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. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.
Genome-wide Analyses Identify KIF5A as a Novel ALS Gene / 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, Cam; 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 Development (CReATe), Consortium; 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; 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; 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; 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, Jr.; van den Berg, Lh; Veldink, Jh; Harms, Mb; Glass, Jd; Stone, Dj; Tienari, P; Silani, V; Chiò, A; Shaw, Ce; Traynor, Bj; Landers, Je. - In: NEURON. - ISSN 0896-6273. - 97:6(2018), pp. 1268-1283. [10.1016/j.neuron.2018.02.027]
Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
Mandrioli J;
2018
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. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.
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