Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease

Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.


As a Mendelian neurodegenerative disorder, the genetic risk of Huntington's disease (HD) is conferred entirely by an HTT CAG repeat expansion whose length is the primary determinant of the rate of pathogenesis leading to disease onset. To investigate the pathogenic process that precedes disease, we used genome-wide association (GWA) analysis to identify loci harboring genetic variations that alter the age at neurological onset of HD. A chromosome 15 locus displays two independent effects that accelerate or delay onset by 6.1 years and 1.4 years, respectively, whereas a chromosome 8 locus hastens onset by 1.6 years. Association at MLH1 and pathway analysis of the full GWA results support a role for DNA handling and repair mechanisms in altering the course of HD. Our findings demonstrate that HD disease modification in humans occurs in nature and offer a genetic route to identifying in-human validated therapeutic targets in this and other Mendelian disorders.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Age of Onset
  • Chromosomes, Human, Pair 15
  • Chromosomes, Human, Pair 8
  • Genes, Modifier*
  • Genome-Wide Association Study*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / epidemiology
  • Huntington Disease / genetics*
  • Huntington Disease / physiopathology
  • MutL Protein Homolog 1
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / metabolism
  • Trinucleotide Repeats


  • Adaptor Proteins, Signal Transducing
  • HTT protein, human
  • Huntingtin Protein
  • MLH1 protein, human
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • MutL Protein Homolog 1