Journal article
Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
Neuron (Cambridge, Mass.), v 97(6), pp 1267-1288
21 Mar 2018
PMID: 29566793
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
• Loss-of-function mutations in KIF5A are a cause of amyotrophic lateral sclerosis
• ALS-associated KIF5A mutations are distinct from HSP and CMT mutations in KIF5A
• Identification of KIF5A highlights the role of cytoskeleton in ALS pathogenesis
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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- Title
- Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- Creators
- Aude Nicolas - National Institute on AgingKevin P. Kenna - University of Massachusetts Chan Medical SchoolAlan E. Renton - Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USANicola Ticozzi - Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyFaraz Faghri - National Institute on AgingRuth Chia - Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USAJanice A. Dominov - University of Massachusetts Chan Medical SchoolBrendan J. Kenna - University of Massachusetts Chan Medical SchoolMike A. Nalls - Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USAPamela Keagle - University of Massachusetts Chan Medical SchoolAlberto M. Rivera - National Institute on AgingWouter van Rheenen - University Medical Center UtrechtNatalie A. Murphy - National Institute on AgingJoke J.F.A. van Vugt - University Medical Center UtrechtJoshua T. Geiger - National Institute of Neurological Disorders and StrokeRick A. Van der Spek - University Medical Center UtrechtHannah A. Pliner - National Institute on AgingShankaracharya - University of Massachusetts Chan Medical SchoolBradley N. Smith - Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King’s College London, London SE5 9RS, UKGiuseppe Marangi - National Institute on AgingSimon D. Topp - Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King’s College London, London SE5 9RS, UKYevgeniya Abramzon - Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USAAthina Soragia Gkazi - King's College LondonJohn D. Eicher - Genetics and Pharmacogenomics, MRL, Merck & Co., Inc., Boston, MA 02115, USAAoife Kenna - University of Massachusetts Chan Medical SchoolGiancarlo LogroscinoIlaria BartolomeiMaria Rita MurruEmanuela CostantinoCarla PaniRoberta PudduCarla CareddaValeria PirasStefania TranquilliStefania CuccuDaniela CorongiuMaurizio MelisAntonio MiliaFrancesco MarrosuMaria Giovanna MarrosuGianluca FlorisAntonino CannasGianluigi MancardiPaola OrigonePaola MandichSebastiano CavallaroKalliopi MarinouRiccardo SideriSilvana PencoLorena MoscaGiuseppe Lauria PinterMassimo CorboPaola CarreraNicola FiniAntonio FasanoLucio TremolizzoAlessandro ArosioCarlo FerrareseGioacchino TedeschiMaria Rosaria MonsurròGiovanni PiccirilloCinzia FemianoAnna TiccaEnzo OrtuRossella SpataroTiziana CollettiMarcella ZollinoAmelia ConteMarco LuigettiSerena LattanteMarialuisa SantarelliAntonio PetrucciMaura PugliattiAngelo PirisiLeslie D. ParishPatrizia OcchineriFabio GianniniClaudia RicciMichele BenigniTea B. CauDaniela LoiCristina MogliaMaura BrunettiMarco BarberisGabriella RestagnoFederico CasaleGiuseppe MarraliGiuseppe FudaIrene OssolaStefania CammarosanoAntonio CanosaAntonio IlardiUmberto ManeraMaurizio GrassanoRaffaella TanelFabrizio PisanoGabriele Mora - ALS (Czechia)Andrea Calvo - University of TurinLetizia Mazzini - “Maggiore della Carità” University Hospital, Novara, ItalyNilo Riva - Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, ItalyJessica Mandrioli - Department of Neuroscience, St. Agostino Estense Hospital, Azienda Ospedaliero Universitaria di Modena, Modena, ItalyClaudia Caponnetto - Ospedale Policlinico San MartinoStefania Battistini - University of SienaPaolo Volanti - ALS (Czechia)Vincenzo La Bella - ALS Clinical Research Center, University of Palermo, Palermo, ItalyFrancesca L. Conforti - Institute of Neurological SciencesGiuseppe Borghero - University of CagliariSonia Messina - University of MessinaIsabella L. Simone - University of Bari Aldo MoroFrancesca Trojsi - Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania “Luigi Vanvitelli,” Naples, ItalyFabrizio Salvi - “Il Bene” Center for Immunological and Rare Neurological Diseases at Bellaria Hospital, IRCCS, Istituto delle Scienze Neurologiche, Bologna, ItalyFrancesco O. Logullo - Marche Polytechnic UniversitySandra D’Alfonso - Università degli Studi del Piemonte Orientale “Amedeo Avogadro”Lucia Corrado - Università degli Studi del Piemonte Orientale “Amedeo Avogadro”Margherita Capasso - Department of Neurology, University of Chieti, Chieti, ItalyLuigi Ferrucci - National Institutes of HealthDavid B. Goldstein - Columbia UniversityNeil A. ShneiderSiddharthan ChandranSuvankar PalGeorgios ManousakisStanley H. AppelEricka SimpsonLeo WangRichard BedlackDavid LacomisDhruv SareenAlexander ShermanLucie BruijnMichelle PennyCristiane de Araujo Martins Moreno - Columbia UniversitySitharthan Kamalakaran - Columbia UniversityAndrew S. Allen - Duke UniversityBraden E. Boone - HudsonAlpha Institute for BiotechnologyJohn P. CarulliAlessandra ChesiWendy K. Chung - Columbia UniversityElizabeth T. CirulliGregory M. CooperJulien CouthouisAaron G. Day-WilliamsPatrick A. DionYujun Han - Duke UniversitySebastian D. HayesAngela L. JonesJonathan KeeblerBrian J. KruegerBrittany N. LasseigneShawn E. Levy - HudsonAlpha Institute for BiotechnologyYi-Fan Lu - Duke UniversityTom ManiatisSlavé Petrovski - The University of MelbourneAlya R. RaphaelZhong Ren - Columbia UniversityKatherine B. SimsJohn F. StaropoliLindsay L. WaiteQuanli Wang - Columbia UniversityJack R. Wimbish - HudsonAlpha Institute for BiotechnologyWinnie W. XinAaron D. Gitler - Stanford University School of MedicineTim Harris - Bioverativ, 225 2nd Avenue, Waltham, MA 02145, USARichard M. Myers - HudsonAlpha Institute for BiotechnologyJustin KwanJames R. Broach - Georgetown University Medical CenterXimena Arcila-LondonoEdward B. LeeVivianna M. Van Deerlin - Raymond and Ruth Perelman School of Medicine at the University of PennsylvaniaTerry Heiman-Patterson - Drexel UniversityNoah ZaitlenGregory A. CoxEfthimios DardiotisEran HornsteinMolly G. Hammell - Cold Spring Harbor LaboratoryNikolaos A. PatsopoulosJoshua DubnauAvindra NathHemali Phatnani - New York Genome CenterRajeeva Lochan Musunuri - New York Genome CenterUday Shankar Evani - New York Genome CenterAvinash Abhyankar - New York Genome CenterMichael C. Zody - New York Genome CenterSteven Finkbeiner - University of California, San FranciscoJulia Kaye - Gladstone Institute of Neurological Disease, San Francisco, CA, USAStacia K. Wyman - Gladstone Institute of Neurological Disease, San Francisco, CA, USAAlex LeNail - Massachusetts Institute of TechnologyLeandro Lima - Gladstone Institute of Neurological Disease, San Francisco, CA, USAErnest Fraenkel - Massachusetts Institute of TechnologyClive N. Svendsen - Cedars-Sinai Medical CenterLeslie M. Thompson - University of California, IrvineJennifer E. Van Eyk - Cedars-Sinai Medical CenterJames D. Berry - Harvard Medical SchoolTimothy M. Miller - Department of Neurology, Washington University School of Medicine, St. Louis, MO, USAStephen J. Kolb - The Ohio State University Wexner Medical CenterMerit Cudkowicz - Harvard Medical SchoolEmily Baxi - Johns Hopkins UniversityRosa Rademakers - Mayo Clinic in FloridaStephan ZüchnerRebecca SchuleJacob McCauley - University of MiamiSumaira HussainAnne CooleyMarielle WallaceChristine ClaymanRichard BarohnJeffrey StatlandAndrea SwensonCarlayne JacksonJaya TrivediShaida KhanJonathan KatzLiberty JenkinsTed BurnsKelly GwathmeyJames CaressCorey McMillanLauren ElmanJeannine HeckmannYuen SoDavid WalkSamuel MaiserJinghui ZhangMichael Benatar - University of MiamiJ. Paul Taylor - Howard Hughes Medical InstituteEvadnie Rampersaud - St. Jude Children's Research HospitalGang Wu - St. Jude Children's Research HospitalJoanne Wuu - University of MiamiFabiola De MarchiStefania CortiMauro CeroniGabriele SicilianoMassimiliano FilostoMaurizio InghilleriSilvia PeverelliClaudia ColombritaBarbara PolettiLuca MadernaRoberto Del BoStella GagliardiGiorgia QuerinCinzia BertolinViviana PensatoBarbara CastellottiGiuseppe Lauria - University of MilanFederico Verde - IRCCS Istituto Auxologico ItalianoIsabella Fogh - IRCCS Istituto Auxologico ItalianoCinzia Tiloca - IRCCS Istituto Auxologico ItalianoGiacomo P. Comi - Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoGianni Sorarù - Department of Neurosciences, University of Padova, Padova, ItalyCristina Cereda - Genomic (Brazil)Vincent MeiningerGérard BessonEmmeline LagrangePierre ClavelouNathalie GuyPhilippe CouratierPatrick VourchVéronique DanelEmilien BernardGwendal LemassonPhilippe Corcia - ALS (Czechia)Hannu Laaksovirta - Helsinki University HospitalLiisa Myllykangas - Helsinki University HospitalLilja Jansson - Helsinki University HospitalMiko Valori - Helsinki University HospitalJohn Ealing - Salford Royal NHS Foundation TrustHisham Hamdalla - Salford Royal NHS Foundation TrustSara Rollinson - University of ManchesterStuart Pickering-Brown - Faculty of Human and Medical Sciences, University of Manchester, Manchester M13 9PT, UKRichard W. Orrell - Department of Clinical Neuroscience, Institute of Neurology, University College London, London NW3 2PG, UKKatie C. Sidle - Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square House, London WC1N 3BG, UKAndrea Malaspina - Queen Mary University of LondonJohn Hardy - Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square House, London WC1N 3BG, UKAndrew B. Singleton - National Institutes of HealthJanel O. Johnson - Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USASampath Arepalli - National Institute on AgingPeter C. Sapp - University of Massachusetts Chan Medical SchoolDiane McKenna-Yasek - University of Massachusetts Chan Medical SchoolMeraida Polak - Emory University School of MedicineSeneshaw Asress - Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USASafa Al-Sarraj - King's College LondonAndrew King - King's College LondonClaire Troakes - Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King’s College London, London SE5 9RS, UKCaroline Vance - King's College LondonJacqueline de Belleroche - Imperial College LondonFrank Baas - Leiden University Medical CenterAnneloor L.M.A. ten Asbroek - Department of Neurogenetics and Neurology, Academic Medical Centre, Amsterdam, the NetherlandsJosé Luis Muñoz-Blanco - Hospital General Universitario Gregorio MarañónDena G. Hernandez - National Institute on AgingJinhui Ding - National Institute on AgingJ. Raphael Gibbs - Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USASonja W. Scholz - National Institute of Neurological Disorders and StrokeMary Kay Floeter - National Institute of Neurological Disorders and StrokeRoy H. Campbell - Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USAFrancesco Landi - Università Cattolica del Sacro CuoreRobert Bowser - Division of Neurology, Barrow Neurological Institute, Phoenix, AZ, USAStefan M. Pulst - University of UtahJohn M. Ravits - University of California San DiegoDaniel J.L. MacGowan - Mount Sinai Beth IsraelJanine Kirby - University of SheffieldErik P. Pioro - Cleveland ClinicRoger Pamphlett - The University of SydneyGlenn Gerhard - Pennsylvania State UniversityTravis L. Dunckley - Translational Genomics Research InstituteChristopher B. Brady - Research and Development Service, Veterans Affairs Boston Healthcare System, Boston, MA, USANeil W. Kowall - Boston UniversityJuan C. Troncoso - Departments of Pathology and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAIsabelle Le Ber - Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, Institut du Cerveau et la Moelle (ICM), Assistance Publique Hôpitaux de Paris (AP-HP) – Hôpital Pitié-Salpêtrière, Paris, FranceKevin Mouzat - Université de MontpellierSerge Lumbroso - Université de MontpellierFreya Kamel - Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC 27709, USALudo Van Den Bosch - KU LeuvenRobert H. Baloh - Cedars-Sinai Medical CenterTim M. Strom - Ludwig-Maximilians-Universität MünchenThomas Meitinger - Institute of Human Genetics, Technische Universität München, Munich, GermanyAleksey Shatunov - Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King’s College London, London SE5 9RS, UKKristel R. Van Eijk - University Medical Center UtrechtMamede de Carvalho - University of LisbonMaarten Kooyman - SURFsara (Netherlands)Bas Middelkoop - University Medical Center UtrechtMatthieu Moisse - KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), B-3000 Leuven, BelgiumRussell L. McLaughlin - Trinity College DublinMichael A. Van Es - University Medical Center UtrechtMarkus Weber - Kantonsspital St. GallenKevin B. Boylan - Mayo Clinic in FloridaMarka Van Blitterswijk - Mayo Clinic in FloridaKaren E. Morrison - Faculty of Medicine, University of Southampton, Southampton, UKA. Nazli Basak - Suna and Inan Kırac Foundation, Neurodegeneration Research Laboratory, Bogazici University, Istanbul, TurkeyJesús S. Mora - ALS (Czechia)Vivian E. Drory - Department of Neurology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, IsraelPamela J. Shaw - Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UKMartin R. Turner - University of OxfordKevin Talbot - University of OxfordOrla Hardiman - Trinity College DublinKelly L. Williams - Macquarie UniversityJennifer A. Fifita - Macquarie UniversityGarth A. Nicholson - Macquarie UniversityIan P. Blair - Centre for MND Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, AustraliaGuy A. Rouleau - McGill UniversityJesús Esteban-Pérez - Centro de Investigación Biomédica en RedAlberto García-Redondo - Centro de Investigación Biomédica en RedAmmar Al-Chalabi - Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King’s College London, London SE5 9RS, UKAhmad Al KheifatAnnelot DekkerMarc GotkineWinston HideAlfredo IacoangeliMatthew KiernanJonathan Mill - University of ExeterMiguel Mitne NetoJesus Mora PardinaStephen NewhouseSusana PintoSara PulitWilliam SprovieroGijs TazelaarMayana ZatzDenis C. BauerNatalie A. TwineEkaterina Rogaeva - Tanz Centre for Research of Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, CanadaLorne Zinman - Division of Neurology, Department of Internal Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, CanadaLyle W. Ostrow - Johns Hopkins UniversityNicholas J. Maragakis - Johns Hopkins UniversityJeffrey D. Rothstein - Johns Hopkins UniversityZachary Simmons - Pennsylvania State UniversityJohnathan Cooper-Knock - University of SheffieldAlexis Brice - Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, Institut du Cerveau et la Moelle (ICM), Assistance Publique Hôpitaux de Paris (AP-HP) – Hôpital Pitié-Salpêtrière, Paris, FranceStephen A. Goutman - University of MichiganEva L. Feldman - University of MichiganSummer B. Gibson - University of UtahFranco Taroni - Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico “Carlo Besta,” Milan 20133, ItalyAntonia Ratti - IRCCS Istituto Auxologico ItalianoCinzia Gellera - Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico “Carlo Besta,” Milan 20133, ItalyProject MinE ALS Sequencing ConsortiumPhilip Van Damme - KU LeuvenWim Robberecht - KU LeuvenPietro Fratta - Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London, UKMario Sabatelli - Pontifícia Universidade Católica de São PauloChristian Lunetta - NEuroMuscular Omnicenter (NEMO), Serena Onlus Foundation, Milan, ItalyAlbert C. Ludolph - Albert Einstein College of MedicinePeter M. Andersen - Umeå UniversityJochen H. Weishaupt - Albert Einstein College of MedicineWilliam Camu - Université de MontpellierJohn Q. Trojanowski - University of PennsylvaniaRobert H. Brown - University of Massachusetts Chan Medical SchoolLeonard H. van den Berg - University Medical Center UtrechtJan H. Veldink - University Medical Center UtrechtMatthew B. Harms - Columbia UniversityJonathan D. Glass - Emory University School of MedicineDavid J. Stone - Genetics and Pharmacogenomics, MRL, Merck & Co., Inc., West Point, PA 19486, USAPentti Tienari - Department of Neurology, Helsinki University Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki FIN-02900, FinlandVincenzo Silani - IRCCS Istituto Auxologico ItalianoAdriano Chiò - University of TurinChristopher E. Shaw - King's College LondonBryan J. Traynor - Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USAJohn E. Landers - University of Massachusetts Chan Medical School
- Publication Details
- Neuron (Cambridge, Mass.), v 97(6), pp 1267-1288
- Publisher
- Elsevier
- Number of pages
- 22
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurology
- Web of Science ID
- WOS:000428235400013
- Scopus ID
- 2-s2.0-85044172835
- Other Identifier
- 991021864310704721
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- Industry collaboration
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- Web of Science research areas
- Neurosciences