期刊
GENOME BIOLOGY
卷 22, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13059-021-02275-5
关键词
Neurodegenerative disorders; DNA methylation; Mixed-linear models; Methylation profile score; Out-of-sample classification; Inflammatory markers
资金
- EU Joint Programme -Neurodegenerative Disease Research (JPND)
- Australian National Health and Medical Research (NHMRC) Council [1151854]
- NHMRC [1083187, 1173790, 1078901, 1113400, 1132524, 1095127, 1060992]
- Motor Neurone Disease Research Institute of Australia Ice Bucket Challenge grant
- Centre for Research Excellence from the Australian National Health and Medical Research Council (NHMRC)
- (NHMRC)/Australian Research Council Strategic Award [401162]
- NHMRC Project [1405325]
- United Kingdom, Medical Research Council [MR/L501529/1, MR/R024804/1]
- Economic and Social Research Council [ES/L008238/1]
- Motor Neurone Disease Association
- European Community's Health Seventh Framework Programme (FP7/2007-2013) [259867]
- Horizon 2020 Programme (H2020-PHC-2014-two-stage) [633413]
- MND Association
- Wellcome Trust
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [772376 - EScORIAL]
- Health-Holland, Top Sector Life Sciences Health
- Netherlands, ZONMW [733051071]
- National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre
- National Health and Medical Research Council (NHMRC) [1078901, 1113400, 1078037, 1103418, 1107258, 1127440]
- Australian Research Council (ARC) [DP160102400, FT180100186]
- Mater Foundation
- ForeFront, a large collaborative research group
- ARC (Centre of Excellence in Cognition and its Disorders Memory Program) [CE10001021]
- Australian National Health and Medical Research Council [1084560]
- University of Otago Research Grant
- Jim and Mary Carney Charitable Trust (Whangarei, New Zealand)
- Commonwealth Scientific Industrial and research Organization (CSIRO)
- Edith Cowan University (ECU)
- Mental Health Research institute (MHRI)
- National Ageing Research Institute (NARI)
- Austin Health
- CogState Ltd.
- National Health and Medical Research Council (NHMRC)
- Dementia Collaborative Research Centres program (DCRC2)
- Science and Industry Endowment Fund (SIEF)
- Cooperative Research Centre (CRC) for Mental Health [20100104]
- EFPIA
- SMEs as part of InnoMed (Innovative Medicines in Europe) - European Union of the Sixth Framework program [FP6 2004-LIFESCIHEALTH-5]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- AbbVie
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Eisai Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.
- Fujirebio
- GE Healthcare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development LLC.
- Lumosity
- Lundbeck
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging
- Servier
- Takeda Pharmaceutical Company
- Transition Therapeutics
- Canadian Institutes of Health Research
- National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London
- Economic and Social Research Council [ES/L008238/1] Funding Source: researchfish
- National Institute for Health Research [NIHR202421] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1113400, 1151854, 1173790, 1084560, 1083187, 1060992] Funding Source: NHMRC
This study identified shared differentially methylated positions in whole blood between neurodegenerative disorders, indicating shared pathogenic mechanisms. Immune abnormalities caused by different neurodegenerative diseases may be interrelated to some extent.
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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