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In general, age-at-onset of the polyglutamine diseases is inversely correlated with the size of the respective inherited expanded CAG repeat. Expanded CAG repeats are also somatically unstable in certain tissues, and age-at-onset of Huntington\u2019s disease corrected for individual HTT CAG repeat length (i.e. residual age-at-onset), is modified by repeat instability-related DNA maintenance\/repair genes as demonstrated by recent genome-wide association studies. Modification of one polyglutamine disease (e.g. Huntington\u2019s disease) by the repeat length of another (e.g. ATXN3, CAG expansions in which cause spinocerebellar ataxia 3) has also been hypothesized. Consequently, we determined whether age-at-onset in Huntington\u2019s disease is modified by the CAG repeats of other polyglutamine disease genes. We found that the CAG measured repeat sizes of other polyglutamine disease genes that were polymorphic in Huntington\u2019s disease participants but did not influence Huntington\u2019s disease age-at-onset. Additional analysis focusing specifically on ATXN3 in a larger sample set (n = 1388) confirmed the lack of association between Huntington\u2019s disease residual age-at-onset and ATXN3 CAG repeat length. Additionally, neither our Huntington\u2019s disease onset modifier genome-wide association studies single nucleotide polymorphism data nor imputed short tandem repeat data supported the involvement of other polyglutamine disease genes in modifying Huntington\u2019s disease. By contrast, our genome-wide association studies based on imputed short tandem repeats revealed significant modification signals for other genomic regions. Together, our short tandem repeat genome-wide association studies show that modification of Huntington\u2019s disease is associated with short tandem repeats that do not involve other polyglutamine disease-causing genes, refining the landscape of Huntington\u2019s disease modification and highlighting the importance of rigorous data analysis, especially in genetic studies testing candidate modifiers.<\/jats:p>","DOI":"10.1093\/braincomms\/fcae016","type":"journal-article","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T03:22:07Z","timestamp":1706066527000},"source":"Crossref","is-referenced-by-count":13,"title":["Modification of Huntington\u2019s disease by short tandem repeats"],"prefix":"10.1093","volume":"6","author":[{"given":"Eun Pyo","family":"Hong","sequence":"first","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital 1 , Boston, MA 02114 , USA"},{"name":"Department of Neurology, Harvard Medical School , 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Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University , Cardiff CF24 4HQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Branduff","family":"McAllister","sequence":"additional","affiliation":[{"name":"Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University , Cardiff CF24 4HQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Lobanov","sequence":"additional","affiliation":[{"name":"Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University , Cardiff CF24 4HQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley","family":"Jones","sequence":"additional","affiliation":[{"name":"Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University , Cardiff CF24 4HQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Holmans","sequence":"additional","affiliation":[{"name":"Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University , Cardiff CF24 4HQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung","family":"Kwak","sequence":"additional","affiliation":[{"name":"Molecular System Biology, CHDI Foundation , Princeton, NJ 08540 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Orth","sequence":"additional","affiliation":[{"name":"University Hospital of Old Age Psychiatry and Psychotherapy, Bern University , CH-3000 Bern 60 , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7663-4080","authenticated-orcid":false,"given":"Marc","family":"Ciosi","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vilija","family":"Lomeikaite","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8298-8264","authenticated-orcid":false,"given":"Darren G","family":"Monckton","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Carver College of Medicine and Department of Biostatistics, College of Public Health, University of Iowa , Iowa City, IA 52242 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Lucente","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital 1 , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa C","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital 1 , Boston, MA 02114 , USA"},{"name":"Department of Neurology, Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy","family":"Gillis","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital 1 , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcy E","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital 1 , Boston, MA 02114 , USA"},{"name":"Department of Neurology, Harvard Medical School , Boston, MA 02115 , USA"},{"name":"Medical and Population Genetics Program, The Broad Institute of M.I.T. and Harvard , Cambridge, MA 02142 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Sequeiros","sequence":"additional","affiliation":[{"name":"UnIGENe, IBMC\u2014Institute for Molecular and Cell Biology, i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em 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