Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
Paul J. Hop(University Medical Center Utrecht), Ramona A.J. Zwamborn(University Medical Center Utrecht), Eilís Hannon(University of Exeter), Gemma Shireby(University of Exeter), Marta F. Nabais(The University of Queensland), Emma Walker(University of Exeter), Wouter van Rheenen(University Medical Center Utrecht), Joke J.F.A. van Vugt(University Medical Center Utrecht), Annelot M. Dekker(University Medical Center Utrecht), Henk‐Jan Westeneng(University Medical Center Utrecht), Gijs H.P. Tazelaar(University Medical Center Utrecht), Kristel R. van Eijk(University Medical Center Utrecht), Matthieu Moisse(Allen Institute for Brain Science), Denis Baird(Biogen (United States)), Ahmad Al Khleifat(King's College London), Alfredo Iacoangeli(King's College London), Nicola Ticozzi(University of Milan), Antonia Ratti(University of Milan), Johnathan Cooper‐Knock(University of Sheffield), Karen Morrison(Queen's University Belfast), Pamela J. Shaw(University of Sheffield), A. Nazlı Başak(Koç University), Adriano Chiò(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Andrea Calvo(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Cristina Moglia(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Antonio Canosa(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Maura Brunetti(University of Turin), Maurizio Grassano(University of Turin), Marc Gotkine(Hebrew University of Jerusalem), Yossef Lerner(Hebrew University of Jerusalem), Michal Zabari(Hebrew University of Jerusalem), Patrick Vourc’h(Université de Tours), Philippe Corcia(Université de Tours), P. Couratier(Inserm), Jesús S. Mora Pardina(Hospital Universitario San Rafael), Teresa Salas(Hospital Universitario La Paz), Patrick A. Dion(Montreal Neurological Institute and Hospital), Jay P. Ross(Montreal Neurological Institute and Hospital), Robert D. Henderson(Royal Brisbane and Women's Hospital), Susan Mathers(Calvary Health Care Bethlehem), Pamela A. McCombe(The University of Queensland), Merrilee Needham(Murdoch University), Garth Nicholson(Concord Repatriation General Hospital), Dominic B. Rowe(Macquarie University), Roger Pamphlett(The University of Sydney), Karen A. Mather(UNSW Sydney), Perminder S. Sachdev(UNSW Sydney), Sarah Furlong(Macquarie University), Fleur C. Garton(The University of Queensland), Anjali K. Henders(The University of Queensland), Tian Lin(The University of Queensland), Shyuan T. Ngo(The University of Queensland), Frederik J. Steyn(The University of Queensland), Leanne Wallace(The University of Queensland), Kelly L. Williams(Macquarie University), Miguel Mitne Neto(Universidade de São Paulo), Ruben J. Cauchi(University of Malta), Ian P. Blair(Macquarie University), Matthew C. Kiernan(The University of Sydney), Vivian Drory(Tel Aviv University), Mónica Povedano(Bellvitge University Hospital), Mamede de Carvalho(University of Lisbon), Susana Pinto(University of Lisbon), Markus Weber(Kantonsspital St. Gallen), Guy A. Rouleau(Montreal Neurological Institute and Hospital), Vincenzo Silani(University of Milan), John E. Landers(University of Massachusetts Chan Medical School), Christopher E. Shaw(King's College London), Peter M. Andersen(Umeå University), Allan F. McRae(The University of Queensland), Michael A. van Es(University Medical Center Utrecht), R. Jeroen Pasterkamp(University Medical Center Utrecht), Naomi R. Wray(The University of Queensland), Russell L. McLaughlin(Trinity College Dublin), Orla Hardiman(Trinity College Dublin), Kevin P. Kenna(University Medical Center Utrecht), Ellen Tsai(Biogen (United States)), Heiko Runz(Biogen (United States)), Ammar Al‐Chalabi(King's College London), Leonard H. van den Berg(University Medical Center Utrecht), Philip Van Damme(Allen Institute for Brain Science), Jonathan Mill(University of Exeter), Jan H. Veldink(University Medical Center Utrecht), Bastiaan T. Heijmans(Leiden University Medical Center), Peter A.C. t Hoen(Leiden University Medical Center), Joyce van Meurs(Erasmus University Rotterdam), Rick Jansen(Montreal Neurological Institute and Hospital), Lude Franke(University Medical Center Groningen), Dorret I. Boomsma(Amsterdam Neuroscience), René Pool(Queen's University Belfast), Jenny van Dongen, Joukje J. Hottenga, Marleen M. J. van Greevenbroek(Maastricht University Medical Centre), Coen D.A. Stehouwer, Carla Kallen, Casper G. Schalkwijk, Cisca Wijmenga, Lude Franke(University Medical Center Groningen), Sasha Zhernakova, Ettje F. Tigchelaar, P. Eline Slagboom, Marian Beekman, Joris Deelen, Diana van Heemst(Leiden University Medical Center), Jan H. Veldink(University Medical Center Utrecht), Leonard H. van den Berg(University Medical Center Utrecht), Cornelia M. van Duijn(Erasmus MC), Bert A. Hofman(Royal Brisbane and Women's Hospital), Aaron Isaacs, André G. Uitterlinden, Joyce van Meurs(Erasmus University Rotterdam), P. Mila Jhamai, Michaël Verbiest(University Medical Center Utrecht), H. Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij(University Medical Center Utrecht), Nico Lakenberg(University of Milan), Hailiang Mei(Leiden University Medical Center), Maarten van Iterson, Michiel van Galen, Jan Bot(University Medical Center Utrecht), Dasha V. Zhernakova, Rick Jansen(Montreal Neurological Institute and Hospital), Peter van ‘t Hof(Umeå University), Patrick Deelen(Montreal Neurological Institute and Hospital), Irene Nooren, Peter A.C. t Hoen(Leiden University Medical Center), Bastiaan T. Heijmans(Leiden University Medical Center), Matthijs Moed, Lude Franke(University Medical Center Groningen), Martijn Vermaat, Dasha V. Zhernakova, René Luijk(Queen's University Belfast), Marc Jan Bonder(Hebrew University of Jerusalem), Maarten van Iterson, Patrick Deelen(Montreal Neurological Institute and Hospital), Freerk van Dijk(University Medical Center Groningen), Michiel van Galen, Wibowo Arindrarto, Szymon M. Kielbasa(Leiden University Medical Center), Morris A. Swertz(Queen's University Belfast), Erik W. van Zwet, Rick Jansen(Montreal Neurological Institute and Hospital), Peter A.C. t Hoen(Leiden University Medical Center), Bastiaan T. Heijmans(Leiden University Medical Center), Ammar Al‐Chalabi(King's College London), Naomi R. Wray(The University of Queensland), Gilbert Bensimon(Sorbonne Université), Orla Hardiman(Trinity College Dublin), Adriano Chiò(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Jan H. Veldink(University Medical Center Utrecht), George Davey Smith(At Bristol), Jonathan Mill(University of Exeter)
Cited by 91Open Access
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.
Related Papers
No related papers found
Powered by citation graph analysis