Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Abstract

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.

Metadata

Item Type:	Article
Authors/Creators:	Nicolas, A Kenna, KP Renton, AE Ticozzi, N Faghri, F Chia, R Dominov, JA Kenna, BJ Nalls, MA Keagle, P Rivera, AM van Rheenen, W Murphy, NA van Vugt, JJFA Geiger, JT Van der Spek, RA Pliner, HA Shankaracharya Smith, BN Marangi, G Topp, SD Abramzon, Y Gkazi, AS Eicher, JD Kenna, A ITALSGEN Consortium Mora, G Calvo, A Mazzini, L Riva, N Mandrioli, J Caponnetto, C Battistini, S Volanti, P La Bella, V Conforti, FL Borghero, G Messina, S Simone, IL Trojsi, F Salvi, F Logullo, FO D'Alfonso, S Corrado, L Capasso, M Ferrucci, L Genomic Translation for ALS Care (GTAC) Consortium Moreno, CDAM Kamalakaran, S Goldstein, DB ALS Sequencing Consortium Gitler, AD Harris, T Myers, RM NYGC ALS Consortium Phatnani, H Musunuri, RL Evani, US Abhyankar, A Zody, MC Answer ALS Foundation Kaye, J Finkbeiner, S Wyman, SK LeNail, A Lima, L Fraenkel, E Svendsen, CN Thompson, LM Van Eyk, JE Berry, JD Miller, TM Kolb, SJ Cudkowicz, M Baxi, E Clinical Research in ALS and Related Disorders for Therapeutic D Benatar, M Taylor, JP Rampersaud, E Wu, G Wuu, J SLAGEN Consortium Lauria, G Verde, F Fogh, I Tiloca, C Comi, GP Sorarù, G Cereda, C French ALS Consortium Corcia, P Laaksovirta, H Myllykangas, L Jansson, L Valori, M Ealing, J Hamdalla, H Rollinson, S Pickering-Brown, S Orrell, RW Sidle, KC Malaspina, A Hardy, J Singleton, AB Johnson, JO Arepalli, S Sapp, PC McKenna-Yasek, D Polak, M Asress, S Al-Sarraj, S King, A Troakes, C Vance, C de Belleroche, J Baas, F Ten Asbroek, ALMA Muñoz-Blanco, JL Hernandez, DG Ding, J Gibbs, JR Scholz, SW Floeter, MK Campbell, RH Landi, F Bowser, R Pulst, SM Ravits, JM MacGowan, DJL Kirby, J https://orcid.org/0000-0002-7468-5917 Pioro, EP Pamphlett, R Broach, J Gerhard, G Dunckley, TL Brady, CB Kowall, NW Troncoso, JC Le Ber, I Mouzat, K Lumbroso, S Heiman-Patterson, TD Kamel, F Van Den Bosch, L Baloh, RH Strom, TM Meitinger, T Shatunov, A Van Eijk, KR de Carvalho, M Kooyman, M Middelkoop, B Moisse, M McLaughlin, RL Van Es, MA Weber, M Boylan, KB Van Blitterswijk, M Rademakers, R Morrison, KE Basak, AN Mora, JS Drory, VE Shaw, PJ https://orcid.org/0000-0002-8925-2567 Turner, MR Talbot, K Hardiman, O Williams, KL Fifita, JA Nicholson, GA Blair, IP Rouleau, GA Esteban-Pérez, J García-Redondo, A Al-Chalabi, A Project MinE ALS Sequencing Consortium Rogaeva, E Zinman, L Ostrow, LW Maragakis, NJ Rothstein, JD Simmons, Z Cooper-Knock, J https://orcid.org/0000-0002-0873-8689 Brice, A Goutman, SA Feldman, EL Gibson, SB Taroni, F Ratti, A Gellera, C Van Damme, P Robberecht, W Fratta, P Sabatelli, M Lunetta, C Ludolph, AC Andersen, PM Weishaupt, JH Camu, W Trojanowski, JQ Van Deerlin, VM Brown, RH van den Berg, LH Veldink, JH Harms, MB Glass, JD Stone, DJ Tienari, P Silani, V Chiò, A Shaw, CE Traynor, BJ Landers, JE
Copyright, Publisher and Additional Information:	© 2018 Elsevier. This is an author produced version of a paper subsequently published in Neuron. Uploaded in accordance with the publisher's self-archiving policy. Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Keywords:	ALS; GWAS; KIF5A; WES; WGS; axonal transport; cargo
Dates:	Published: 21 March 2018 Accepted: 26 February 2018
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Funding Information:	Funder Grant number ACADEMY OF MEDICAL SCIENCES SGL018\1007
Depositing User:	Symplectic Sheffield
Date Deposited:	17 Apr 2018 14:24
Last Modified:	21 Mar 2019 01:41
Published Version:	https://doi.org/10.1016/j.neuron.2018.02.027
Status:	Published
Publisher:	Elsevier
Refereed:	Yes
Identification Number:	10.1016/j.neuron.2018.02.027
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:129590