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Cited by 99Epigenetics and DNA MethylationDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

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

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the Australian Imaging Biomarkers and Lifestyle study, Nabais, Marta F., the Alzheimer’s Disease Neuroimaging Initiative, Laws, Simon M., Lin, Tian, Vallerga, Costanza L., Armstrong, Nicola J., Blair, Ian P. +64 more·2021·Genome Biology
DOI 10.1186/s13059-021-02275-5PMC PMC8004462
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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.

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  • The sex-specific meta-analysis included 1284 whole blood samples (632 females and 652 males) from ADNI and AIBL.

    “included DNA methylation data for a total of 1284 whole blood samples (632 females and 652 males).”

    From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [24]

    The Results (Study design; page unavailable) identify AIBL and ADNI as cohorts with whole-blood DNA methylation data, and the Methods (Cohorts description; page unavailable) describe their methylation samples. Our copy does not report a sex-specific meta-analysis of 1,284 samples or the stated breakdown of 632 females and 652 males (searched those numbers and the analysis description). (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Alterations in DNA methylation levels are involved in many diseases, including AD.

    “Alterations of DNA methylation levels have been shown to be involved in many diseases, including AD [19–24].”

    From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [24]

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study, T. A. I. B. A. L., Nabais, M. F., Initiative, T. A. D. N., Laws, S. M., Lin, T., Vallerga, C. L., Armstrong, N. J., Blair, I. P., Kwok, J. B., Mather, K. A., Mellick, G. D., Sachdev, P. S., Wallace, L., Henders, A. K., Zwamborn, R. A. J., Hop, P. J., Lunnon, K., Pishva, E., Roubroeks, J. A. Y., Soininen, H., Tsolaki, M., Mecocci, P., Lovestone, S., Kłoszewska, I., Vellas, B., Furlong, S., Garton, F. C., Henderson, R. D., Mathers, S., McCombe, P. A., Needham, M., Ngo, S. T., Nicholson, G., Pamphlett, R., Rowe, D. B., Steyn, F. J., Williams, K. L., Anderson, T. J., Bentley, S. R., Dalrymple-Alford, J., Fowder, J., Gratten, J., Halliday, G., Hickie, I. B., Kennedy, M., Lewis, S. J. G., Montgomery, G. W., Pearson, J., Pitcher, T. L., Silburn, P., Zhang, F., Visscher, P. M., Yang, J., Stevenson, A. J., Hillary, R. F., Marioni, R. E., Harris, S. E., Deary, I. J., Jones, A. R., Shatunov, A., Iacoangeli, A., van Rheenen, W., van den Berg, L. H., Shaw, P. J., Shaw, C. E., Morrison, K. E., Al-Chalabi, A., Veldink, J. H., Hannon, E., Mill, J., Wray, N. R., & McRae, A. F.
Affiliations
  • The University of Queensland (AU)
  • Edith Cowan University (AU)
  • The University of Sydney (AU)
  • University of South Australia (AU)
  • Griffith University (AU)
  • UNSW Sydney (AU)
  • Utrecht University (NL)
  • University of Exeter (GB)
  • University of Eastern Finland (FI)
  • Aristotle University of Thessaloniki (GR)
  • University of Perugia (IT)
  • Inserm (FR)
  • Medical University of Lodz (PL)
  • Fiona Stanley Hospital (AU)
  • Murdoch University (AU)
  • Concord Repatriation General Hospital (AU)
  • Macquarie University (AU)
  • New Zealand Brain Research Institute (NZ)
  • Institute of Genetics and Cancer (GB)
  • King's College London (GB)
  • Queen's University Belfast (GB)
Corresponding author
McRae, Allan F.
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2021-03-26
Volume
22
Issue
1
Pages
90-90
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/s13059-021-02275-5
PMC
PMC8004462
OpenAlex
W3137908860
Cited by
99
References
19
Citations by year
2026: 10 · 2025: 18 · 2024: 23 · 2023: 24 · 2022: 20 · 2021: 4
FWCI
2.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Research Portal (Queen's University Belfast) (acceptedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • Murdoch University Research Portal (submittedVersion)
  • Australasian Journal of Paramedicine (submittedVersion, cc-by)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • University of Canterbury Research Repository (University of Canterbury) (submittedVersion, cc-by)
  • Griffith Research Online (submittedVersion, cc-by)
Funders
  • Alzheimer's Association (U01 AG016976, U01 AG032984, ADGC-10–196728, U24AG021886, AG033193)
  • Wellcome Trust (108890, 082604/2/07/Z, 082604, /Z/15/Z, 108890/Z/15/Z)
  • Health Research Board (JPI-JPND-2017-1)
  • Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
  • Université de Lille
  • National Institute for Health and Care Research (NF-SI-0617-10077, NIHR202421)
  • Motor Neurone Disease Association (TURNER/OCT15/972-797)
  • University of Exeter
  • Commonwealth Scientific and Industrial Research Organisation
  • Agence Nationale de la Recherche (ANR-17-JPCD-0001)
  • Institut National de la Santé et de la Recherche Médicale
  • University of Queensland
  • ZonMw (733051071)
  • Bundesministerium für Bildung und Forschung (01GI0102, 01GI0711, 01GI0420)
  • Erasmus Medisch Centrum
  • Hjartavernd (N01-AG-1-2100)
  • Centre hospitalier régional universitaire de Lille
  • National Institutes of Health (N01-AG-1-2100, 5u01ag024904-10, NIA AG081220, AG016976, AG021886)
  • Medical Research Council (503480, MR/R024804/1)
  • Economic and Social Research Council (ES/L008238/1)
  • National Health and Medical Research Council (1110414, 1079679)
  • National Institute on Aging (U01-AG-024904, AG 016976, N01-AG12100, AG081220, U01AG016976, NIA AG081220, U01AG032984, AG033193, AG032984, R01AG033193, AG021886, U24AG021886)
  • National Heart, Lung, and Blood Institute (HL-105756, R01HL105756, AG033193)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
DNA methylation, neurodegenerative diseases, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, differentially methylated positions, blood DNA methylation, inflammation, healthy aging, genetic heterogeneity
MeSH terms
Alleles, Blood Cells, Disease Susceptibility, Humans, Biomarkers, Case-Control Studies, DNA Methylation, Neurodegenerative Diseases, Genetic Predisposition to Disease, Gene Expression Profiling, Epigenesis, Genetic, Genome-Wide Association Study, Genetic Loci

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