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B48 DNA repair pathways as a common genetic mechanism modulating the age at onset in polyglutamine diseases
  1. Conceição Bettencourt¥,1,2,
  2. Davina Hensman Moss¥,3,
  3. Michael Flower¥,3,
  4. Sarah Wiethoff¥,1,4,
  5. Alexis Brice5,6,
  6. Cyril Goizet7,8,
  7. Giovanni Stevanin5,9,
  8. Georgios Koutsis10,
  9. Georgia Karadima10,
  10. Marios Panas10,
  11. Petra Yescas-Gómez11,
  12. Lizbeth Esmeralda García-Velázquez11,
  13. María Elisa Alonso-Vilatela11,
  14. Manuela Lima12,13,14,
  15. Mafalda Raposo12,13,14,
  16. Bryan Traynor15,
  17. Mary Sweeney16,
  18. Nicholas Wood1,
  19. Paola Giunti1,17,
  20. Alexandra Durr5,6,
  21. for the French SPATAX network,
  22. Peter Holmans18,
  23. Henry Houlden§,1,16,
  24. Sarah J Tabrizi3,
  25. Lesley Jones§,18
  1. 1Department of Molecular Neuroscience, Institute of Neurology, University College London, London , UK
  2. 2Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK
  3. 3Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
  4. 4Centre for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany
  5. 5Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Paris, France
  6. 6APHP, Department of Genetics, University Hospital Pitié-Salpêtrière, Paris, France
  7. 7Univ. Bordeaux, Laboratoire Maladies Rares: Génétique et Métabolisme, INSERM1211, Bordeaux, France
  8. 8CHU Pellegrin, Service de Génétique Médicale, Bordeaux, France
  9. 9Ecole Pratique des Hautes Etudes, Paris, France
  10. 10Neurogenetics Unit, 1st Department of Neurology, University of Athens Medical School, Eginition Hospital, Athens, Greece
  11. 11Neurogenetics Department. National Institute of Neurology and Neurosurgery, “Manuel Velasco Suárez”, Mexico City, Mexico
  12. 12Department of Biology, University of the Azores, Ponta Delgada, Portugal
  13. 13Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
  14. 14Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal
  15. 15Laboratory of Neurogenetics, National Institute of Ageing, NIH, Bethesda, MD, USA
  16. 16Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, UK
  17. 17Ataxia Centre, Institute of Neurology, University College London, London,UK
  18. 18MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
  19. ¥These authors contributed equally to this work
  20. §These authors supervised this work


Background Over 30 human diseases are caused by expansion of unstable microsatellite sequences. Nine of these are caused by expanded CAG tracts encoding polyglutamines in different genes. This subgroup of diseases, usually referred to as the polyglutamine diseases which include Huntington’s disease (HD), several spinocerebellar ataxias (SCAs), and spinal and bulbar muscular atrophy, are amongst the commonest hereditary neurodegenerative diseases. Longer CAG repeat tracts are associated with earlier ages at onset (AAO), but this does not account for all the variance, suggesting the existence of additional modifying factors. DNA repair pathways have been recently associated with the HD motor AAO in a recent HD GWAS. We therefore aimed to confirm the association between HD motor AAO and DNA repair pathways; and to investigate whether these modifying effects of variants in DNA repair genes can be extended to other polyglutamine diseases.

Methods 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.

Results In an overall analysis of DNA repair pathway, we found the most significant association with AAO 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), and SCA6 (p = 0.00162). Testing individual SNPs, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10−5) and all SCAs (p = 2.22 × 10−4), and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10−5). All these associations follow the same direction as in the HD GWAS.

Conclusions We show that DNA repair genes significantly modify the AAO not only in HD, but also in polyglutamine SCAs. This suggests a common pathogenic mechanism for these diseases, which could operate through the observed somatic expansion of repeats. Manipulation of DNA repair pathways may offer novel therapeutic opportunities in multiple diseases.

  • Genetic modifiers Polyglutamine disease Spinocerebellar ataxias Genotyping DNA repair

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