Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
Authors: Hop Paul J. , Zwamborn Ramona A.J. , Hannon Eilis , Shireby Gemma L. , Nabais Marta F. , Walker Emma M. , van Rheenen Wouter , van Vugt Joke J.F.A. , Dekker Annelot M. , Westeneng Henk-Jan , Tazelaar Gijs H.P. , van Eijk Kristel R. , Moisse Matthieu , Baird Denis , Al Khleifat Ahmad , Iacoangeli Alfredo , Ticozzi Nicola , Ratti Antonia , Cooper-Knock Jonathan , Morrison Karen E. , Shaw Pamela J. , Basak A. Nazli , Chiò Adriano , Calvo Andrea , Moglia Cristina , Canosa Antonio , Brunetti Maura , Grassano Maurizio , Gotkine Marc , Lerner Yossef , Zabari Michal , Vourc’h Patrick , Corcia Philippe , Couratier Philippe , Mora Pardina Jesus S. , Salas Teresa , Dion Patrick , Ross Jay P. , Henderson Robert D. , Mathers Susan , McCombe Pamela A. , Needham Merrilee , Nicholson Garth , Rowe Dominic B. , Pamphlett Roger , Mather Karen A. , Sachdev Perminder S. , Furlong Sarah , Garton Fleur C. , Henders Anjali K. , Lin Tian , Ngo Shyuan T. , Steyn Frederik J. , Wallace Leanne , Williams Kelly L. ,   BIOS Consortium,   Brain MEND Consortium, Neto Miguel Mitne , Cauchi Ruben J. , Blair Ian P. , Kiernan Matthew C. , Drory Vivian , Povedano Monica , de Carvalho Mamede , Pinto Susana , Weber Markus , Rouleau Guy A. , Silani Vincenzo , Landers John E. , Shaw Christopher E. , Andersen Peter M. , McRae Allan F. , van Es Michael A. , Pasterkamp R. Jeroen , Wray Naomi R. , McLaughlin Russell L. , Hardiman Orla , Kenna Kevin P. , Tsai Ellen , Runz Heiko , Al-Chalabi Ammar , van den Berg Leonard H. , Van Damme Philip , Mill Jonathan , Veldink Jan H. , Heijmans Bastiaan T. , t Hoen Peter A.C. , van Meurs Joyce , Jansen Rick , Franke Lude , Boomsma Dorret I. , Pool Rene , van Dongen Jenny , Hottenga Joukje J. , van Greevenbroek Marleen M.J. , Stehouwer Coen D.A. , van der Kallen Carla J.H. , Schalkwijk Casper G. , Wijmenga Cisca , Franke Lude , Zhernakova Sasha , Tigchelaar Ettje F. , Slagboom P. Eline , Beekman Marian , Deelen Joris , van Heemst Diana , Veldink Jan H. , van den Berg Leonard H. , van Duijn Cornelia M. , Hofman Bert A. , Isaacs Aaron , Uitterlinden Andre G. , van Meurs Joyce , Jhamai P. Mila , Verbiest Michael , Suchiman H. Eka D. , Verkerk Marijn , van der Breggen Ruud , van Rooij Jeroen , Lakenberg Nico , Mei Hailiang , van Iterson Maarten , van Galen Michiel , Bot Jan , Zhernakova Dasha V. , Jansen Rick , van ‘t Hof Peter , Deelen Patrick , Nooren Irene , t Hoen Peter A.C. , Heijmans Bastiaan T. , Moed Matthijs , Franke Lude , Vermaat Martijn , Zhernakova Dasha V. , Luijk Rene , Jan Bonder Marc , van Iterson Maarten , Deelen Patrick , van Dijk Freerk , van Galen Michiel , Arindrarto Wibowo , Kielbasa Szymon M. , Swertz Morris A. , van Zwet Erik W. , Jansen Rick , t Hoen Peter A.C. , Heijmans Bastiaan T. , Al-Chalabi Ammar , Wray Naomi R. , Bensimon Gilbert , Hardiman Orla , Chio Adriano , Veldink Jan H. , Smith George Davey , Mill Jonathan 
Published: February 2022

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.