Modification of Huntington's disease by short tandem repeats

Hong, Eun Pyo, Ramos, Eliana Marisa, Aziz, N. Ahmad, Massey, Thomas H. ORCID: https://orcid.org/0000-0002-9804-2131, McAllister, Branduff, Lobanov, Sergey ORCID: https://orcid.org/0000-0002-3126-1903, Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Kwak, Seung, Orth, Michael, Ciosi, Marc, Lomeikaite, Vilija, Monckton, Darren G., Long, Jeffrey D., Lucente, Diane, Wheeler, Vanessa C., Gillis, Tammy, MacDonald, Marcy E., Sequeiros, Jorge, Gusella, James F. and Lee, Jong-Min 2024. Modification of Huntington's disease by short tandem repeats. Brain Communications 6 (2) , fcae016. 10.1093/braincomms/fcae016

Preview

PDF - Published Version Available under License Creative Commons Attribution. Download (921kB) | Preview

Abstract

Expansions of glutamine-coding CAG trinucleotide repeats cause a number of neurodegenerative diseases, including Huntington's disease (HD) and several of the spinocerebellar ataxias (SCAs). 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 HD 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 (GWAS). Modification of one polyglutamine disease (e.g., HD) by the repeat length of another (e.g., ATXN3, CAG expansions in which cause SCA3) has also been hypothesized. Consequently, we determined whether age-at-onset in HD is modified by the CAG repeats of other polyglutamine disease genes. We found that the CAG measured repeat sizes of other polyglutamine disease genes were polymorphic in HD participants but did not influence HD age-at-onset. Additional analysis focusing specifically on ATXN3 in a larger sample set (n = 1,388) confirmed the lack of association between HD residual age-at-onset and ATXN3 CAG repeat length. Additionally, neither our HD onset modifier GWAS single nucleotide polymorphism (SNP) data nor imputed short tandem repeat (STR) data supported involvement of other polyglutamine disease genes in modifying HD. By contrast, our GWAS based on imputed STRs revealed significant modification signals for other genomic regions. Together, our STR GWAS show that modification of HD is associated with STRs that do not involve other polyglutamine disease-causing genes, refining the landscape of HD modification and highlighting the importance of rigorous data analysis, especially in genetic studies testing candidate modifiers.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Oxford University Press
ISSN:	2632-1297
Date of First Compliant Deposit:	30 January 2024
Date of Acceptance:	22 January 2024
Last Modified:	17 Apr 2024 13:57
URI:	https://orca.cardiff.ac.uk/id/eprint/165907

Actions (repository staff only)

Edit Item