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

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dc.contributor.authorNabais MF
dc.contributor.authorLaws SM
dc.contributor.authorLin T
dc.contributor.authorVallerga CL
dc.contributor.authorArmstrong NJ
dc.contributor.authorBlair IP
dc.contributor.authorKwok JB
dc.contributor.authorMather KA
dc.contributor.authorMellick GD
dc.contributor.authorSachdev PS
dc.contributor.authorWallace L
dc.contributor.authorHenders AK
dc.contributor.authorZwamborn RAJ
dc.contributor.authorHop PJ
dc.contributor.authorLunnon K
dc.contributor.authorPishva E
dc.contributor.authorRoubroeks JAY
dc.contributor.authorSoininen H
dc.contributor.authorTsolaki M
dc.contributor.authorMecocci P
dc.contributor.authorLovestone S
dc.contributor.authorKłoszewska I
dc.contributor.authorVellas B
dc.contributor.authorFurlong S
dc.contributor.authorGarton FC
dc.contributor.authorHenderson RD
dc.contributor.authorMathers S
dc.contributor.authorMcCombe PA
dc.contributor.authorNeedham M
dc.contributor.authorNgo ST
dc.contributor.authorNicholson G
dc.contributor.authorPamphlett R
dc.contributor.authorRowe DB
dc.contributor.authorSteyn FJ
dc.contributor.authorWilliams KL
dc.contributor.authorAnderson TJ
dc.contributor.authorBentley SR
dc.contributor.authorFowder J
dc.contributor.authorGratten J
dc.contributor.authorHalliday G
dc.contributor.authorHickie IB
dc.contributor.authorKennedy M
dc.contributor.authorLewis SJG
dc.contributor.authorMontgomery GW
dc.contributor.authorPearson J
dc.contributor.authorPitcher TL
dc.contributor.authorSilburn P
dc.contributor.authorZhang F
dc.contributor.authorVisscher PM
dc.contributor.authorYang J
dc.contributor.authorStevenson AJ
dc.contributor.authorHillary RF
dc.contributor.authorMarioni RE
dc.contributor.authorHarris SE
dc.contributor.authorDeary IJ
dc.contributor.authorJones AR
dc.contributor.authorShatunov A
dc.contributor.authorIacoangeli A
dc.contributor.authorvan Rheenen W
dc.contributor.authorvan den Berg LH
dc.contributor.authorShaw PJ
dc.contributor.authorShaw CE
dc.contributor.authorMorrison KE
dc.contributor.authorAl-Chalabi A
dc.contributor.authorVeldink JH
dc.contributor.authorHannon E
dc.contributor.authorMill J
dc.contributor.authorWray NR
dc.contributor.authorMcRae AF
dc.contributor.authorDalrymple-Alford, John
dc.date.accessioned2021-07-11T21:45:50Z
dc.date.available2021-07-11T21:45:50Z
dc.date.issued2021en
dc.date.updated2021-06-29T02:54:15Z
dc.description.abstractBackground: 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.en
dc.identifier.citationNabais MF, Laws SM, Lin T, Vallerga CL, Armstrong NJ, Blair IP, Kwok JB, Mather KA, Mellick GD, Sachdev PS, Wallace L, Henders AK, Zwamborn RAJ, Hop PJ, Lunnon K, Pishva E, Roubroeks JAY, Soininen H, Tsolaki M, Mecocci P, Lovestone S, Kłoszewska I, Vellas B, Furlong S, Garton FC, Henderson RD, Mathers S, McCombe PA, Needham M, Ngo ST, Nicholson G, Pamphlett R, Rowe DB, Steyn FJ, Williams KL, Anderson TJ, Bentley SR, Dalrymple-Alford J, Fowder J, Gratten J, Halliday G, Hickie IB, Kennedy M, Lewis SJG, Montgomery GW, Pearson J, Pitcher TL, Silburn P, Zhang F, Visscher PM, Yang J, Stevenson AJ, Hillary RF, Marioni RE, Harris SE, Deary IJ, Jones AR, Shatunov A, Iacoangeli A, van Rheenen W, van den Berg LH, Shaw PJ, Shaw CE, Morrison KE, Al-Chalabi A, Veldink JH, Hannon E, Mill J, Wray NR, McRae AF (2021). Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders. Genome Biology. 22(1). 90-.en
dc.identifier.doihttp://doi.org/10.1186/s13059-021-02275-5
dc.identifier.issn1474-7596
dc.identifier.issn1474-760X
dc.identifier.urihttps://hdl.handle.net/10092/102198
dc.languageeng
dc.language.isoen
dc.publisherSpringer Science and Business Media LLCen
dc.rights© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.en
dc.rights.urihttp://hdl.handle.net/10092/17651en
dc.subjectneurodegenerative disordersen
dc.subjectDNA methylationen
dc.subjectMixed-linear modelsen
dc.subjectMethylation profile scoreen
dc.subjectOut-of-sample classificationen
dc.subjectinflammatory markersen
dc.subject.anzsrcFields of Research::32 - Biomedical and clinical sciences::3209 - Neurosciences::320905 - Neurology and neuromuscular diseasesen
dc.subject.anzsrcFields of Research::31 - Biological sciences::3105 - Genetics::310504 - Epigenetics (incl. genome methylation and epigenomics)en
dc.titleMeta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disordersen
dc.typeJournal Articleen
uc.collegeFaculty of Science
uc.departmentSchool of Psychology, Speech and Hearing
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