Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

• Autor(a) principal: Akçimen, Fulya
• Data de Publicação: 2020
• Outros Autores: Martins, Sandra, Liao, Calwing, Bourassa, Cynthia V., Catoire, Hélène, Nicholson, Garth A., Riess, Olaf, Raposo, Mafalda, França Júnior, Marcondes Cavalcante, Vasconcelos, João, Lima, Manuela, Lopes-Cendes, Iscia Teresinha, Pereira, Maria Luiza Saraiva, Jardim, Laura Bannach, Sequeiros, Jorge, Dion, Patrick A., Rouleau, Guy A.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UFRGS
• Texto Completo: http://hdl.handle.net/10183/217197
• topic: Doença de Machado-Joseph; Idade de início; Loci gênicos; Estudo de associação genômica ampla; Machado-Joseph disease; GWAS; Age at onset; ATXN3; Modifier

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.