1. Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease
- Author
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Patrick A. Dion, Marcondes C. França, Sandra Martins, Laura Bannach Jardim, Fulya Akçimen, Mafalda Raposo, Cynthia V. Bourassa, Hélène Catoire, Guy A. Rouleau, Olaf Riess, Iscia Lopes-Cendes, Jorge Sequeiros, Maria Luiza Saraiva-Pereira, Garth A. Nicholson, João Vasconcelos, Calwing Liao, Manuela Lima, and Instituto de Investigação e Inovação em Saúde
- Subjects
Adult ,Male ,0301 basic medicine ,Cag expansion ,congenital, hereditary, and neonatal diseases and abnormalities ,Aging ,Ataxia ,DNA repair ,Machado-Joseph disease ,Genome-wide association study ,Repressor Proteins / genetics ,Disease ,Biology ,Polymorphism, Single Nucleotide ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,GWAS ,Humans ,Age of Onset ,Ataxin-3 ,Gene ,Genetics ,modifier ,Machado-Joseph Disease / epidemiology ,ATXN3 ,Cell Biology ,Machado-Joseph Disease / genetics ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,Ataxin-3 / genetics ,Female ,medicine.symptom ,age at onset ,Machado–Joseph disease ,030217 neurology & neurosurgery ,Research Paper ,Genome-Wide Association Study - Abstract
Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study (Pearson's correlation coefficient R2 = 0.62). Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 × 10-5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD. FA and CL were funded by the Fonds de Recherche du Québec–Santé. SM is funded by FCT (CEECIND/00684/2017) and by NORTE-01-0145- FEDER-000008, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). FM and LI are funded by Fundaçao de Amparo a Pesquisa do Estado de São Paulo (FAPESP, 2013/07559-3). MLSP and LBJ were funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (CNPq) and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). GAR holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences.
- Published
- 2020