Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders
Creators
- Nabais, Marta F.1
- Laws, Simon M.2
- Lin, Tian1
- Vallerga, Costanza L.1
- Armstrong, Nicola J.3
- Blair, Ian P.4
- Kwok, John B.5
- Mather, Karen A.6
- Mellick, George D.7
- Sachdev, Perminder S.6
- Wallace, Leanne1
- Henders, Anjali K.1
- Zwamborn, Ramona A. J.8
- Hop, Paul J.8
- Lunnon, Katie9
- Pishva, Ehsan9
- Roubroeks, Janou A. Y.9
- Soininen, Hilkka10
- Tsolaki, Magda11
- Mecocci, Patrizia12
- Lovestone, Simon13
- Kłoszewska, Iwona14
- Vellas, Bruno15
- the Australian Imaging Biomarkers and Lifestyle study
- the Alzheimer's Disease Neuroimaging Initiative
- Furlong, Sarah16
- Garton, Fleur C.1
- Henderson, Robert D.17
- Mathers, Susan18
- McCombe, Pamela A.19
- Needham, Merrilee20
- Ngo, Shyuan T.17
- Nicholson, Garth21
- Pamphlett, Roger22
- Rowe, Dominic B.16
- Steyn, Frederik J.23
- Williams, Kelly L.16
- Anderson, Tim J.24
- Bentley, Steven R.25
- Dalrymple-Alford, John24
- Fowder, Javed7
- Gratten, Jacob26
- Halliday, Glenda27
- Hickie, Ian B.27
- Kennedy, Martin28
- Lewis, Simon J. G.27
- Montgomery, Grant W.1
- Pearson, John29
- Pitcher, Toni L.24
- Silburn, Peter17
- Zhang, Futao1
- Visscher, Peter M.1
- Yang, Jian1
- Stevenson, Anna J.30
- Hillary, Robert F.30
- Marioni, Riccardo E.30
- Harris, Sarah E.31
- Deary, Ian J.31
- Jones, Ashley R.32
- Shatunov, Aleksey32
- Iacoangeli, Alfredo32
- van Rheenen, Wouter8
- van den Berg, Leonard H.8
- Shaw, Pamela J.33
- Shaw, Cristopher E.32
- Morrison, Karen E.34
- Al-Chalabi, Ammar32
- Veldink, Jan H.8
- Hannon, Eilis9
- Mill, Jonathan9
- Wray, Naomi R.1
- McRae, Allan F.1
- 1. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia
- 2. School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Dr, Joondalup, WA, 6027, Australia
- 3. Murdoch University, 90 South St, Murdoch, WA, 6150, Australia
- 4. Australian Centre for Precision Health, University of South Australia Cancer Research Institute, School of Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia
- 5. Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia
- 6. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, 2031, Australia
- 7. Griffith Institute for Drug Discovery (GRIDD), Griffith University, Brisbane, Australia
- 8. Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
- 9. University of Exeter Medical School, RILD Building, RD&E Hospital Wonford, Barrack Road, Exeter, EX2 5DW, UK
- 10. Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland
- 11. 1st Department of Neurology, Memory and Dementia Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece
- 12. Department of Medicine, Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy
- 13. Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK
- 14. Medical University of Lodz, Lodz, Poland
- 15. INSERM U 558, University of Toulouse, Toulouse, France
- 16. Centre for Motor Neuron Disease Research, Macquarie University, Sydney, NSW, 2109, Australia
- 17. Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia
- 18. Calvary Health Care Bethlehem, Parkdale, VIC, 3195, Australia
- 19. Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4019, Australia
- 20. Fiona Stanley Hospital, Perth, WA, 6150, Australia
- 21. ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, NSW, 2139, Australia
- 22. Discipline of Pathology and Department of Neuropathology, Brain and Mind Centre, The University of Sydney, Sydney, NSW, 2050, Australia
- 23. Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane, QLD, 4029, Australia
- 24. New Zealand Brain Research Institute, Christchurch, New Zealand
- 25. Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia
- 26. Mater Research, Translational Research Institute, Brisbane, Australia
- 27. Brain and Mind Research Centre, Sydney Medical School, The University of Sydney, Sydney, Australia
- 28. Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
- 29. Department of Pathology, University of Otago, Christchurch, New Zealand
- 30. Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
- 31. Department of Psychology, Lothian Birth Cohorts group, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK
- 32. Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, SE5 9RX, UK
- 33. SITraN, University of Sheffield, Sheffield, UK
- 34. Queen's University Belfast, Belfast, Northern Ireland, UK
Description
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.