Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

• Autor(es): van Rheenen, Wouter ; Shatunov, Aleksey ; Dekker, Annelot M. ; McLaughlin, Russell L. ; Diekstra, Frank P. ; Pulit, Sara L. ; van der Spek, Rick A. A. ; Võsa, Urmo ; de Jong, Simone ; Robinson, Matthew R. ; Yang, Jian ; Medic, Jelena ; Menelaou, Androniki ; Vajda, Alice ; Ticozzi, Nicola ; Lin, Kuang ; Rogelj, Boris ; Vrabec, Katarina ; Ravnik-Glavač, Metka ; Koritnik, Blaž ; Zidar, Janez ; de Visser, Marianne ; Leonardis, Lea ; Grošelj, Leja Dolenc ; Millecamps, Stéphanie ; Salachas, François ; Meininger, Vincent ; Carvalho, Mamede ; Pinto, Susana ; Mora, Jesus S. ; Rojas-García, Ricardo ; Polak, Meraida ; Goris, An ; Chandran, Siddharthan ; Colville, Shuna ; Swingler, Robert ; Morrison, Karen E. ; Shaw, Pamela J. ; Hardy, John ; Orrell, Richard W. ; Pittman, Alan ; Sidle, Katie ; Fratta, Pietro ; Weber, Markus ; Malaspina, Andrea ; Topp, Simon ; Petri, Susanne ; Abdulla, Susanne ; Drepper, Carsten ; Sendtner, Michael ; Meyer, Thomas ; Ophoff, Roel A. ; Staats, Kim A. ; Wiedau-Pazos, Martina ; Shaw, Christopher E. ; Lomen-Hoerth, Catherine ; Van Deerlin, Vivianna M. ; Trojanowski, John Q. ; Elman, Lauren ; McCluskey, Leo ; Basak, A Nazli ; Tunca, Ceren ; Hamzeiy, Hamid ; Parman, Yesim ; Meitinger, Thomas ; Smith, Bradley N. ; Lichtner, Peter ; Radivojkov-Blagojevic, Milena ; Andres, Christian R. ; Maurel, Cindy ; Bensimon, Gilbert ; Landwehrmeyer, Bernhard ; Brice, Alexis ; Payan, Christine A. M. ; Saker-Delye, Safaa ; Dürr, Alexandra ; Pansarasa, Orietta ; Wood, Nicholas W. ; Tittmann, Lukas ; Lieb, Wolfgang ; Franke, Andre ; Rietschel, Marcella ; Cichon, Sven ; Nöthen, Markus M. ; Amouyel, Philippe ; Tzourio, Christophe ; Dartigues, Jean-François ; Cereda, Cristina ; Uitterlinden, Andre G. ; Rivadeneira, Fernando ; Estrada, Karol ; Hofman, Albert ; Curtis, Charles ; Blauw, Hylke M. ; van der Kooi, Anneke J. ; Del Bo, Roberto ; Comi, Giacomo P. ; D'Alfonso, Sandra ; Fogh, Isabella ; Bertolin, Cinzia ; Sorarù, Gianni ; Mazzini, Letizia ; Pensato, Viviana ; Gellera, Cinzia ; Tiloca, Cinzia ; Ratti, Antonia ; Calvo, Andrea ; Moglia, Cristina ; Brunetti, Maura ; van Doormaal, Perry T. C. ; Arcuti, Simona ; Capozzo, Rosa ; Zecca, Chiara ; Lunetta, Christian ; Penco, Silvana ; Riva, Nilo ; Padovani, Alessandro ; Filosto, Massimiliano ; Muller, Bernard ; Stuit, Robbert Jan ; Tazelaar, Gijs H. P. ; Blair, Ian ; Zhang, Katharine ; McCann, Emily P. ; Fifita, Jennifer A. ; Nicholson, Garth A. ; Rowe, Dominic B. ; Pamphlett, Roger ; Kiernan, Matthew C. ; Grosskreutz, Julian ; Witte, Otto W. ; Koppers, Max ; Ringer, Thomas ; Prell, Tino ; Stubendorff, Beatrice ; Kurth, Ingo ; Hübner, Christian A. ; Leigh, P Nigel ; Casale, Federico ; Chio, Adriano ; Beghi, Ettore ; Pupillo, Elisabetta ; Blokhuis, Anna M. ; Tortelli, Rosanna ; Logroscino, Giancarlo ; Powell, John ; Ludolph, Albert C. ; Weishaupt, Jochen H. ; Robberecht, Wim ; Van Damme, Philip ; Franke, Lude ; Pers, Tune H. ; Brown, Robert H. ; Sproviero, William ; Glass, Jonathan D. ; Landers, John E. ; Hardiman, Orla ; Andersen, Peter M. ; Corcia, Philippe ; Vourc'h, Patrick ; Silani, Vincenzo ; Wray, Naomi R. ; Visscher, Peter M. ; de Bakker, Paul I W. ; Jones, Ashley R. ; van Es, Michael A. ; Pasterkamp, R Jeroen ; Lewis, Cathryn M. ; Breen, Gerome ; Al-Chalabi, Ammar ; van den Berg, Leonard H. ; Veldink, Jan H. ; Kenna, Kevin P. ; van Eijk, Kristel R. ; Harschnitz, Oliver ; Schellevis, Raymond D. ; Brands, William J.
• Data: 2016
• Identificador Persistente: http://hdl.handle.net/10451/48245
• Origem: Repositório da Universidade de Lisboa
• Tipo de Documento: Artigo científico
• Idioma: Inglês
• Contribuidor(es): Repositório Científico de Acesso Aberto da ULisboa

Descrição

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.