Exome Sequencing in Amyotrophic Lateral Sclerosis Identifies Risk Genes and Pathways

Science. 2015 Mar 27;347(6229):1436-41. doi: 10.1126/science.aaa3650. Epub 2015 Feb 19.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / genetics*
  • Autophagy / genetics*
  • Exome / genetics*
  • Female
  • Genes
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Middle Aged
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Risk
  • Sequence Analysis, DNA
  • Sequestosome-1 Protein
  • Transcription Factor TFIIIA / genetics
  • Transcription Factor TFIIIA / metabolism
  • Young Adult

Substances

  • Adaptor Proteins, Signal Transducing
  • OPTN protein, human
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Transcription Factor TFIIIA
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human