CAG Repeat Not Polyglutamine Length Determines Timing of Huntington's Disease Onset

Cell. 2019 Aug 8;178(4):887-900.e14. doi: 10.1016/j.cell.2019.06.036.


Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin's polyglutamine segment, dictates the rate at which Huntington's disease (HD) develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question the fundamental premise that polyglutamine length determines the rate of pathogenesis in the "polyglutamine disorders."

Keywords: CAG repeat; DNA maintenance; DNA repair; Huntington’s disease; age at onset; disease modification; genetic modifier; polyglutamine disease; somatic DNA expansion; trinucleotide repeat.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Alleles
  • Base Sequence / genetics
  • Female
  • Genetic Loci
  • Genome-Wide Association Study
  • Haplotypes / genetics
  • Humans
  • Huntingtin Protein / genetics*
  • Huntington Disease / genetics*
  • Male
  • Middle Aged
  • Peptides / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Trinucleotide Repeat Expansion / genetics*
  • Young Adult


  • HTT protein, human
  • Huntingtin Protein
  • Peptides
  • polyglutamine

Associated data

  • Dryad/10.5061/dryad.5d4s2r8