Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

E.T. Cirulli, B.N. Lasseigne, S. Petrovski, P.C. Sapp, P.A. Dion, C.S. Leblond, J. Couthouis, Y.-F. Lu, Q. Wang, B.J. Krueger, Z. Ren, J. Keebler, Y. Han, S.E. Levy, B.E. Boone, J.R. Wimbish, L.L. Waite, A.L. Jones, J.P. Carulli, A.G. Day-WilliamsJ.F. Staropoli, W.W. Xin, A. Chesi, A.R. Raphael, D. McKenna-Yasek, J. Cady, J. M. B. Vianney de Jong, K. P. Kenna, B. N. Smith, S. Topp, J. Miller, A. Gkazi, A. Al-Chalabi, L.H. van den Berg, J. Veldink, V. Silani, N. Ticozzi, C. E. Shaw, R. H. Baloh, S. Appel, E. Simpson, C. Lagier-Tourenne, S.M. Pulst, S. Gibson, J. Q. Trojanowski, L. Elman, L. McCluskey, M. Grossman, N.A. Shneider, W. K. Chung, J. M. Ravits, J. D. Glass, K. B. Sims, V.M. Van Deerlin, T. Maniatis, S.D. Hayes, A. Ordureau, S. Swarup, J. Landers, F. Baas, A.S. Allen, R.S. Bedlack, J.W. Harper, A.D. Gitler, G. A. Rouleau, R. Brown, M.B. Harms, G.M. Cooper, T. Harris, R.M. Myers, D.B. Goldstein, K.E. Morrison

Research output: Contribution to journalArticlepeer-review

575 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)1436-1441
Issue number6229
Publication statusPublished - 27 Mar 2015


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