Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders
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Laws, Simon M
Lin, Tian
Vallerga, Costanza L
Armstrong, Nicola J
Blair, Ian P
Kwok, John B
Mather, Karen A
Mellick, George D
Sachdev, Perminder S
Wallace, Leanne
Henders, Anjali K
Zwamborn, Ramona AJ
Bentley, Steven R
et al.
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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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Genome Biology
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22
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1
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© 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.
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Environmental sciences
Biological sciences
DNA methylation
Inflammatory markers
Methylation profile score
Mixed-linear models
Neurodegenerative disorders
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Nabais, 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; Bentley, SR; et al, Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders, Genome Biology, 2021, 22 (1), pp. 90