Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS

BIOS Consortium, Brain MEND Consortium

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbereabj0264
JournalScience Translational Medicine
Volume14
Issue number633
DOIs
StatePublished - 23 Feb 2022

Funding

FundersFunder number
ALS-Care
Australian National Health and Medical Research
BRAINSCAPES
Dutch Ministry of Education, Culture, and Science
E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
European Community's Health Seventh Framework Programme259867
Health~Holland, Top Sector Life Sciences & Health
KU Leuven Opening the Future Fund
Ministero della Salute, Ricerca Sanitaria FinalizzataRF-2016-02362405
NHMRC Council1079102
NL-NMD
Netherlands Neuromuscular Center
Suna and Inan Kirac Foundation
South London and Maudsley NHS Foundation Trust
Wellcome Trust
Seventh Framework Programme
EU Joint Programme – Neurodegenerative Disease Research
FightMND
Ulla-Carin Lindquists stiftelse för ALS-forskning
NIHR Maudsley Biomedical Research Centre
Canadian Institutes of Health Research91719350, FRN 159279
Medical Research CouncilMR/R024804/1, MR/L501529/1
Economic and Social Research CouncilES/L008238/1
National Institute for Health and Care Research
Alzheimer's Society
Motor Neurone Disease Association
King's College London
University of Manchester
European Commission
European Research Council
Australian Research Council1024224, 568969, 1405325, 1093083, 1085606, 1045325, 1025243, 401162
National Health and Medical Research Council1078901, 1083187, 1176913, 402703, 1113400, 1151854, 1095215, 1173790
ZonMw
Västerbotten Läns Landsting56103-7002829
Agentschap voor Innovatie door Wetenschap en Technologie140935
Ministero della Salute
Nederlandse Organisatie voor Wetenschappelijk Onderzoek09150161810018
Ministero dell’Istruzione, dell’Università e della Ricerca2017SNW5MB
Hjärnfonden2020-0353, 2012-0262, 2012-0305, 2016-0303, 2018-0310, 2013-0279
KU Leuven
Knut och Alice Wallenbergs Stiftelse2020.0232, 2014.0305, 2012.0091
Prinses Beatrix SpierfondsW.OR20-08, W.F19-03
Vetenskapsrådet2012-3167, 2017-03100
Seventh Framework Programme
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Horizon 2020772376-EScORIAL
Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica
Vlaamse regering
Stichting ALS Nederland
Koç Üniversitesi

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