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

Neuron
Authors
Aude Nicolas
Kevin Kenna
Alan Renton
Nicola Ticozzi
Faraz Faghri
Ruth Chia
Janice Dominov
Brendan Kenna
Mike Nalls
Pamela Keagle
Alberto Rivera
Wouter Van Rheenen
Natalie Murphy
Joke van Vugt
Joshua Geiger
Rick Van der Spek
Hannah Pliner
Bradley Smith
Giuseppe Marangi
Simon Topp
Yevgeniya Abramzon
Athina Gkazi
John 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 Conforti
Giuseppe Borghero
Sonia Messina
Isabella Simone
Francesca Trojsi
Fabrizio Salvi
Francesco Logullo
Sandra D'Alfonso
Lucia Corrado
Margherita Capasso
Luigi Ferrucci
Genomic Translation for ALS Care (GTAC) Consortium
Cristiane Moreno
Sitharthan Kamalakaran
David Goldstein
ALS Sequencing Consortium
Aaron Gitler
Tim Harris
Richard Myers
NYGC ALS Consortium
Hemali Phatnani
Rajeeva Musunuri
Uday Evani
Avinash Abhyankar
Michael Zody
Answer ALS Foundation
Julia Kaye
Steven Finkbeiner
Stacia Wyman
Alex Lenail
Leandro Lima
Ernest Fraenkel
Clive Svendsen
Leslie Thompson
Jennifer Van Eyk
James Berry
Timothy Miller
Stephen Kolb
Merit Cudkowicz
Emily Baxi
Clinical Research in ALS and 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 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 Orrell
Katie Sidle
Andrea Malaspina
John Hardy
Andrew Singleton
Janel Johnson
Sampath Arepalli
Peter Sapp
Diane McKenna-Yasek
Meraida Polak
Seneshaw Asress
Safa Al-Sarraj
Andrew King
Claire Troakes
Caroline Vance
Jacqueline De Belleroche
Frank Baas
Anneloor Asbroek
José Muñoz-Blanco
Dena Hernandez
Jinhui Ding
J Raphael Gibbs
Sonja Scholz
Mary Floeter
Roy Campbell
Francesco Landi
Robert Bowser
Stefan Pulst
John Ravits
Daniel MacGowan
Janine Kirby
Erik Pioro
Roger Pamphlett
James Broach
Glenn Gerhard
Travis Dunckley
Christopher Brady
Neil Kowall
Juan Troncoso
Isabelle Le Ber
Kevin Mouzat
Serge Lumbroso
Terry Heiman-Patterson
Freya Kamel
Ludo Van Den Bosch
Robert Baloh
Tim Strom
Thomas Meitinger
Aleksey Shatunov
Kristel van Eijk
Mamede de Carvalho
Maarten Kooyman
Bas Middelkoop
Matthieu Moisse
Russell McLaughlin
Michael van Es
Markus Weber
Kevin Boylan
Marka Van Blitterswijk
Rosa Rademakers
Karen Morrison
A Nazli Basak
Jesus Mora
Vivian Drory
Pamela Shaw
Martin Turner
Kevin Talbot
Orla Hardiman
Kelly Williams
Jennifer Fifita
Garth Nicholson
Ian Blair
Guy Rouleau
Jesús Esteban-Pérez
Alberto García-Redondo
Ammar Al-Chalabi
Project MinE ALS Sequencing Consortium
Ekaterina Rogaeva
Lorne Zinman
Lyle Ostrow
Nicholas Maragakis
Jeffrey Rothstein
Zachary Simmons
Johnathan Cooper-Knock
Alexis Brice
Stephen Goutman
Eva Feldman
Summer Gibson
Franco Taroni
Antonia Ratti
Cinzia Gellera
Philip Van Damme
Wim Robberecht
Pietro Fratta
Mario Sabatelli
Christian Lunetta
Albert Ludolph
Peter Andersen
Jochen Weishaupt
William Camu
John Trojanowski
Vivianna Van Deerlin
Robert Brown
Leonard Van den Berg
Jan Veldink
Matthew Harms
Jonathan Glass
David Stone
Pentti Tienari
Vincenzo Silani
Adriano Chio
Christopher Shaw
Bryan Traynor
John Landers
Keywords
Female
Humans
Male
Adult
Aged
Middle Aged
Cohort Studies
Amino Acid Sequence
Genome-Wide Association Study
Young Adult
Aged, 80 and over
Amyotrophic Lateral Sclerosis
Kinesin
Loss of Function Mutation
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.
Year of Publication
2018
Journal
Neuron
Volume
97
Issue
6
Pages
1268-1283.e6
Date Published
2018 03 21
ISSN
1097-4199
DOI
10.1016/j.neuron.2018.02.027
PubMed ID
29566793
PubMed Central ID
PMC5867896
Links
Grant list
ZIA AG000933-03 / ImNIH / Intramural NIH HHS / United States
G0600974 / MRC_ / Medical Research Council / United Kingdom
TURNER/JAN13/944-795 / MNDA_ / Motor Neurone Disease Association / United Kingdom
MALASPINA/APR13/817-791 / MNDA_ / Motor Neurone Disease Association / United Kingdom
SHAW/APR15/933-794 / MNDA_ / Motor Neurone Disease Association / United Kingdom
G0900688 / MRC_ / Medical Research Council / United Kingdom
MR/L016397/1 / MRC_ / Medical Research Council / United Kingdom
SHAW/NOV14/985-797 / MNDA_ / Motor Neurone Disease Association / United Kingdom
K25 HL121295 / HL / NHLBI NIH HHS / United States
U54 NS091046 / NS / NINDS NIH HHS / United States
MR/K01014X/1 / MRC_ / Medical Research Council / United Kingdom
ALCHALABI-DOBSON/APR14/829-791 / MNDA_ / Motor Neurone Disease Association / United Kingdom
P50 AG005146 / AG / NIA NIH HHS / United States
MR/L501529/1 / MRC_ / Medical Research Council / United Kingdom
P01 AG017586 / AG / NIA NIH HHS / United States
R56 NS061867 / NS / NINDS NIH HHS / United States
U54 NS092091 / NS / NINDS NIH HHS / United States
R35 NS097261 / NS / NINDS NIH HHS / United States
R01 MD009164 / MD / NIMHD NIH HHS / United States
R01 NS061867 / NS / NINDS NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
I01 BX002466 / BX / BLRD VA / United States
MR/M008606/1 / MRC_ / Medical Research Council / United Kingdom
R01 NS073873 / NS / NINDS NIH HHS / United States
MCLAUGHLIN/OCT15/957-799 / MNDA_ / Motor Neurone Disease Association / United Kingdom
MR/L021803/1 / MRC_ / Medical Research Council / United Kingdom
K23 ES027221 / ES / NIEHS NIH HHS / United States
FRATTA/JAN15/946-795 / MNDA_ / Motor Neurone Disease Association / United Kingdom
G0500289 / MRC_ / Medical Research Council / United Kingdom
Z01 AG000949 / ImNIH / Intramural NIH HHS / United States
SMITH/APR16/847-791 / MNDA_ / Motor Neurone Disease Association / United Kingdom
MC_PC_17115 / MRC_ / Medical Research Council / United Kingdom
P01 NS084974 / NS / NINDS NIH HHS / United States
MR/R024804/1 / MRC_ / Medical Research Council / United Kingdom
WT_ / Wellcome Trust / United Kingdom
SMITH/OCT16/888-792 / MNDA_ / Motor Neurone Disease Association / United Kingdom

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