. Montgomery
- Institute for Molecular Bioscience, The University of Queensland
- John Pearson
- Department of Pathology, University of Otago
- Toni L. Pitcher
- New Zealand Brain Research Institute
- Peter Silburn
- Queensland Brain Institute, The University of Queensland
- Futao Zhang
- Institute for Molecular Bioscience, The University of Queensland
- Peter M. Visscher
- Institute for Molecular Bioscience, The University of Queensland
- Jian Yang
- Institute for Molecular Bioscience, The University of Queensland
- Anna J. Stevenson
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh
- Robert F. Hillary
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh
- Riccardo E. Marioni
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh
- Sarah E. Harris
- Department of Psychology, Lothian Birth Cohorts group, University of Edinburgh
- Ian J. Deary
- Department of Psychology, Lothian Birth Cohorts group, University of Edinburgh
- Ashley R. Jones
- Department of Basic and Clinical Neuroscience, King’s College London, Institute of Psychiatry, Psychology and Neuroscience
- Aleksey Shatunov
- Department of Basic and Clinical Neuroscience, King’s College London, Institute of Psychiatry, Psychology and Neuroscience
- Alfredo Iacoangeli
- Department of Basic and Clinical Neuroscience, King’s College London, Institute of Psychiatry, Psychology and Neuroscience
- Wouter van Rheenen
- Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht University
- Leonard H. van den Berg
- Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht University
- Pamela J. Shaw
- SITraN, University of Sheffield
- Cristopher E. Shaw
- Department of Basic and Clinical Neuroscience, King’s College London, Institute of Psychiatry, Psychology and Neuroscience
- Karen E. Morrison
- Queen’s University Belfast
- Ammar Al-Chalabi
- Department of Basic and Clinical Neuroscience, King’s College London, Institute of Psychiatry, Psychology and Neuroscience
- Jan H. Veldink
- Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht University
- Eilis Hannon
- University of Exeter Medical School, RILD Building, RD&E Hospital Wonford
- Jonathan Mill
- University of Exeter Medical School, RILD Building, RD&E Hospital Wonford
- Naomi R. Wray
- Institute for Molecular Bioscience, The University of Queensland
- Allan F. McRae
- Institute for Molecular Bioscience, The University of Queensland
- DOI
- https://doi.org/10.1186/s13059-021-02275-5
- Journal volume & issue
-
Vol. 22,
no. 1
pp. 1 – 30
Abstract
Abstract 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.
Keywords
- Neurodegenerative disorders
- DNA methylation
- Mixed-linear models
- Methylation profile score
- Out-of-sample classification
- Inflammatory markers
