Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Elizabeth T. Cirulli(Duke University), Brittany N. Lasseigne(HudsonAlpha Institute for Biotechnology), Slavé Petrovski(Columbia University), Peter C. Sapp(University of Massachusetts Chan Medical School), Patrick A. Dion(Montreal Neurological Institute and Hospital), Claire S. Leblond(Montreal Neurological Institute and Hospital), Julien Couthouis(Stanford University), Yifan Lu(Columbia University), Quanli Wang(Columbia University), Brian J. Krueger(Columbia University), Zhong Ren(Columbia University), Jonathan Keebler(Duke University), Yujun Han(Duke University), Shawn Levy(HudsonAlpha Institute for Biotechnology), Braden Boone(HudsonAlpha Institute for Biotechnology), Jack R. Wimbish(HudsonAlpha Institute for Biotechnology), Lindsay L. Waite(HudsonAlpha Institute for Biotechnology), Angela L. Jones(HudsonAlpha Institute for Biotechnology), John P. Carulli(Biogen (United States)), Kelly L. Williams(Biogen (United States)), John F. Staropoli(Biogen (United States)), Winnie Xin(Harvard University Press), Alessandra Chesi(Stanford University), Alya R. Raphael(Stanford University), Diane McKenna‐Yasek(University of Massachusetts Chan Medical School), Janet Cady(Washington University in St. Louis), J.M.B.V. de Jong(Amsterdam UMC Location University of Amsterdam), Kevin P. Kenna(Trinity College Dublin), Bradley Smith(King's College London), Simon Topp(King's College London), Jack W. Miller(King's College London), Soragia Athina Gkazi(King's College London), Ammar Al‐Chalabi(King's College London), Leonard H. van den Berg(University Medical Center Utrecht), Jan H. Veldink(University Medical Center Utrecht), Vincenzo Silani(IRCCS Istituto Auxologico Italiano), Nicola Ticozzi(IRCCS Istituto Auxologico Italiano), Christopher E. Shaw(King's College London), Robert H. Baloh(Cedars-Sinai Medical Center), Stanley H. Appel(Cornell University), Ericka Simpson(Cornell University), Clotilde Lagier‐Tourenne(Ludwig Cancer Research), Stefan M. Pulst(University of Utah), Summer Gibson(University of Utah), John Q. Trojanowski(University of Pennsylvania), Lauren Elman(University of Pennsylvania), Leo McCluskey(University of Pennsylvania), Murray Grossman(University of Pennsylvania), Neil A. Shneider(Columbia University), Wendy K. Chung(Columbia University), John Ravits(University of California San Diego), Jonathan D. Glass(Emory University), Katherine B. Sims(Harvard University Press), Vivianna M. Van Deerlin(University of Pennsylvania), Tom Maniatis(Columbia University), Sebastian Hayes(Biogen (United States)), Alban Ordureau(Harvard University), Sharan Swarup(Harvard University), John E. Landers(University of Massachusetts Chan Medical School), Frank Baas(Amsterdam UMC Location University of Amsterdam), Andrew S. Allen(Duke University), Richard Bedlack(Durham VA Medical Center), J. Wade Harper(Harvard University), Aaron D. Gitler(Stanford University), Guy A. Rouleau(Montreal Neurological Institute and Hospital), Robert H. Brown(University of Massachusetts Chan Medical School), Matthew B. Harms(Washington University in St. Louis), Gregory M. Cooper(HudsonAlpha Institute for Biotechnology), Tim Harris(Biogen (United States)), R Myers(HudsonAlpha Institute for Biotechnology), David B. Goldstein(Columbia University)
Science
February 21, 2015
10.1126/science.aaa3650
Cited by 980Open Access
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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.

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