Article Text

PDF
115
DNA REPAIR PATHWAYS MODULATE ONSET IN POLYGLUTAMINE DISEASES
  1. Conceição Bettencourt1,
  2. Davina Hensman Moss2,
  3. Michael Flower2,
  4. Sarah Wiethoff1,
  5. Paola Giunti1,
  6. Alexandra Durr3,
  7. Peter Holmans4,
  8. Henry Houlden1,
  9. Sarah Tabrizi2,
  10. Lesley Jones4
  1. 1 University College London
  2. 2 Institute of Neurology
  3. 3 Sorbonne Universités, UPMC University Paris
  4. 4 Cardiff University

Abstract

Over 30 diseases are caused by expansion of microsatellite sequences; nine by expanded CAG tracts encoding polyglutamines. These include Huntington's disease (HD), several spinocerebellar ataxias (SCAs), and spinal and bulbar muscular atrophy. Longer CAG repeats are associated with earlier age-at-onset (AAO), but studies suggest additional modifying factors. DNA repair pathways were recently associated with HD motor AAO in a GWAS. We aimed to investigate whether the modifying effects of DNA repair gene variants can be extended to other polyglutamine diseases.

We collected an independent cohort of 1462 subjects with HD and polyglutamine SCAs, and genotyped SNPs selected from the most significant hits in the HD study.

In an overall analysis of DNA repair pathways, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs, p=1.43×10−5). Significant associations were also found for HD (p=0.00194), all SCAs (p=0.00107), SCA2 (p=0.0035), SCA6 (p=0.00162). Two SNPs showed individual significant associations. All associations follow the same direction as the HD GWAS.

We show DNA repair genes modify AAO not only in HD, but also in polyglutamine SCAs. This suggests a common pathogenic mechanism for these diseases. Manipulation of DNA repair pathways may offer therapeutic opportunities in multiple diseases.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.