Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Cirulli, ET; Lasseigne, BN; Petrovski, S; Sapp, PC; Dion, PA; Leblond, CS; Couthouis, J; Lu, Y-F; Wang, Q; Krueger, BJ; Ren, Z; Keebler, J; Han, Y; Levy, SE; Boone, BE; Wimbish, JR; Waite, LL; Jones, AL; Carulli, JP; Day-Williams, AG; Staropoli, JF; Xin, WW; Chesi, A; Raphael, AR; McKenna-Yasek, D; Cady, J; Vianney de Jong, JMB; Kenna, KP; Smith, BN; Topp, S; Miller, J; Gkazi, A; FALS Sequencing Consortium, ; Al-Chalabi, A; van den Berg, LH; Veldink, J; Silani, V; Ticozzi, N; Shaw, CE; Baloh, RH; Appel, S; Simpson, E; Lagier-Tourenne, C; Pulst, SM; Gibson, S; Trojanowski, JQ; Elman, L; McCluskey, L; Grossman, M; Shneider, NA; Chung, WK; Ravits, JM; Glass, JD; Sims, KB; Van Deerlin, VM; Maniatis, T; Hayes, SD; Ordureau, A; Swarup, S; Landers, J; Baas, F; Allen, AS; Bedlack, RS; Harper, JW; Gitler, AD; Rouleau, GA; Brown, R; Harms, MB; Cooper, GM; Harris, T; Myers, RM; Goldstein, DB

Published Date

  • March 27, 2015

Published In

Volume / Issue

  • 347 / 6229

Start / End Page

  • 1436 - 1441

PubMed ID

  • 25700176

Pubmed Central ID

  • PMC4437632

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

Digital Object Identifier (DOI)

  • 10.1126/science.aaa3650


  • eng

Conference Location

  • United States