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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

Fulya Akçimen1,2, Sandra Martins3,4, Calwing Liao1,2, Cynthia V. Bourassa2,5, Hélène Catoire2,5, Garth A. Nicholson6, Olaf Riess7, Mafalda Raposo8, Marcondes C. França9, João Vasconcelos10, Manuela Lima8, Iscia Lopes-Cendes11,12, Maria Luiza Saraiva-Pereira13,14, Laura B. Jardim13,15, Jorge Sequeiros4,16,17, Patrick A. Dion2,5, Guy A. Rouleau1,2,5
  • 1Department of Human Genetics, McGill University, Montréal, Québec, Canada
  • 2Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada
  • 3i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
  • 4IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
  • 5Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada
  • 6University of Sydney, Department of Medicine, Concord Hospital, Concord, Australia
  • 7Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
  • 8Faculdade 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
  • 9Department of Neurology, Faculty of Medical Sciences, UNICAMP, São Paulo, Campinas, Brazil
  • 10School of Medical Sciences, Department of Medical Genetics and Genomic Medicine, University of Campinas (UNICAMP), São Paulo, Campinas, Brazil
  • 11The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), São Paulo, Campinas, Brazil
  • 12Departamento de Neurologia, Hospital do Divino Espírito Santo, Ponta Delgada, Portugal
  • 13Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
  • 14Depto. de Bioquímica – ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
  • 15Depto de Medicina Interna, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
  • 16Institute for Molecular and Cell Biology (IBMC), Universidade do Porto, Porto, Portugal
  • 17Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
Received: November 20, 2019Accepted: January 27, 2020Published: March 23, 2020
https://doi.org/10.18632/aging.102825

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.