| Literature DB >> 35196023 |
Paul J Hop1, Ramona A J Zwamborn1, Eilis Hannon2, Gemma L Shireby2, Marta F Nabais2,3, Emma M Walker2, Wouter van Rheenen1, Joke J F A van Vugt1, Annelot M Dekker1, Henk-Jan Westeneng1, Gijs H P Tazelaar1, Kristel R van Eijk1, Matthieu Moisse4,5,6, Denis Baird7,8, Ahmad Al Khleifat9, Alfredo Iacoangeli9,10,11, Nicola Ticozzi12,13, Antonia Ratti12,14, Jonathan Cooper-Knock15, Karen E Morrison16, Pamela J Shaw15, A Nazli Basak17, Adriano Chiò18,19, Andrea Calvo18,19, Cristina Moglia18,19, Antonio Canosa18,19, Maura Brunetti18, Maurizio Grassano18, Marc Gotkine20,21, Yossef Lerner20,21, Michal Zabari20,21, Patrick Vourc'h22,23, Philippe Corcia23,24, Philippe Couratier25,26, Jesus S Mora Pardina27, Teresa Salas28, Patrick Dion29, Jay P Ross29,30, Robert D Henderson31, Susan Mathers32, Pamela A McCombe33, Merrilee Needham34,35,36, Garth Nicholson37, Dominic B Rowe38, Roger Pamphlett39, Karen A Mather40,41, Perminder S Sachdev40,42, Sarah Furlong38, Fleur C Garton3, Anjali K Henders3, Tian Lin3, Shyuan T Ngo33,43,44, Frederik J Steyn33,45, Leanne Wallace3, Kelly L Williams38, Miguel Mitne Neto46, Ruben J Cauchi47, Ian P Blair38, Matthew C Kiernan48,49, Vivian Drory50,51, Monica Povedano52, Mamede de Carvalho53, Susana Pinto53, Markus Weber54, Guy A Rouleau29, Vincenzo Silani12,13, John E Landers55, Christopher E Shaw9, Peter M Andersen56, Allan F McRae3, Michael A van Es1, R Jeroen Pasterkamp57, Naomi R Wray3,44, Russell L McLaughlin58, Orla Hardiman59, Kevin P Kenna1,57, Ellen Tsai7, Heiko Runz7, Ammar Al-Chalabi9,60, Leonard H van den Berg1, Philip Van Damme4,5,6, Jonathan Mill2, Jan H Veldink1.
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.Entities:
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Year: 2022 PMID： 35196023 DOI： 10.1126/scitranslmed.abj0264
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 19.319