Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
Paul J. Hop, Ramona A.J. Zwamborn, Eilís Hannon, Gemma Shireby, Marta F. Nabais, Emma 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 Ratti, Johnathan Cooper‐Knock, Karen Morrison, Pamela J. Shaw, A. Nazlı Başak, Adriano Chiò, Andrea Calvo, Cristina Moglia, Antonio Canosa, Maura Brunetti, Maurizio Grassano, Marc Gotkine, Yossef Lerner, Michal Zabari, Patrick Vourc’h, Philippe Corcia, P. Couratier, Jesús S. Mora Pardina, Teresa Salas, Patrick A. Dion, Jay P. Ross, Robert D. Henderson, Susan Mathers, Pamela A. McCombe, Merrilee Needham, Garth Nicholson, Dominic B. Rowe, Roger Pamphlett, Karen A. Mather, Perminder S. Sachdev, Sarah Furlong, Fleur C. Garton, Anjali K. Henders, Tian Lin, Shyuan T. Ngo, Frederik J. Steyn, Leanne Wallace, Kelly L. Williams, Miguel Mitne Neto, Ruben J. Cauchi, Ian P. Blair, Matthew C. Kiernan, Vivian Drory, Mónica Povedano, Mamede de Carvalho, Susana Pinto, Markus Weber, Guy A. Rouleau, Vincenzo Silani, John E. Landers, Christopher E. Shaw, Peter M. Andersen, Allan F. McRae, Michael A. van Es, R. Jeroen Pasterkamp, Naomi R. Wray, Russell L. McLaughlin, Orla Hardiman, Kevin P. Kenna, Ellen Tsai, Heiko Runz, Ammar Al‐Chalabi, Leonard H. van den Berg, Philip Van Damme, Jonathan Mill, Jan H. Veldink, Bastiaan T. Heijmans, Peter A.C. t Hoen, Joyce van Meurs, Rick Jansen, Lude Franke, Dorret I. Boomsma, René Pool, Jenny van Dongen, Joukje J. Hottenga, Marleen M. J. van Greevenbroek, Coen D.A. Stehouwer, Carla Kallen, Casper G. Schalkwijk, Cisca Wijmenga, Lude Franke, Sasha Zhernakova, Ettje F. Tigchelaar
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.