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

the Australian Imaging Biomarkers and Lifestyle study, the Alzheimer's Disease Neuroimaging Initiative

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10 Citations (Scopus)

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.

Original languageEnglish
Article number90
JournalGenome Biology
Volume22
Issue number1
DOIs
Publication statusPublished - 26 Mar 2021

Bibliographical note

Funding Information:Australian ALS cohort: This work was directly funded by EU Joint Programme - Neurodegenerative Disease Research (JPND), co-funded through the Australian National Health and Medical Research (NHMRC) Council: 1151854 as well as NHMRC 1083187, 1173790, 1078901, 1113400. Additional funding was provided by the Motor Neurone Disease Research Institute of Australia Ice Bucket Challenge grant for the SALSA-SGC consortium. The Older Australian Twins Study (OATS, used for controls) was facilitated through Twins Research Australia, a national resource in part supported by a Centre for Research Excellence from the Australian National Health and Medical Research Council (NHMRC). Funding for this study was awarded by the (NHMRC)/Australian Research Council Strategic Award (Grant 401162) and the NHMRC Project grant 1405325. We would also like to thank Prof. Nigel Laing for facilitating access to blood samples in West Australia.

KCL ALS cohort: The project is supported through the following funding organizations under the aegis of JPND - www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)) and through the Motor Neurone Disease Association. The cohort collection was partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The work leading up to this publication was funded by the European Community’s Health Seventh Framework Programme (FP7/2007–2013; grant agreement number 259867) and Horizon 2020 Programme (H2020-PHC-2014-two-stage; grant agreement number 633413). Samples used in this research were in part obtained from the UK National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust.

NL ALS cohort: This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 772376 - EScORIAL”). The collaboration project is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This is in part an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND - www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1, the Netherlands, ZONMW, grant no. 733051071) and through the Motor Neurone Disease Association. This study represents independent research part funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre. Samples used in this research were in part obtained from the UK National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. We would like to thank people with MND and their families for their participation in this project.

SGDP cohort: This research was supported by the National Health and Medical Research Council (NHMRC: 1078037, 1078901, 1103418, 1107258, 1127440, 1113400), the Australian Research Council (ARC: DP160102400 and FT180100186), and the Mater Foundation. Support also came from ForeFront, a large collaborative research group dedicated to the study of neurodegenerative diseases and funded by the NHMRC (Program Grant 1132524, Dementia Research Team Grant 1095127, NeuroSleep Centre of Research Excellence 1060992) and ARC (Centre of Excellence in Cognition and its Disorders Memory Program CE10001021). The Queensland Parkinson’s Project (QPP) was supported by a grant from the Australian National Health and Medical Research Council (1084560) to GWM. The New Zealand Brain Research Institute (NZBRI) cohort was funded by a University of Otago Research Grant, together with financial support from the Jim and Mary Carney Charitable Trust (Whangarei, New Zealand). We thank Allison Miller for processing and handling of NZBRI samples.

AIBL cohort: Funding for the AIBL study was provided in part by the study partners [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.]. The AIBL study has also received support from the National Health and Medical Research Council (NHMRC) and the Dementia Collaborative Research Centres program (DCRC2), as well as funding from the Science and Industry Endowment Fund (SIEF) and the Cooperative Research Centre (CRC) for Mental Health—funded through the CRC Program (Grant ID:20100104), an Australian Government Initiative. We thank all those who took part as a participant in the AIBL study for their commitment and dedication to helping advance research into the early detection and causation of AD.

AddNeuroMed cohort: The AddNeuroMed data are from a public–private partnership supported by EFPIA companies and SMEs as part of InnoMed (Innovative Medicines in Europe), an Integrated Project funded by the European Union of the Sixth Framework program priority FP6 2004-LIFESCIHEALTH-5. Clinical leads responsible for data collection are Iwona Kłoszewska (Lodz), Simon Lovestone (London), Patrizia Mecocci (Perugia), Hilkka Soininen (Kuopio), Magda Tsolaki (Thessaloniki), and Bruno Vellas (Toulouse) and imaging leads are Andy Simmons (London), Lars-Olad Wahlund (Stockholm) and Christian Spenger (Zurich) and bioinformatics leads are Richard Dobson (London) and Stephen Newhouse (London).

ADNI cohort: Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: 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; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.
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© 2021, The Author(s).

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