Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Elizabeth T. Cirulli, Brittany N. Lasseigne, Slavé Petrovski, Peter C. Sapp, Patrick A. Dion, Claire S. Leblond, Julien Couthouis, Yi Fan Lu, Quanli Wang, Brian J. Krueger, Zhong Ren, Jonathan Keebler, Yujun Han, Shawn E. Levy, Braden E. Boone, Jack R. Wimbish, Lindsay L. Waite, Angela L. Jones, John P. Carulli, Aaron G. Day-WilliamsJohn F. Staropoli, Winnie W. Xin, Alessandra Chesi, Alya R. Raphael, Diane McKenna-Yasek, Janet Cady, J. M B Vianney De Jong, Kevin P. Kenna, Bradley N. Smith, Simon Topp, Jack Miller, Athina Gkazi, Ammar Al-Chalabi, Leonard H. Van Den Berg, Jan Veldink, Vincenzo Silani, Nicola Ticozzi, Christopher E. Shaw, Robert H. Baloh, Stanley Appel, Ericka Simpson, Clotilde Lagier-Tourenne, Stefan M. Pulst, Summer Gibson, John Q. Trojanowski, Lauren Elman, Leo McCluskey, Murray Grossman, Neil A. Shneider, Wendy K. Chung, John M. Ravits, Jonathan D. Glass, Katherine B. Sims, Vivianna M. Van Deerlin, Tom Maniatis, Sebastian D. Hayes, Alban Ordureau, Sharan Swarup, John Landers, Frank Baas, Andrew S. Allen, Richard S. Bedlack, J. Wade Harper, Aaron D. Gitler, Guy A. Rouleau, Robert Brown, Matthew B. Harms, Gregory M. Cooper, Tim Harris, Richard M. Myers, David B. Goldstein

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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.

Original languageEnglish
Pages (from-to)1436-1441
Number of pages6
JournalScience
Volume347
Issue number6229
DOIs
Publication statusPublished - Mar 27 2015

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ASJC Scopus subject areas

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Cite this

Cirulli, E. T., Lasseigne, B. N., Petrovski, S., Sapp, P. C., Dion, P. A., Leblond, C. S., Couthouis, J., Lu, Y. F., Wang, Q., Krueger, B. J., Ren, Z., Keebler, J., Han, Y., Levy, S. E., Boone, B. E., Wimbish, J. R., Waite, L. L., Jones, A. L., Carulli, J. P., ... Goldstein, D. B. (2015). Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science, 347(6229), 1436-1441. https://doi.org/10.1126/science.aaa3650