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

  • Nabais, Marta F.1, 2
  • Laws, Simon M.3
  • Lin, Tian1
  • Vallerga, Costanza L.1, 4
  • Armstrong, Nicola J.5
  • Blair, Ian P.6
  • Kwok, John B.7
  • Mather, Karen A.8, 9
  • Mellick, George D.10
  • Sachdev, Perminder S.8, 11
  • Wallace, Leanne1
  • Henders, Anjali K.1
  • Zwamborn, Ramona A. J.12
  • Hop, Paul J.12
  • Lunnon, Katie2
  • Pishva, Ehsan2
  • Roubroeks, Janou A. Y.2
  • Soininen, Hilkka13
  • Tsolaki, Magda14
  • Mecocci, Patrizia15
  • And 50 more
  • 1 The University of Queensland, Brisbane, QLD, 4072, Australia , Brisbane (Australia)
  • 2 University of Exeter Medical School, RILD Building, RD&E Hospital Wonford, Barrack Road, Exeter, EX2 5DW, UK , Exeter (United Kingdom)
  • 3 Edith Cowan University, 270 Joondalup Dr, Joondalup, WA, 6027, Australia , Joondalup (Australia)
  • 4 University Medical Center, Rotterdam, 3015GD, The Netherlands , Rotterdam (Netherlands)
  • 5 Murdoch University, 90 South St, Murdoch, WA, 6150, Australia , Murdoch (Australia)
  • 6 University of South Australia, Adelaide, SA, 5001, Australia , Adelaide (Australia)
  • 7 The University of Sydney, Sydney, Australia , Sydney (Australia)
  • 8 University of New South Wales, Sydney, NSW, 2031, Australia , Sydney (Australia)
  • 9 Neuroscience Research Australia Institute, Randwick, NSW, 2031, Australia , Randwick (Australia)
  • 10 Griffith University, Brisbane, Australia , Brisbane (Australia)
  • 11 Neuropsychiatric Institute, The Prince of Wales Hospital, UNSW, Randwick, NSW, 2031, Australia , Randwick (Australia)
  • 12 Utrecht University, Utrecht, The Netherlands , Utrecht (Netherlands)
  • 13 University of Eastern Finland, Kuopio, Finland , Kuopio (Finland)
  • 14 Aristotle University of Thessaloniki, Thessaloniki, Greece , Thessaloniki (Greece)
  • 15 University of Perugia, Perugia, Italy , Perugia (Italy)
  • 16 University of Oxford, Oxford, UK , Oxford (United Kingdom)
  • 17 Medical University of Lodz, Lodz, Poland , Lodz (Poland)
  • 18 University of Toulouse, Toulouse, France , Toulouse (France)
  • 19 Macquarie University, Sydney, NSW, 2109, Australia , Sydney (Australia)
  • 20 The University of Queensland, Brisbane, QLD, 4019, Australia , Brisbane (Australia)
  • 21 Royal Brisbane and Women’s Hospital, Brisbane, QLD, 4029, Australia , Brisbane (Australia)
  • 22 Calvary Health Care Bethlehem, Parkdale, VIC, 3195, Australia , Parkdale (Australia)
  • 23 Fiona Stanley Hospital, Perth, WA, 6150, Australia , Perth (Australia)
  • 24 Notre Dame University, Fremantle, WA, 6160, Australia , Fremantle (Australia)
  • 25 Murdoch University, Perth, WA, 6150, Australia , Perth (Australia)
  • 26 ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, NSW, 2139, Australia , Sydney (Australia)
  • 27 The University of Sydney, Sydney, NSW, 2050, Australia , Sydney (Australia)
  • 28 New Zealand Brain Research Institute, Christchurch, New Zealand , Christchurch (New Zealand)
  • 29 University of Otago, Christchurch, New Zealand , Christchurch (New Zealand)
  • 30 University of Canterbury, Christchurch, New Zealand , Christchurch (New Zealand)
  • 31 Mater Research, Translational Research Institute, Brisbane, Australia , Brisbane (Australia)
  • 32 The University of Queensland, Brisbane, Australia , Brisbane (Australia)
  • 33 Westlake University, Hangzhou, Zhejiang, China , Hangzhou (China)
  • 34 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China , Hangzhou (China)
  • 35 University of Edinburgh, Edinburgh, EH4 2XU, UK , Edinburgh (United Kingdom)
  • 36 University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK , Edinburgh (United Kingdom)
  • 37 King’s College London, Institute of Psychiatry, Psychology and Neuroscience, London, SE5 9RX, UK , London (United Kingdom)
  • 38 University of Sheffield, Sheffield, UK , Sheffield (United Kingdom)
  • 39 Queen’s University Belfast, Belfast, Northern Ireland, UK , Belfast (United Kingdom)
  • 40 King’s College Hospital, London, SE5 9RS, UK , London (United Kingdom)
  • 41 King’s College London, London, SE5 8AF, UK , London (United Kingdom)
Published Article
Publication Date
Mar 26, 2021
DOI: 10.1186/s13059-021-02275-5
Springer Nature


BackgroundPeople 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.ResultsWe 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.ConclusionsWe 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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