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

Paul Hop , Ramona Zwamborn (1) , Eilis Hannon , Gemma Shireby , Marta Nabais , Emma Walker , Wouter van Rheenen , Joke van Vugt (2) , Annelot Dekker , Henk-Jan Westeneng , Gijs Tazelaar , Kristel van Eijk (1) , Matthieu Moisse , Denis Baird , Ahmad Al Khleifat , Alfredo Iacoangeli (3, 4, 5) , Nicola Ticozzi (6, 7) , Antonia Ratti , Jonathan Cooper-Knock , Karen Morrison , Pamela Shaw (8) , a Nazli Basak (9) , Adriano Chiò (10) , Adriano Chio (10, 11) , Andrea Calvo , Cristina Moglia , Antonio Canosa , Maura Brunetti , Maurizio Grassano , Marc Gotkine , Yossef Lerner , Michal Zabari , Patrick Vourc'H (12, 13) , Philippe Corcia (13) , Philippe Couratier , Jesus Mora Pardina , Teresa Salas , Patrick Dion , Jay Ross , Robert Henderson , Susan Mathers , Pamela Mccombe , Merrilee Needham , Garth Nicholson , Dominic Rowe , Roger Pamphlett , Karen Mather , Perminder Sachdev , Sarah Furlong , Fleur Garton , Anjali Henders , Tian Lin , Shyuan Ngo , Frederik Steyn , Leanne Wallace , Kelly Williams , Miguel Mitne Neto , Ruben Cauchi , Ian Blair , Matthew Kiernan , Vivian Drory , Monica Povedano , Mamede de Carvalho , Susana Pinto , Markus Weber , Guy Rouleau , Vincenzo Silani , John Landers , Christopher Shaw , Peter Andersen , Allan Mcrae , Michael van Es , R Jeroen Pasterkamp , Naomi Wray , Naomi Wray , Russell Mclaughlin , Orla Hardiman , Orla Hardiman , Kevin Kenna , Ellen Tsai , Heiko Runz , Ammar Al-Chalabi , Ammar Al-Chalabi , Leonard van den Berg , Leonard van den Berg , Philip van Damme , Jonathan Mill , Jonathan Mill , Jan Veldink , Jan Veldink , Jan Veldink , Ramona A.J. Zwamborn , Joke J.F.A. van Vugt , Gijs H.P. Tazelaar , A. Nazli Basak , Patrick Vourc’h , R. Jeroen Pasterkamp , Bastiaan Heijmans , Peter A.C. T Hoen , Joyce van Meurs , Rick Jansen , Lude Franke , Dorret Boomsma , Rene Pool , Jenny van Dongen , Joukje Hottenga , Marleen M.J. van Greevenbroek , Coen D.A. Stehouwer , Carla J.H. van der Kallen , Casper Schalkwijk , Cisca Wijmenga , Lude Franke , Sasha Zhernakova , Ettje Tigchelaar , P. Eline Slagboom , Marian Beekman , Joris Deelen , Diana van Heemst , Cornelia van Duijn , Bert Hofman , Aaron Isaacs , Andre Uitterlinden , Joyce van Meurs , P. Mila Jhamai , Michael Verbiest , H. Eka D. Suchiman , Marijn Verkerk , Ruud van der Breggen , Jeroen van Rooij , Nico Lakenberg , Hailiang Mei , Maarten van Iterson , Michiel van Galen , Jan Bot , Dasha Zhernakova , Rick Jansen , Patrick Deelen , Irene Nooren , Peter A.C. T Hoen , Bastiaan Heijmans , Matthijs Moed , Lude Franke , Martijn Vermaat , Dasha Zhernakova , Rene Luijk , Marc Jan Bonder , Maarten van Iterson , Patrick Deelen , Freerk van Dijk , Michiel van Galen , Wibowo Arindrarto , Szymon Kielbasa , Morris Swertz , Erik van Zwet , Rick Jansen , Peter A.C. T Hoen , Bastiaan Heijmans , Gilbert Bensimon , George Davey Smith

1 Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht
2 University Medical Center [Utrecht]
3 Maurice Wohl Clinical Neuroscience Institut
4 Institute of Psychiatry, Psychology & Neuroscience, King's College London
5 NIHR Biomedical Research Centre [London]
6 IAI - Istituto Auxologico Italiano IRCCS Ospedale San Luca [Milan, Italy]
7 Centro Dino Ferrari [Milano]
8 The Institute of Neuroscience [Sheffield]
9 Koç University
10 UNITO - Università degli studi di Torino = University of Turin
11 A.O.U - Città della Salute e della Scienza di Torino
12 Laboratoire de Biochimie [CHRU Tours]
13 iBraiN - Imaging, Brain & Neuropsychiatry

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.

Domaines: Sciences du Vivant [q-bio]

Paul Hop, Ramona Zwamborn, Eilis Hannon, Gemma Shireby, Marta Nabais, et al.. Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS. Science Translational Medicine, 2022, 14 (633), pp.eabj0264. ⟨10.1126/scitranslmed.abj0264⟩. ⟨hal-03939741⟩