期刊
AGING-US
卷 12, 期 6, 页码 4742-4756出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.102825
关键词
Machado-Joseph disease; GWAS; age at onset; ATXN3; modifier
资金
- Fonds de Recherche du Quebec-Sante
- FCT [CEECIND/00684/2017]
- Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) [NORTE-01-0145-FEDER-000008]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/07559-3]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil (CNPq)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Canada Research Chair in Genetics of the Nervous System
- Wilder Penfield Chair in Neurosciences
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 R-2 = 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 x 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.
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