To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases, hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth Type 2 (CMT2). In contrast, ALS associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss of function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
Nicolas, Aude and Kenna, Kevin P. and Renton, Alan E. and Ticozzi, Nicola and Faghri, Faraz and Chia, Ruth and Dominov, Janice A. and Kenna, Brendan J. and Nalls, Mike A. and Keagle, Pamela and Rivera, Alberto M. and Rheenen, Wouter van and Murphy, Natalie A. and Vugt, Joke J.F.A. van and Geiger, Joshua T. and Van der Spek, Rick A. and Pliner, Hannah A. and Smith, Bradley N. and Marangi, Giuseppe and Topp, Simon D. and Abramzon, Yevgeniya and Gkazi, Athina Soragia and Eicher, John D. and Kenna, Aoife and Consortium, ITALSGEN and Mora, Gabriele and Calvo, Andrea and Mazzini, Letizia and Riva, Nilo and Mandrioli, Jessica and Caponnetto, Claudia and Battistini, Stefania and Volanti, Paolo and Bella, Vincenzo La and Conforti, Francesca L. and Borghero, Giuseppe and Messina, Sonia and Simone, Isabella L. and Trojsi, Francesca and Salvi, Fabrizio and Logullo, Francesco O. and D’Alfonso, Sandra and Corrado, Lucia and Capasso, Margherita and Ferrucci, Luigi and (GTAC) Consortium, Genomic Translation for ALS Care and Martins Moreno, Cristiane de Araujo and Kamalakaran, Sitharthan and Goldstein, David B. and Consortium, The ALS Sequencing and Gitler, Aaron D. and Harris, Tim and Myers, Richard M. and Consortium, NYGC ALS and Phatnani, Hemali and Musunuri, Rajeeva Lochan and Evani, Uday Shankar and Abhyankar, Avinash and Zody, Michael Charles and Foundation, Answer ALS and Kaye, Julia and Finkbeiner, Steven and Wyman, Stacia and Lenail, Alex and Lima, Leandro and Fraenkel, Ernest and Svendsen, Clive N. and Thompson, Leslie M. and Van Eyk, Jennifer E. and Berry, James D. and Miller, Timothy M. and Kolb, Stephen J. and Cudkowicz, Merit and Baxi, Emily and Development (CReATe) Consortium, Clinical Research in ALS and Related Disorders for Therapeutic and Benatar, Michael and Taylor, J. Paul and Rampersaud, Evadnie and Wu, Gang and Wuu, Joanne and Consortium, SLAGEN and Lauria, Giuseppe and Verde, Federico and Fogh, Isabella and Tiloca, Cinzia and Comi, Giacomo P. and Sorarù, Gianni and Cereda, Cristina and Consortium, French ALS and Corcia, Philippe and Laaksovirta, Hannu and Myllykangas, Liisa and Jansson, Lilja and Valori, Miko and Ealing, John and Hamdallah, Hesham and Rollinson, Sara and Pickering-Brown, Stuart and Orrell, Richard W. and Sidle, Katie C. and Malaspina, Andrea and Hardy, John and Singleton, Andrew B. and Johnson, Janel O. and Arepalli, Sampath and Sapp, Peter C. and McKenna-Yasek, Diane and Polak, Meraida and Asress, Seneshaw and Al-Sarraj, Safa and King, Andrew and Troakes, Claire and Vance, Caroline and Belleroche, Jacqueline de and Baas, Frank and Asbroek, Anneloor LMA ten and Muñoz-Blanco, José Luis and Hernandez, Dena G. and Ding, Jinhui and Gibbs, J. Raphael and Scholz, Sonja W. and Floeter, Mary Kay and Campbell, Roy H. and Landi, Francesco and Pulst, Stefan M. and Ravits, John M. and MacGowan, Daniel J. L. and Kirby, Janine and Pioro, Erik and Pamphlett, Roger and Broach, James and Gerhard, Glenn and Dunckley, Travis L. and Brady, Christopher B. and Kowall, Neil W. and Troncoso, Juan and Le Ber, Isabelle and Mouzat, Kevin and Lumbroso, Serge and Heiman-Patterson, Terry D. and Kamel, Freya and Bosch, Ludo Van Den and Baloh, Robert H. and Strom, Tim M. and Meitinger, Thomas and Shatunov, Aleksey and Van Eijk, Kristel R. and de Carvalho, Mamede and Kooyman, Maarten and Middelkoop, Bas and Moisse, Matthieu and McLaughlin, Russell L. and Van Es, Michael A. and Weber, Markus and Boylan, Kevin B. and Van Blitterswijk, Marka and Rademakers, Rosa and Morrison, Karen E. and Basak, A. Nazli and Mora, Jesús S. and Drory, Vivian E. and Shaw, Pamela J. and Turner, Martin R. and Talbot, Kevin and Hardiman, Orla and Williams, Kelly L. and Fifita, Jennifer A. and Nicholson, Garth A. and Blair, Ian P. and Rouleau, Guy A. and Esteban-Pérez, Jesús and García-Redondo, Alberto and Al-Chalabi, Ammar and , Project MinE ALS Sequencing Consortium and Rogaeva, Ekaterina and Zinman, Lorne and Ostrow, Lyle and Maragakis, Nicholas J. and Rothstein, Jeffrey D. and Simmons, Zachary and Cooper-Knock, Johnathan and Brice, Alexis and Goutman, Stephen A. and Feldman, Eva L. and Gibson, Summer B. and Taroni, Franco and Ratti, Antonia and Gellera, Cinzia and Van Damme, Philip and Robberecht, Wim and Fratta, Pietro and Sabatelli, Mario and Lunetta, Christian and Ludolph, Albert C. and Andersen, Peter M. and Weishaupt, Jochen H. and Camu, William and Trojanowski, John Q. and Van Deerlin, Vivianna M. and Brown, Robert H. and van den Berg, Leonard H. and Veldink, Jan H. and Harms, Matthew B. and Glass, Jonathan D. and Stone, David J. and Tienari, Pentti and Silani, Vincenzo and Chiò, Adriano and Shaw, Christopher E. and Traynor, Bryan J. and Landers, John E., Genome-Wide Analyses Identify KIF5A as a Novel ALS Gene (April 3, 2018). Available at SSRN: https://ssrn.com/abstract=3155776
This is a paper under consideration at Cell Press and has not been peer-reviewed.