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Neuron. 2018 Mar 21;97(6):1268-1283.e6. doi: 10.1016/j.neuron.2018.02.027.

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.

Collaborators (336)

Logullo FO, Simone I, Logroscino G, Salvi F, Bartolomei I, Borghero G, Murru MR, Costantino E, Pani C, Puddu R, Caredda C, Piras V, Tranquilli S, Cuccu S, Corongiu D, Melis M, Milia A, Marrosu F, Marrosu MG, Floris G, Cannas A, Tranquilli S, Capasso M, Caponnetto C, Mancardi G, Origone P, Mandich P, Conforti FL, Cavallaro S, Mora G, Marinou K, Sideri R, Penco S, Mosca L, Lunetta C, Pinter GL, Corbo M, Riva N, Carrera P, Volanti P, Mandrioli J, Fini N, Fasano A, Tremolizzo L, Arosio A, Ferrarese C, Trojsi F, Tedeschi G, Monsurrò MR, Piccirillo G, Femiano C, Ticca A, Ortu E, La Bella V, Spataro R, Colletti T, Sabatelli M, Zollino M, Conte A, Luigetti M, Lattante S, Marangi G, Santarelli M, Petrucci A, Pugliatti M, Pirisi A, Parish LD, Occhineri P, Giannini F, Battistini S, Ricci C, Benigni M, Cau TB, Loi D, Calvo A, Moglia C, Brunetti M, Barberis M, Restagno G, Casale F, Marrali G, Fuda G, Ossola I, Cammarosano S, Canosa A, Ilardi A, Manera U, Grassano M, Tanel R, Pisano F, Harms MB, Goldstein DB, Shneider NA, Goutman S, Simmons Z, Miller TM, Chandran S, Pal S, Manousakis G, Appel SH, Simpson E, Wang L, Baloh RH, Gibson S, Bedlack R, Lacomis D, Sareen D, Sherman A, Bruijn L, Penny M, Allen AS, Appel S, Baloh RH, Bedlack RS, Boone BE, Brown R, Carulli JP, Chesi A, Chung WK, Cirulli ET, Cooper GM, Couthouis J, Day-Williams AG, Dion PA, Gibson S, Gitler AD, Glass JD, Goldstein DB, Han Y, Harms MB, Harris T, Hayes SD, Jones AL, Keebler J, Krueger BJ, Lasseigne BN, Levy SE, Lu YF, Maniatis T, McKenna-Yasek D, Miller TM, Myers RM, Petrovski S, Pulst SM, Raphael AR, Ravits JM, Ren Z, Rouleau GA, Sapp PC, Shneider NA, Simpson E, Sims KB, Staropoli JF, Waite LL, Wang Q, Wimbish JR, Xin WW, Phatnani H, Kwan J, Sareen D, Broach JR, Simmons Z, Arcila-Londono X, Lee EB, Van Deerlin VM, Shneider NA, Fraenkel E, Ostrow LW, Baas F, Zaitlen N, Berry JD, Malaspina A, Fratta P, Cox GA, Thompson LM, Finkbeiner S, Dardiotis E, Miller TM, Chandran S, Pal S, Hornstein E, MacGowan DJ, Heiman-Patterson T, Hammell MG, Patsopoulos NA, Dubnau J, Nath A, Kaye J, Finkbeiner S, Wyman S, LeNail A, Lima L, Fraenkel E, Rothstein JD, Svendsen CN, Thompson LM, Van Eyk J, Maragakis NJ, Berry JD, Glass JD, Miller TM, Kolb SJ, Baloh RH, Cudkowicz M, Baxi E, Benatar M, Taylor JP, Wu G, Rampersaud E, Wuu J, Rademakers R, Züchner S, Schule R, McCauley J, Hussain S, Cooley A, Wallace M, Clayman C, Barohn R, Statland J, Ravits J, Swenson A, Jackson C, Trivedi J, Khan S, Katz J, Jenkins L, Burns T, Gwathmey K, Caress J, McMillan C, Elman L, Pioro E, Heckmann J, So Y, Walk D, Maiser S, Zhang J, Silani V, Ticozzi N, Gellera C, Ratti A, Taroni F, Lauria G, Verde F, Fogh I, Tiloca C, Comi GP, Sorarù G, Cereda C, D'Alfonso S, Corrado L, De Marchi F, Corti S, Ceroni M, Mazzini L, Siciliano G, Filosto M, Inghilleri M, Peverelli S, Colombrita C, Poletti B, Maderna L, Del Bo R, Gagliardi S, Querin G, Bertolin C, Pensato V, Castellotti B, Camu W, Mouzat K, Lumbroso S, Corcia P, Meininger V, Besson G, Lagrange E, Clavelou P, Guy N, Couratier P, Vourch P, Danel V, Bernard E, Lemasson G, Al Kheifat A, Al-Chalabi A, Andersen P, Basak AN, Blair IP, Chio A, Cooper-Knock J, Corcia P, Couratier P, de Carvalho M, Dekker A, Drory V, Redondo AG, Gotkine M, Hardiman O, Hide W, Iacoangeli A, Glass J, Kenna K, Kiernan M, Kooyman M, Landers J, McLaughlin R, Middelkoop B, Mill J, Neto MM, Moisse M, Pardina JM, Morrison K, Newhouse S, Pinto S, Pulit S, Robberecht W, Shatunov A, Shaw P, Shaw C, Silani V, Sproviero W, Tazelaar G, Ticozzi N, van Damme P, van den Berg L, van der Spek R, van Eijk K, van Es M, van Rheenen W, van Vugt J, Veldink J, Weber M, Williams KL, Zatz M, Bauer DC, Twine NA.

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.

KEYWORDS:

ALS; GWAS; KIF5A; WES; WGS; axonal transport; cargo

PMID:
29566793
PMCID:
PMC5867896
DOI:
10.1016/j.neuron.2018.02.027
[Indexed for MEDLINE]
Free PMC Article

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