Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Franco Taroni; Antonia Ratti; Cinzia Gellera; Philip van Damme; Wim Robberecht; Pietro Fratta; Mario Sabatelli; Christian Lunetta; Albert C. Ludolph; Peter M. Andersen; Jochen H. Weishaupt; William Camu; John Q. Trojanowski; Vivianna M. van Deerlin; Robert H. Brown; Leonard H. van Den Berg; Jan H. Veldink; Matthew B. Harms; Jonathan D. Glass; David J. Stone; Pentti Tienari; Vincenzo Silani; Adriano Chiò; Christopher E. Shaw; Bryan J. Traynor; John E. Landers; Aude Nicolas; Kevin P. Kenna; Alan E. Renton; Nicola Ticozzi; Faraz Faghri; Ruth Chia; Janice A. Dominov; Brendan J. Kenna; Mike A. Nalls; Pamela Keagle; Alberto M. Rivera; Wouter Van Rheenen; Natalie A. Murphy; Joke J. F. A. Van Vugt; Joshua T. Geiger; Rick A. van Der Spek; Hannah A. Pliner; Null Shankaracharya; Bradley N. Smith; Giuseppe Marangi; Simon D. Topp; Yevgeniya Abramzon; Athina Soragia Gkazi; John D. Eicher; Aoife Kenna; Italsgen Consortium; Gabriele Mora; Andrea Calvo; Letizia Mazzini; Nilo Riva; Jessica Mandrioli; Claudia Caponnetto; Stefania Battistini; Paolo Volanti; Vincenzo La Bella; Francesca L. Conforti; Giuseppe Borghero; Sonia Messina; Isabella L. Simone; Francesca Trojsi; Fabrizio Salvi; Francesco O. Logullo; Sandra d'Alfonso; Lucia Corrado; Margherita Capasso; Luigi Ferrucci; Genomic Translation For Als Care (gtac) Consortium; Cristiane de Araujo Martins Moreno; Sitharthan Kamalakaran; David B. Goldstein; Als Sequencing Consortium; Aaron D. Gitler; Tim Harris; Richard M. Myers; Nygc Als Consortium; Hemali Phatnani; Rajeeva Lochan Musunuri; Uday Shankar Evani; Avinash Abhyankar; Michael C. Zody; Answer Als Foundation; Julia Kaye; Steven Finkbeiner; Stacia K. Wyman; Alex Lenail; Leandro Lima; Ernest Fraenkel; Clive N. Svendsen; Leslie M. Thompson; Jennifer E. van Eyk; James D. Berry; Timothy M. Miller; Stephen J. Kolb; Merit Cudkowicz; Emily Baxi; Clinical Research In Als; Related Disorders For Therapeutic Development (create) Consortium; Michael Benatar; J. Paul Taylor; Evadnie Rampersaud; Gang Wu; Joanne Wuu; Slagen Consortium; Giuseppe Lauria; Federico Verde; Isabella Fogh; Cinzia Tiloca; Giacomo P. Comi; Gianni Sorarù; Cristina Cereda; French Als Consortium; Philippe Corcia; Hannu Laaksovirta; Liisa Myllykangas; Lilja Jansson; Miko Valori; John Ealing; Hisham Hamdalla; Sara Rollinson; Stuart Pickering-Brown; Richard W. Orrell; Katie C. Sidle; Andrea Malaspina; John Hardy; Andrew B. Singleton; Janel O. Johnson; Sampath Arepalli; Peter C. Sapp; Diane Mckenna-Yasek; Meraida Polak; Seneshaw Asress; Safa Al-Sarraj; Andrew King; Claire Troakes; Caroline Vance; Jacqueline De Belleroche; Frank Baas; Anneloor L. M. A. ten Asbroek; José Luis Muñoz-Blanco; Dena G. Hernandez; Jinhui Ding; J. Raphael Gibbs; Sonja W. Scholz; Mary Kay Floeter; Roy H. Campbell; Francesco Landi; Robert Bowser; Stefan M. Pulst; John M. Ravits; Daniel J. L. Macgowan; Janine Kirby; Erik P. Pioro; Roger Pamphlett; James Broach; Glenn Gerhard; Travis L. Dunckley; Christopher B. Brady; Neil W. Kowall; Juan C. Troncoso; Isabelle Le Ber; Kevin Mouzat; Serge Lumbroso; Terry D. Heiman-Patterson; Freya Kamel; Ludo van den Bosch; Robert H. Baloh; Tim M. Strom; Thomas Meitinger; Aleksey Shatunov; Kristel R. van Eijk; Mamede De Carvalho; Maarten Kooyman; Bas Middelkoop; Matthieu Moisse; Russell L. Mclaughlin; Michael A. van Es; Markus Weber; Kevin B. Boylan; Marka van Blitterswijk; Rosa Rademakers; Karen E. Morrison; A. Nazli Basak; Jesús S. Mora; Vivian E. Drory; Pamela J. Shaw; Martin R. Turner; Kevin Talbot; Orla Hardiman; Kelly L. Williams; Jennifer A. Fifita; Garth A. Nicholson; Ian P. Blair; Guy A. Rouleau; Jesús Esteban-Pérez; Alberto Garc'Ia-Redondo; Ammar Al-Chalabi; Project Mine Als Sequencing Consortium; Ekaterina Rogaeva; Lorne Zinman; Lyle W. Ostrow; Nicholas J. Maragakis; Jeffrey D. Rothstein; Zachary Simmons; Johnathan Cooper-Knock; Alexis Brice; Stephen A. Goutman; Eva L. Feldman; Summer B. Gibson

doi:10.1016/j.neuron.2018.02.027

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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Journal article

Open access

Peer reviewed

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, …

Neuron, Vol.97(6), pp.1268--1283.e6

2018

DOI: https://doi.org/10.1016/j.neuron.2018.02.027

PMCID: PMC5867896

PMID: 29566793

Abstract

Amyotrophic Lateral Sclerosis

Amino Acid Sequence

GWAS

axonal transport

ALS

Humans

Female

Male

Adult

Aged

Middle Aged

80 and over

Cohort Studies

Young Adult

Genome-Wide Association Study

cargo

KIF5A

Kinesin

Loss of Function Mutation

WES

WGS

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.

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Title: Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
Creators - without role: Franco Taroni
Antonia Ratti
Cinzia Gellera
Philip van Damme - KU Leuven
Wim Robberecht - KU Leuven
Pietro Fratta
Mario Sabatelli - Università Cattolica del Sacro Cuore
Christian Lunetta
Albert C. Ludolph - Universität Ulm
Peter M. Andersen - Umeå University
Jochen H. Weishaupt - Universität Ulm
William Camu - University Medical Center Utrecht
John Q. Trojanowski - University of Pennsylvania
Vivianna M. van Deerlin
Robert H. Brown - University of Massachusetts Chan Medical School
Leonard H. van Den Berg
Jan H. Veldink - University Medical Center Utrecht
Matthew B. Harms
Jonathan D. Glass - Emory University
David J. Stone - National Institute on Aging
Pentti Tienari - University of Helsinki
Vincenzo Silani
Adriano Chiò - University of Turin
Christopher E. Shaw - King's College London
Bryan J. Traynor - National Institute on Aging
John E. Landers - University of Massachusetts Chan Medical School
Aude Nicolas - National Institute on Aging
Kevin P. Kenna - University of Massachusetts Chan Medical School
Alan E. Renton - National Institute on Aging
Nicola Ticozzi - IRCCS Istituto Auxologico Italiano
Faraz Faghri - University of Illinois Urbana-Champaign
Ruth Chia - National Institute on Aging
Janice A. Dominov - University of Massachusetts Chan Medical School
Brendan J. Kenna - University of Massachusetts Chan Medical School
Mike A. Nalls - Data Tecnica International
Pamela Keagle - University of Massachusetts Chan Medical School
Alberto M. Rivera - National Institute on Aging
Wouter Van Rheenen
Natalie A. Murphy - National Institute on Aging
Joke J. F. A. Van Vugt
Joshua T. Geiger - National Institute of Neurological Disorders and Stroke
Rick A. van Der Spek
Hannah A. Pliner - National Institute on Aging
Null Shankaracharya
Bradley N. Smith - King's College London
Giuseppe Marangi
Simon D. Topp - King's College London
Yevgeniya Abramzon - National Institute on Aging
Athina Soragia Gkazi
John D. Eicher - Merck & Co., Inc., Rahway, NJ, USA
Aoife Kenna - University of Massachusetts Chan Medical School
Italsgen Consortium
Gabriele Mora - Fondazione Salvatore Maugeri
Andrea Calvo - University of Turin
Letizia Mazzini
Nilo Riva - San Raffaele University of Rome
Jessica Mandrioli - Azienda Unita' Sanitaria Locale Di Modena
Claudia Caponnetto - Ospedale Policlinico San Martino
Stefania Battistini - University of Siena
Paolo Volanti - Fondazione Salvatore Maugeri
Vincenzo La Bella - University of Palermo
Francesca L. Conforti - Institute of Neurological Sciences
Giuseppe Borghero
Sonia Messina - University of Messina
Isabella L. Simone - University of Bari Aldo Moro
Francesca Trojsi - University of Campania "Luigi Vanvitelli"
Fabrizio Salvi
Francesco O. Logullo
Sandra d'Alfonso
Lucia Corrado
Margherita Capasso - University of Chieti-Pescara
Luigi Ferrucci - National Institute on Aging
Genomic Translation For Als Care (gtac) Consortium
Cristiane de Araujo Martins Moreno
Sitharthan Kamalakaran - Columbia University
David B. Goldstein - Columbia University
Als Sequencing Consortium
Aaron D. Gitler - Stanford University
Tim Harris
Richard M. Myers - HudsonAlpha Institute for Biotechnology
Nygc Als Consortium
Hemali Phatnani - New York Genome Center
Rajeeva Lochan Musunuri - New York Genome Center
Uday Shankar Evani - New York Genome Center
Avinash Abhyankar - New York Genome Center
Michael C. Zody - New York Genome Center
Answer Als Foundation
Julia Kaye - Gladstone Institutes
Steven Finkbeiner - Gladstone Institutes
Stacia K. Wyman - Gladstone Institutes
Alex Lenail - Massachusetts Institute of Technology
Leandro Lima - Laboratoire de Biométrie et Biologie Evolutive
Ernest Fraenkel - Massachusetts Institute of Technology
Clive N. Svendsen - Cedars-Sinai Medical Center
Leslie M. Thompson - University of California, Irvine
Jennifer E. van Eyk - Cedars-Sinai Medical Center
James D. Berry - Massachusetts General Hospital
Timothy M. Miller
Stephen J. Kolb - The Ohio State University Wexner Medical Center
Merit Cudkowicz - Massachusetts General Hospital
Emily Baxi - Johns Hopkins University
Clinical Research In Als
Related Disorders For Therapeutic Development (create) Consortium
Michael Benatar - University of Miami
J. Paul Taylor - St. Jude Children's Research Hospital
Evadnie Rampersaud - St. Jude Children's Research Hospital
Gang Wu - St. Jude Children's Research Hospital
Joanne Wuu - University of Miami
Slagen Consortium
Giuseppe Lauria - Fondazione IRCCS Istituto Neurologico Carlo Besta
Federico Verde - IRCCS Istituto Auxologico Italiano
Isabella Fogh - IRCCS Istituto Auxologico Italiano
Cinzia Tiloca - IRCCS Istituto Auxologico Italiano
Giacomo P. Comi - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Gianni Sorarù - University of Padua
Cristina Cereda - Center for Genomic Science
French Als Consortium
Philippe Corcia - Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours]
Hannu Laaksovirta - Helsinki University Hospital
Liisa Myllykangas - Helsinki University Hospital
Lilja Jansson - Helsinki University Hospital
Miko Valori - Helsinki University Hospital
John Ealing - Salford Royal NHS Foundation Trust
Hisham Hamdalla - Salford Royal NHS Foundation Trust
Sara Rollinson - University of Manchester
Stuart Pickering-Brown - University of Manchester
Richard W. Orrell - University College London
Katie C. Sidle - University College London
Andrea Malaspina - Queen Mary University of London
John Hardy - University College London
Andrew B. Singleton - National Institute on Aging
Janel O. Johnson - National Institute on Aging
Sampath Arepalli - National Institute on Aging
Peter C. Sapp - University of Massachusetts Chan Medical School
Diane Mckenna-Yasek
Meraida Polak - Emory University
Seneshaw Asress
Safa Al-Sarraj - King's College London
Andrew King - King's College London
Claire Troakes - King's College London
Caroline Vance - King's College London
Jacqueline De Belleroche
Frank Baas - SURFsara (Netherlands)
Anneloor L. M. A. ten Asbroek
José Luis Muñoz-Blanco - Hospital General Universitario Gregorio Marañón
Dena G. Hernandez - National Institute on Aging
Jinhui Ding - National Institute on Aging
J. Raphael Gibbs - National Institute on Aging
Sonja W. Scholz - National Institute of Neurological Disorders and Stroke
Mary Kay Floeter - National Institute of Neurological Disorders and Stroke
Roy H. Campbell - University of Illinois Urbana-Champaign
Francesco Landi - Università Cattolica del Sacro Cuore
Robert Bowser - Barrow Neurological Institute
Stefan M. Pulst
John M. Ravits - University of California, San Diego
Daniel J. L. Macgowan - Mount Sinai Beth Israel
Janine Kirby - University of Sheffield
Erik P. Pioro - The Neurological Institute
Roger Pamphlett - University of Sydney
James Broach - Princeton University
Glenn Gerhard - Penn State Milton S. Hershey Medical Center
Travis L. Dunckley - Translational Genomics Research Institute
Christopher B. Brady - Boston University
Neil W. Kowall - VA Boston Healthcare System
Juan C. Troncoso - Johns Hopkins Medicine
Isabelle Le Ber - Sorbonne Université
Kevin Mouzat - Institute for Neurosciences of Montpellier
Serge Lumbroso - Laboratoire de Biochimie
Terry D. Heiman-Patterson - Drexel University
Freya Kamel - National Institute of Environmental Health Sciences
Ludo van den Bosch - KU Leuven
Robert H. Baloh - Johns Hopkins University
Tim M. Strom - Helmholtz Zentrum München
Thomas Meitinger - Technical University of Munich
Aleksey Shatunov
Kristel R. van Eijk - University Medical Center Utrecht
Mamede De Carvalho
Maarten Kooyman
Bas Middelkoop - Fondazione IRCCS Istituto Neurologico Carlo Besta
Matthieu Moisse - KU Leuven
Russell L. Mclaughlin - Trinity College Dublin
Michael A. van Es - University Medical Center Utrecht
Markus Weber - KU Leuven
Kevin B. Boylan
Marka van Blitterswijk - Mayo Clinic in Florida
Rosa Rademakers - Centro Clinico Nemo
Karen E. Morrison - University of Southampton
A. Nazli Basak
Jesús S. Mora - Hospital Universitario San Rafael
Vivian E. Drory - Tel Aviv Sourasky Medical Center
Pamela J. Shaw - Emory University
Martin R. Turner - University of Oxford
Kevin Talbot - University of Oxford
Orla Hardiman - Trinity College Dublin
Kelly L. Williams
Jennifer A. Fifita - Macquarie University
Garth A. Nicholson - Anzac Research Institute
Ian P. Blair
Guy A. Rouleau
Jesús Esteban-Pérez - Centro de Investigación Biomédica en Red
Alberto Garc'Ia-Redondo
Ammar Al-Chalabi - Maurice Wohl Clinical Neuroscience Institut
Project Mine Als Sequencing Consortium
Ekaterina Rogaeva - University of Toronto
Lorne Zinman - Marche Polytechnic University
Lyle W. Ostrow
Nicholas J. Maragakis - Johns Hopkins University
Jeffrey D. Rothstein
Zachary Simmons
Johnathan Cooper-Knock - University of Cagliari
Alexis Brice - Sorbonne Université
Stephen A. Goutman - University of Michigan–Ann Arbor
Eva L. Feldman - University of Michigan–Ann Arbor
Summer B. Gibson - University of Utah
Publication Details: Neuron, Vol.97(6), pp.1268--1283.e6
Identifiers: 9938645709311
Academic Unit: Institut des Neurosciences de Montpellier - INM
Language: English
Resource Type: Journal article
Local Fields: hal-02345947