Journal article
Modification of Huntington's disease by short tandem repeats
Brain communications, Vol.6(2), fcae016
03/01/2024
DOI: 10.1093/braincomms/fcae016
PMCID: PMC10917446
PMID: 38449714
Abstract
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.
Details
- Title: Subtitle
- Modification of Huntington's disease by short tandem repeats
- Creators
- Eun Pyo Hong - Massachusetts General HospitalEliana Marisa Ramos - Massachusetts General HospitalN Ahmad Aziz - German Center for Neurodegenerative DiseasesThomas H Massey - Cardiff UniversityBranduff McAllister - Cardiff UniversitySergey Lobanov - Cardiff UniversityLesley Jones - Cardiff UniversityPeter Holmans - Cardiff UniversitySeung Kwak - CHDI FoundationMichael OrthMarc Ciosi - University of GlasgowVilija Lomeikaite - University of GlasgowDarren G Monckton - University of GlasgowJeffrey D Long - University of IowaDiane Lucente - Massachusetts General HospitalVanessa C Wheeler - Massachusetts General HospitalTammy Gillis - Massachusetts General HospitalMarcy E MacDonald - Massachusetts General HospitalJorge Sequeiros - i3S - Instituto de Investigação e Inovação em Saúde, Universidade do PortoJames F Gusella - Massachusetts General HospitalJong-Min Lee - Massachusetts General Hospital
- Resource Type
- Journal article
- Publication Details
- Brain communications, Vol.6(2), fcae016
- DOI
- 10.1093/braincomms/fcae016
- PMID
- 38449714
- PMCID
- PMC10917446
- NLM abbreviation
- Brain Commun
- ISSN
- 2632-1297
- eISSN
- 2632-1297
- Grant note
- DOI: 10.13039/100005725, name: CHDI Foundation; DOI: 10.13039/100000002, name: U.S. National Institutes of Health, award: NS082079, NS091161, NS016367, NS049206, NS105709, NS119471; DOI: 10.13039/501100000265, name: Medical Research Council, award: MR/L010305/1, MR/P001629/1; name: Cardiff University School of Medicine studentship, award: SFRH/BD/44335/2008; name: Alzheimer’s Association Research Grant, award: AARG-19-616534; name: European Research Council Starting Grant, award: 101041677
- Language
- English
- Electronic publication date
- 01/23/2024
- Date published
- 03/01/2024
- Academic Unit
- Psychiatry; Biostatistics
- Record Identifier
- 9984548852802771
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