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@ARTICLE{Hong:268518,
author = {Hong, Eun Pyo and Ramos, Eliana Marisa and Aziz, N Ahmad
and Massey, Thomas H and McAllister, Branduff and Lobanov,
Sergey and Jones, Lesley and Holmans, Peter and Kwak, Seung
and Orth, Michael and Ciosi, Marc and Lomeikaite, Vilija and
Monckton, Darren G and Long, Jeffrey D and Lucente, Diane
and Wheeler, Vanessa C and Gillis, Tammy and MacDonald,
Marcy E and Sequeiros, Jorge and Gusella, James F and Lee,
Jong-Min},
title = {{M}odification of {H}untington's disease by short tandem
repeats.},
journal = {Brain communications},
volume = {6},
number = {2},
issn = {2632-1297},
address = {[Großbritannien]},
publisher = {Guarantors of Brain},
reportid = {DZNE-2024-00264},
pages = {fcae016},
year = {2024},
abstract = {Expansions of glutamine-coding CAG trinucleotide repeats
cause a number of neurodegenerative diseases, including
Huntington's disease and several of spinocerebellar ataxias.
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's 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's
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's 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's disease
participants but did not influence Huntington's disease
age-at-onset. Additional analysis focusing specifically on
ATXN3 in a larger sample set (n = 1388) confirmed the lack
of association between Huntington's disease residual
age-at-onset and ATXN3 CAG repeat length. Additionally,
neither our Huntington's 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's 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's
disease is associated with short tandem repeats that do not
involve other polyglutamine disease-causing genes, refining
the landscape of Huntington's disease modification and
highlighting the importance of rigorous data analysis,
especially in genetic studies testing candidate modifiers.},
keywords = {Huntington’s disease (Other) / Huntington’s disease
(Other) / Huntington’s disease (Other) / ATXN3 (Other) /
Huntington’s disease (Other) / genetic modification
(Other) / polyglutamine disease (Other) / short tandem
repeat (Other)},
cin = {AG Aziz},
ddc = {610},
cid = {I:(DE-2719)5000071},
pnm = {354 - Disease Prevention and Healthy Aging (POF4-354)},
pid = {G:(DE-HGF)POF4-354},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38449714},
pmc = {pmc:PMC10917446},
doi = {10.1093/braincomms/fcae016},
url = {https://pub.dzne.de/record/268518},
}