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Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom.
University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom.
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2022 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 14, no 633, article id eabj0264Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Association for the Advancement of Science , 2022. Vol. 14, no 633, article id eabj0264
National Category
Neurology
Research subject
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-194403DOI: 10.1126/scitranslmed.abj0264ISI: 000760127200002Scopus ID: 2-s2.0-85128472001OAI: oai:DiVA.org:umu-194403DiVA, id: diva2:1656069
Funder
The Swedish Brain Foundation, 2012-0262The Swedish Brain Foundation, 2012-0305The Swedish Brain Foundation, 2013-0279The Swedish Brain Foundation, 2016-0303The Swedish Brain Foundation, 2018-0310The Swedish Brain Foundation, 2020-0353Swedish Research Council, 2012-3167Swedish Research Council, 2017-03100Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, 2020.0232Region Västerbotten, 56103-7002829Konung Gustaf V:s och Drottning Victorias FrimurarestiftelseAvailable from: 2022-05-04 Created: 2022-05-04 Last updated: 2023-09-05Bibliographically approved

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Andersen, Peter M.

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