Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 14, Issue 633, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abj0264
Keywords
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Categories
Funding
- Dutch Research Council (NWO) [09150161810018, 91719350]
- Prinses Beatrix Spierfond [W.F19-03]
- Prinses Beatrix Spierfonds [W.OR20-08]
- Canadian Institutes of Health Research [FRN 159279]
- European Research Council (ERC) under the European Union 2020 research and innovation program [772376-EScORIAL]
- Swedish Brain Foundation [2012-0262, 2012-0305, 2013-0279, 2016-0303, 2018-0310, 2020-0353]
- Swedish Research Council [2012-3167, 2017-03100]
- Knut and Alice Wallenberg Foundation [2012.0091, 2014.0305, 2020.0232]
- Ulla-Carin Lindquist Foundation
- Vasterbotten County Council [56103-7002829]
- King Gustaf V's and Queen Victoria's Freemason's Foundation
- United Kingdom, Medical Research Council [MR/L501529/1, MR/R024804/1]
- Economic and Social Research Council [ES/L008238/1]
- Motor Neurone Disease Association (MNDA)
- National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust
- King's College London
- NIHR Senior Investigator Award
- MND Association
- Wellcome Trust
- Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester
- Gravitation program of the Dutch Ministry of Education, Culture, and Science
- Netherlands Organization for Scientific Research (BRAINSCAPES)
- Alzheimer's Society
- FightMND Mid-Career Fellowship
- Italian Ministry of Health
- AriSLA
- E-Rare Joint Transnational Call
- MNDA
- NIHR Maudsley Biomedical Research Centre
- Netherlands ALS Foundation
- Netherlands Organization for Health Research and Development (Vici scheme)
- European Community's Health Seventh Framework Programme [259867]
- Netherlands Organization for Health Research and Development (the STRENGTH project, through the EU Joint Programme-Neurodegenerative Disease Research, JPND)
- IWT [140935]
- ALS Liga Belgie
- National Lottery of Belgium
- KU Leuven Opening the Future Fund
- E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
- KU Leuven fund Een Hart voor ALS
- KU Leuven fund Laeversfonds voor ALS Onderzoek
- KU Leuven fund Valery Perrier Race against ALS Fund
- Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata) [RF-2016-02362405]
- Progetti di Rilevante Interesse Nazionale program of the Ministry of Education, University and Research [2017SNW5MB]
- European Commission's Health Seventh Framework Programme (FP7/2007-2013) [259867]
- Joint ProgrammeNeurodegenerative Disease Research (Strength, ALS-Care and Brain-Mend projects) - Italian Ministry of Education, University, and Research
- Italian Ministry of Education, University and Research
- Australian National Health and Medical Research (NHMRC) Council [1151854, 1083187, 1173790, 1078901, 1113400, 1095215, 1176913, 402703]
- Motor Neurone Disease Research Institute of Australia Ice Bucket Challenge grant
- Centre for Research Excellence from the Australian NHMRC Council [NHMRC 1079102]
- NHMRC/Australian Research Council Strategic Award [401162]
- NHMRC [1405325, 1024224, 1025243, 1045325, 1085606, 568969, 1093083]
- Health Holland, Top Sector Life Sciences Health
- ALS Foundation Netherlands
- Suna and Inan Kirac Foundation
- Koc University
- Canadian Institutes of Health
- ARSla
- National Health and Medical Research Council of Australia [1083187, 1085606, 1093083, 1151854, 1176913] Funding Source: NHMRC
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This study conducted a blood-based epigenome-wide association study meta-analysis and identified differentially methylated positions (DMPs) and genes associated with ALS. The study also found independent associations between ALS and high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake, with cholesterol biosynthesis potentially causally related to ALS. Additionally, DNA methylation at several DMPs and blood cell proportion estimates were associated with survival rate in patients.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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