Accès ouvert déclaré
2021
preprint
Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Wouter van Rheenen, Rick A. A. van der Spek, Mark K. Bakker, Joke J.F.A. van Vugt, Paul J. Hop, Ramona A.J. Zwamborn, Niek de Klein, Harm-Jan Westra, Olivier B. Bakker, Patrick Deelen, Gemma Shireby, Eilís Hannon, Matthieu Moisse, Denis Baird, Restuadi Restuadi, Egor Dolzhenko, Annelot M. Dekker, Klara Gawor, Henk‐Jan Westeneng, Gijs H.P. Tazelaar, Kristel R. van Eijk, Maarten Kooyman, Ross P. Byrne, Mark A. Doherty, Mark Heverin, Ahmad Al Khleifat, Alfredo Iacoangeli, Aleksey Shatunov, Nicola Ticozzi, Johnathan Cooper‐Knock, Bradley Smith, Marta Gromicho, Siddharthan Chandran, Suvankar Pal, Karen Morrison, Pamela J. Shaw, John Hardy, Richard W. Orrell, Michael Sendtner, Thomas Meyer, Nazlı Başak, Anneke J. van der Kooi, Antonia Ratti, Isabella Fogh, Cinzia Gellera, Stefania Corti, Cristina Cereda, Daisy Sproviero, Sandra D’Alfonso, Gianni Sorarú, Gabriele Siciliano, Massimiliano Filosto, Alessandro Padovani, Adriano Chiò, Andrea Calvo, Cristina Moglia, Maura Brunetti, Antonio Canosa, Maurizio Grassano, Ettore Beghi, Elisabetta Pupillo, Giancarlo Logroscino, Beatrice Nefussy, Alma Osmanovic, Angelica Nordin, Yossef Lerner, Michal Zabari, Marc Gotkine, Robert H. Baloh, Shaughn Bell, Patrick Vourc’h, Philippe Corcia, Philippe Couratier, Stéphanie Millecamps, Vincent Meininger, François Salachas, Jesús S. Mora Pardina, Abdelilah Assialioui, Ricardo Rojas‐García, Patrick A. Dion, Jay P. Ross, Albert C. Ludolph, Jochen H. Weishaupt, Dávid Brenner, Axel Freischmidt, Gilbert Bensimon, Alexis Brice, Alexandra Dürr, Christine Payan, Safa Saker-Delye, Nicholas Wood, Simon Topp, Rosa Rademakers, Lukas Tittmann, Wolfgang Lieb, André Franke, Stephan Ripke, Alice Braun, Julia Kraft, David C. Whiteman, Catherine M. Olsen, André G. Uitterlinden, Albert Hofman, Marcella Rietschel, Sven Cichon, Markus M. Nöthen, Philippe Amouyel, Bryan J. Traynor, Adrew B. Singleton, Miguel Mitne‐Neto, Ruben J. Cauchi, Roel A. Ophoff, Martina Wiedau‐Pazos, Catherine Lomen‐Hoerth, Vivianna M. Van Deerlin, Julian Großkreutz, Annekathrin Rödiger, Nayana Gaur, Alexander Jörk, Tabea Barthel, Erik Theele, Benjamin Ilse, Beatrice Stubendorff, Otto W. Witte, Robert Steinbach, Christian A. Hübner, Caroline Graff, Lev Brylev, Vera Fominykh, V. S. Demeshonok, Anastasia Ataulina, Boris Rogelj, Blaž Koritnik, Janez Zidar, Metka Ravnik‐Glavač, Damjan Glavač, Zorica Stević, Vivian E. Drory, Mónica Povedano, Ian P. Blair, Matthew C. Kiernan, Beben Benyamin, Robert D. Henderson, Sarah Furlong, Susan Mathers, Pamela McCombe, Merrilee Needham, Shyuan T. Ngo, Garth A. Nicholson, Roger Pamphlett, Dominic B. Rowe, Frederik J. Steyn, Kelly L. Williams, Karen A. Mather, Perminder S. Sachdev, Anjali K. Henders, Leanne Wallace, Mamede de Carvalho, Susana Pinto, Susanne Petri, Markus Weber, Guy A. Rouleau, Vincenzo Silani, Charles Curtis, Gerome Breen, Jonathan D. Glass, Robert H. Brown, John E. Landers, Christopher E. Shaw, Peter M. Andersen, Ewout J. N. Groen, Michael A. van Es, R. Jeroen Pasterkamp, Dongsheng Fan, Fleur C. Garton, Allan F. McRae, George Davey Smith, Tom R. Gaunt, Michael A. Eberle, Jonathan Mill, Russell L. McLaughlin, Orla Hardiman, Kevin P. Kenna, Naomi R. Wray, Ellen Tsai, Heiko Runz, Lude Franke, Ammar Al‐Chalabi, Philip Van Damme, Leonard H. van den Berg, Jan H. Veldink
6Citations signalées, ce qui n’est pas une note de qualité
93Institutions déclarées
17Pays d’affiliation déclarés
Rattachement africain : nl, gb, be, us, au, ie, it, pt, de, tr, il, se, fr, es, ca, ch, cu.
Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions 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. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
- Date Crossref
- 15/03/2021
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Les institutions déclarées
Une affiliation ne permet pas de déduire la nationalité d’un auteur.
Les sujets associés
Amyotrophic Lateral Sclerosis ResearchNeurological diseases and metabolismNeurogenetic and Muscular Disorders Research