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, Claire Troakes

Research output: Contribution to journalArticlepeer-review

663 Citations (Scopus)


Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. Here we report the results of a moderate-scale sequencing study aimed at identifying new genes contributing to predisposition for ALS. We performed whole exome sequencing of 2,874 ALS patients and compared them to 6,405 controls. Several known ALS genes were found to be associated, and the non-canonical IκB kinase family TANK-Binding Kinase 1 (TBK1) 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
Issue number6229
Early online date27 Mar 2015
Publication statusPublished - 27 Mar 2015


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