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

Author(s):Show less -

Akcimen, Fulya ^{[1, 2]} ; Martins, Sandra ^{[3, 4]} ; Liao, Calwing ^{[1, 2]} ; Bourassa, V, Cynthia ; Catoire, Helene ^{[5, 6]} ; Nicholson, Garth A. ^[7] ; Riess, Olaf ^[8] ; Raposo, Mafalda ^{[9, 10]} ; Franca, Marcondes C. ^[11] ; Vasconcelos, Joao ^[12] ; Lima, Manuela ^{[9, 10]} ; Lopes-Cendes, Iscia ^{[13, 14]} ; Saraiva-Pereira, Maria Luiza ^{[15, 16]} ; Jardim, Laura B. ^{[15, 17]} ; Sequeiros, Jorge ^{[4, 18, 19]} ; Dion, Patrick A. ^{[5, 6]} ; Rouleau, Guy A. ^{[1, 5, 6]}

Affiliation:Show less -

^[1] McGill Univ, Dept Human Genet, Montreal, PQ - Canada

^[2] McGill Univ, Montreal Neurol Inst & Hosp, Montreal, PQ - Canada

^[3] Univ Porto, i3S, Porto - Portugal

^[4] Univ Porto, IPATIMUP Inst Mol Pathol & Immunol, Porto - Portugal

^[5] Bourassa, Cynthia, V, McGill Univ, Montreal Neurol Inst & Hosp, Montreal, PQ - Canada

^[6] Bourassa, Cynthia, V, McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ - Canada

^[7] Univ Sydney, Concord Hosp, Dept Med, Concord - Australia

^[8] Univ Tubingen, Inst Med Genet & Appl Genom, Tubingen - Germany

^[9] Univ Acores, Fac Ciencias & Tecnol, Porto - Portugal

^[10] Univ Porto, IBMC, I3S, Porto - Portugal

^[11] Univ Estadual Campinas, Dept Neurol, Fac Med Sci, Campinas - Brazil

^[12] Univ Estadual Campinas, Sch Med Sci, Dept Med Genet & Genom Med, UNICAMP, Campinas - Brazil

^[13] Brazilian Inst Neurosci & Neurotechnol BRAINN, Campinas - Brazil

^[14] Hosp Divino Espirito Santo, Dept Neurol, Ponta Delgada - Portugal

^[15] HCPA, Med Genet Serv, Porto Alegre, RS - Brazil

^[16] Univ Fed Rio Grande do Sul, Dept Bioquim ICBS, Porto Alegre, RS - Brazil

^[17] Univ Fed Rio Grande do Sul, Dept Med Interna, Porto Alegre, RS - Brazil

^[18] Univ Porto, Inst Mol & Cell Biol IBMC, Porto - Portugal

^[19] Univ Porto, Inst Ciencias Biomed Abel Salazar, Porto - Portugal

• Document type: Journal article
• Source: AGING-US; v. 12, n. 6, p. 4742-4756, MAR 31 2020.
• Web of Science Citations: 0

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 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. (AU)

• FAPESP's process: 13/07559-3 - BRAINN - The Brazilian Institute of Neuroscience and Neurotechnology
• Grantee: Fernando Cendes
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC