Title: | Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology |
Authors: | Rheenen, Wouter van Spek, Rick A.A. van der Bakker, Mark K. Vugt, Joke J.F.A. van Hop, Paul J. Zwamborn, Ramona A. J. Klein, Niek de Westra, Harm-Jan Bakker, Olivier B. Deelen, Patrick Shireby, Gemma Hannon, Eilis Moisse, Matthieu Baird, Denis Restuadi, Restuadi Dolzhenko, Egor Dekker, Annelot M. Gawor, Klara Westeneng, Henk-Jan Tazelaar, Gijs H.P. Eijk, Kristel R. van Kooyman, Maarten Byrne, Ross P. Doherty, Mark Heverin, Mark Khleifat, Ahmad Al Iacoangeli, Alfredo Shatunov, Aleksey Ticozzi, Nicola Cooper-Knock, Johnathan Smith, Bradley N. Gromicho, Marta Chandran, Siddharthan Pal, Suvankar Morrison, Karen E. Shaw, Pamela J. Hardy, John Orrell, Richard W. Sendtner, Michael Meyer, Thomas Başak, Nazli Kooi, Anneke J. van der Ratti, Antonia Fogh, Isabella Gellera, Cinzia Lauria, Giuseppe Corti, Stefania Cereda, Cristina Sproviero, Daisy D’Alfonso, Sandra Sorarù, Gianni Siciliano, Gabriele Filosto, Massimiliano Padovani, Alessandro Chiò, Adriano Calvo, Andrea Moglia, Cristina Brunetti, Maura Canosa, Antonio Grassano, Maurizio Beghi, Ettore Pupillo, Elisabetta Logroscino, Giancarlo Nefussy, Beatrice Osmanovic, Alma Nordin, Angelica Lerner, Yossef Zabari, Michal Gotkine, Marc Baloh, Robert H. Bell, Shaughn Vourc’h, Patrick Corcia, Philippe Couratier, Philippe Millecamps, Stéphanie Meininger, Vincent Salachas, François Mora Pardina, Jesus S. Assialioui, Abdelilah Rojas-García, Ricardo Dion, Patrick A. Ross, Jay P. Ludolph, Albert C. Weishaupt, Jochen H. Brenner, David Freischmidt, Axel Bensimon, Gilbert Brice, Alexis Durr, Alexandra Payan, Christine A.M. Saker-Delye, Safa Wood, Nicholas W. Topp, Simon Rademakers, Rosa Tittmann, Lukas Lieb, Wolfgang Franke, Andre Ripke, Stephan Braun, Alice Kraft, Julia Whiteman, David C. Olsen, Catherine M. Uitterlinden, Andre G. Hofman, Albert Rietschel, Marcella Cichon, Sven Nöthen, Markus M. Amouyel, Philippe Traynor, Bryan J. Singleton, Andrew B. Mitne Neto, Miguel Cauchi, Ruben J. Ophoff, Roel A. Wiedau-Pazos, Martina Lomen-Hoerth, Catherine Deerlin, Vivianna M. van Grosskreutz, Julian Roediger, Annekathrin Gaur, Nayana Jörk, Alexander Barthel, Tabea Theele, Erik Ilse, Benjamin Stubendorff, Beatrice Witte, Otto W. Steinbach, Robert Hübner, Christian A. Graff, Caroline Brylev, Lev Fominykh, Vera Demeshonok, Vera Ataulina, Anastasia Rogelj, Boris Koritnik, Blaž Zidar, Janez Ravnik-Glavač, Metka Glavač, Damjan Stević, Zorica Drory, Vivian Povedano, Monica Blair, Ian P. Kiernan, Matthew C. Benyamin, Beben Henderson, Robert D. Furlong, Sarah Mathers, Susan McCombe, Pamela A. Needham, Merrilee Ngo, Shyuan T. Nicholson, Garth A. Pamphlett, Roger Rowe, Dominic B. Steyn, Frederik J. Williams, Kelly L. Mather, Karen A. Sachdev, Perminder S. Henders, Anjali K. Wallace, Leanne Carvalho, Mamede de Pinto, Susana Petri, Susanne Weber, Markus Rouleau, Guy A. Silani, Vincenzo Curtis, Charles J. Breen, Gerome Glass, Jonathan D. Brown Jr., Robert H. Landers, John E. Shaw, Christopher E. Andersen, Peter M. Groen, Ewout J.N. Es, Michael A. van Jeroen Pasterkamp, R. Fan, Dongsheng Garton, Fleur C. McRae, Allan F. Davey Smith, George Gaunt, Tom R. Eberle, Michael A. Mill, Jonathan McLaughlin, Russell L. Hardiman, Orla Kenna, Kevin P. Wray, Naomi R. Tsai, Ellen Runz, Heiko Franke, Lude Al-Chalabi, Ammar Damme, Philip Van Berg, Leonard H. van den Veldink, Jan H. |
Authors: | SLALOM Consortium PARALS Consortium SLAGEN Consortium SLAP Consortium |
Keywords: | Genomes Amyotrophic lateral sclerosis -- Diagnosis Nervous system -- Degeneration |
Issue Date: | 2021 |
Publisher: | Nature Publishing Group |
Citation: | Van Rheenen, W., Van Der Spek, R. A., Bakker, M. K., Van Vugt, J. J., Hop, P. J., Zwamborn, R. A., ... & Nicholson, G. A. (2021). Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nature genetics, 53(12), 1636-1648. |
Abstract: | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. |
URI: | https://www.um.edu.mt/library/oar/handle/123456789/103513 |
Appears in Collections: | Scholarly Works - FacM&SPB
|
Items in OAR@UM are protected by copyright, with all rights reserved, unless otherwise indicated.