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Ann Neurol. 2016 Jun;79(6):983-90. doi: 10.1002/ana.24656. Epub 2016 May 6.

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

Author information

1
Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
2
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
3
Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
4
Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany.
5
Inserm 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
APHP, Department of Genetics, University Hospital Pitié-Salpêtrière, 75013 Paris, France.
7
Université Bordeaux, Laboratoire Maladies Rares: Génétique et Métabolisme, INSERM1211, Bordeaux, France.
8
CHU Pellegrin, Service de Génétique Médicale, F-33000, Bordeaux, France.
9
Ecole Pratique des Hautes Etudes, 75014 Paris, France.
10
Neurogenetics Unit, 1st Department of Neurology, University of Athens Medical School, Eginition Hospital, 115 28 Athens, Greece.
11
Neurogenetics Department, National Institute of Neurology and Neurosurgery, "Manuel Velasco Suárez", Mexico City CP14269, Mexico.
12
Department of Biology, University of the Azores, 9500-321 Ponta Delgada, Portugal.
13
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4150-180 Porto, Portugal.
14
Institute for Molecular and Cell Biology (IBMC), University of Porto, 4150-180 Porto, Portugal.
15
Laboratory of Neurogenetics, National Institute of Aging, NIH, Bethesda, MD 20892, USA.
16
Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, University College London Hospitals, London WC1N 3BG, United Kingdom.
17
Ataxia Center, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
18
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, CF24 4HQ, United Kingdom.

Abstract

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;79:983-990.

PMID:
27044000
PMCID:
PMC4914895
DOI:
10.1002/ana.24656
[Indexed for MEDLINE]
Free PMC Article

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