Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.
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 None., 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.
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.