Research Paper Volume 12, Issue 6 pp 4742—4756
Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease
- 1 Department of Human Genetics, McGill University, Montréal, Québec, Canada
- 2 Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada
- 3 i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- 4 IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
- 5 Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada
- 6 University of Sydney, Department of Medicine, Concord Hospital, Concord, Australia
- 7 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
- 8 Faculdade de Ciências e Tecnologia, Universidade dos Açores e Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- 9 Department of Neurology, Faculty of Medical Sciences, UNICAMP, São Paulo, Campinas, Brazil
- 10 School of Medical Sciences, Department of Medical Genetics and Genomic Medicine, University of Campinas (UNICAMP), São Paulo, Campinas, Brazil
- 11 The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), São Paulo, Campinas, Brazil
- 12 Departamento de Neurologia, Hospital do Divino Espírito Santo, Ponta Delgada, Portugal
- 13 Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
- 14 Depto. de Bioquímica – ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- 15 Depto de Medicina Interna, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- 16 Institute for Molecular and Cell Biology (IBMC), Universidade do Porto, Porto, Portugal
- 17 Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
Received: November 20, 2019 Accepted: January 27, 2020 Published: March 23, 2020
https://doi.org/10.18632/aging.102825How to Cite
Copyright © 2020 Akçimen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.