Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
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van Rheenen, Wouter | Shatunov, Aleksey | Dekker, Annelot | Mclaughlin, Russell | Diekstra, Frank | Pulit, Sara | van der Spek, Rick | Võsa, Urmo | de Jong, Simone | Robinson, Matthew | Yang, Jian | Fogh, Isabella | van Doormaal, Perry Tc | Tazelaar, Gijs | Koppers, Max | Blokhuis, Anna | Sproviero, William | Jones, Ashley | Kenna, Kevin | van Eijk, Kristel | Harschnitz, Oliver | Schellevis, Raymond | Brands, William | Medic, Jelena | Menelaou, Androniki | Vajda, Alice | Ticozzi, Nicola | Lin, Kuang | Rogelj, Boris | Vrabec, Katarina | Ravnik-Glavač, Metka | Koritnik, Blaž | Zidar, Janez | Leonardis, Lea | Grošelj, Leja Dolenc | Millecamps, Stéphanie | Salachas, François | Meininger, Vincent | de Carvalho, Mamede | Pinto, Susana | Mora, Jesus | Rojas-García, Ricardo | Polak, Meraida | Chandran, Siddharthan | Colville, Shuna | Swingler, Robert | Morrison, Karen | Shaw, Pamela | Hardy, John | Orrell, Richard | Pittman, Alan | Sidle, Katie | Fratta, Pietro | Malaspina, Andrea | Topp, Simon | Petri, Susanne | Abdulla, Susanne | Drepper, Carsten | Sendtner, Michael | Meyer, Thomas | Ophoff, Roel | Staats, Kim | Wiedau-Pazos, Martina | Lomen-Hoerth, Catherine | van Deerlin, Vivianna | Trojanowski, John | Elman, Lauren | Mccluskey, Leo | Basak, a Nazli | Tunca, Ceren | Hamzeiy, Hamid | Parman, Yesim | Meitinger, Thomas | Lichtner, Peter | Radivojkov-Blagojevic, Milena | Andres, Christian | Maurel, Cindy | Bensimon, Gilbert | Landwehrmeyer, Bernhard | Brice, Alexis | Payan, Christine | Saker-Delye, Safaa | Dürr, Alexandra | Wood, Nicholas | Tittmann, Lukas | Lieb, Wolfgang | Franke, Andre | Rietschel, Marcella | Cichon, Sven | Nöthen, Markus | Amouyel, Philippe | Tzourio, Christophe | Dartigues, Jean-François | Uitterlinden, Andre | Rivadeneira, Fernando | Estrada, Karol | Hofman, Albert | Curtis, Charles | Blauw, Hylke | van der Kooi, Anneke | de Visser, Marianne | Goris, An | Weber, Markus | Shaw, Christopher | Smith, Bradley | Pansarasa, Orietta | Cereda, Cristina | del Bo, Roberto | Comi, Giacomo | d'Alfonso, Sandra | Bertolin, Cinzia | Sorarù, Gianni | Mazzini, Letizia | Pensato, Viviana | Gellera, Cinzia | Tiloca, Cinzia | Ratti, Antonia | Calvo, Andrea | Moglia, Cristina | Brunetti, Maura | Arcuti, Simona | Capozzo, Rosa | Zecca, Chiara | Lunetta, Christian | Penco, Silvana | Riva, Nilo | Padovani, Alessandro | Filosto, Massimiliano | Muller, Bernard | Stuit, Robbert Jan | Blair, Ian | Zhang, Katharine | Mccann, Emily | Fifita, Jennifer | Nicholson, Garth | Rowe, Dominic | Pamphlett, Roger | Kiernan, Matthew | Grosskreutz, Julian | Witte, Otto | Ringer, Thomas | Prell, Tino | Stubendorff, Beatrice | Kurth, Ingo | Hübner, Christian | Leigh, P Nigel | Casale, Federico | Chio, Adriano | Beghi, Ettore | Pupillo, Elisabetta | Tortelli, Rosanna | Logroscino, Giancarlo | Powell, John | Ludolph, Albert | Weishaupt, Jochen | Robberecht, Wim | van Damme, Philip | Franke, Lude | Pers, Tune | Brown, Robert | Glass, Jonathan | Landers, John | Hardiman, Orla | Andersen, Peter | Corcia, Philippe | Vourc'H, Patrick | Silani, Vincenzo | Wray, Naomi | Visscher, Peter | de Bakker, Paul | van Es, Michael | Pasterkamp, R Jeroen | Lewis, Cathryn | Breen, Gerome | Al-Chalabi, Ammar | van den Berg, Leonard | Veldink, Jan
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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.
