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

BIOS Consortium, Brain MEND Consortium, Paul J. Hop, Ramona A.J. Zwamborn, Eilis Hannon, Gemma L. Shireby, Marta F. Nabais, Emma M. Walker, Wouter van Rheenen, Joke J.F.A. van Vugt, Annelot M. Dekker, Henk Jan Westeneng, Gijs H.P. Tazelaar, Kristel R. van Eijk, Matthieu Moisse, Denis Baird, Ahmad Al Khleifat, Alfredo Iacoangeli, Nicola Ticozzi, Antonia RattiJonathan Cooper-Knock, Karen E. Morrison, Pamela J. Shaw, A. Nazli Basak, Adriano Chiò, Andrea Calvo, Cristina Moglia, Antonio Canosa, Maura Brunetti, Maurizio Grassano, Marc Gotkine, Yossef Lerner, Michal Zabari, Patrick Vourc'H, Philippe Corcia, Philippe Couratier, Jesus S. Mora Pardina, Teresa Salas, Patrick Dion, Jay P. Ross, Robert D. Henderson, Susan Mathers, Pamela A. McCombe, Merrilee Needham, Jan H. Veldink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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
Number of pages16
JournalScience Translational Medicine
Issue number633
Publication statusPublished - 23-Feb-2022


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