DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Conceição Bettencourt (1, 2) , Davina J. Hensman Moss (3) , Michael Flower (3) , Sarah Wiethoff (4, 1) , Alexis Brice (5, 6) , Cyril Goizet (7, 8) , Giovanni Stevanin (9, 5) , Georgios Koutsis (10) , Georgia Karadima (10) , Marios Panas (10) , Petra Yescas-Gómez (11) , Lizbeth Esmeralda García-Velázquez (11) , María Elisa Alonso-Vilatela (11) , Manuela Lima (12, 13, 14) , Mafalda Raposo (12, 13, 14) , Bryan Traynor (15) , Mary Sweeney (16) , Nicholas Wood (1) , Paola Giunti (17, 1) , Alexandra Durr (5, 6) , Peter Holmans (18) , Henry Houlden (1, 16) , Sarah J. Tabrizi (3) , Lesley Jones (18)

1 Department of Molecular Neuroscience
2 Department of Clinical and Experimental Epilepsy
3 Department of Neurodegenerative Diseases, Institute of Neurology
4 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
5 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
6 CHU Pitié-Salpêtrière [AP-HP]
7 Service de génétique médicale
8 Laboratoire Maladies Rares: Génétique et Métabolisme
9 EPHE - École Pratique des Hautes Études
10 University of Athens Medical School [Athens]
11 National Institute of Neurology and Neurosurgery
12 University of the Azores
13 Universidade do Porto = University of Porto
14 ICBAS - BMC –Institute for Molecular and Cell Biology
15 National Institute of Aging
16 National Hospital for Neurology & Neurosurgery
17 UCL - University College of London [London]
18 MRC Centre for Neuropsychiatric Genetics and Genomics

Objective The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome-wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases. Methods We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single-nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study. Results In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, 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 in the same direction as in the HD GWAS. Interpretation We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016

Domaines: Neurosciences [q-bio.NC]

Conceição Bettencourt, Davina J. Hensman Moss, Michael Flower, Sarah Wiethoff, Alexis Brice, et al.. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases. Annals of Indian Academy of Neurology, 2016, ⟨10.1002/ana.24656⟩. ⟨hal-01313687⟩