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.
Overview publication
Title | Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS. |
Date | February 23rd, 2022 |
Issue name | Science translational medicine |
Issue number | v14.633:eabj0264 |
DOI | 10.1126/scitranslmed.abj0264 |
PubMed | 35196023 |
Authors | |
Info | Heijmans BT, T Hoen PAC, van Meurs J, Jansen R, Franke L, Boomsma DI, Pool R, van Dongen J, Hottenga JJ, van Greevenbroek MMJ, Stehouwer CDA, van der Kallen CJH, Schalkwijk CG, Wijmenga C, Franke L, Zhernakova S, Tigchelaar EF, Slagboom PE, Beekman M, Deelen J, van Heemst D, Veldink JH, van den Berg LH, van Duijn CM, Hofman BA, Isaacs A, Uitterlinden AG, van Meurs J, Jhamai PM, Verbiest M, Suchiman HED, Verkerk M, van der Breggen R, van Rooij J, Lakenberg N, Mei H, van Iterson M, van Galen M, Bot J, Zhernakova DV, van 't Hof P, Deelen P, Nooren I, Heijmans BT, Moed M, Franke L, Vermaat M, Zhernakova DV, Luijk R, Jan Bonder M, van Iterson M, Deelen P, van Dijk F, van Galen M, Arindrarto W, Kielbasa SM, Swertz MA, van Zwet EW, Al-Chalabi A, Wray NR, Bensimon G, Hardiman O, Chio A, Smith GD, Mill J |
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