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, FALS Sequencing Consortium

Research output: Contribution to journalArticlepeer-review

732 Scopus citations


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 (US)
Pages (from-to)1436-41
Number of pages6
JournalScience (New York, N.Y.)
Issue number6229
StatePublished - Mar 27 2015


  • Adaptor Proteins, Signal Transducing
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis
  • Autophagy
  • Exome
  • Female
  • Genes
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Middle Aged
  • Protein Binding
  • Protein-Serine-Threonine Kinases
  • Risk
  • Sequence Analysis, DNA
  • Transcription Factor TFIIIA
  • Young Adult


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