Genetics modulate gray matter variation beyond disease burden in prodromal Huntington's disease

PREDICT-HD Investigators and Coordinators of the Huntington Study Group

Research output: Contribution to journalArticle

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by an expansion mutation of the cytosine-adenine-guanine (CAG) trinucleotide in the HTT gene. Decline in cognitive and motor functioning during the prodromal phase has been reported, and understanding genetic influences on prodromal disease progression beyond CAG will benefit intervention therapies. From a prodromal HD cohort (N = 715), we extracted gray matter (GM) components through independent component analysis and tested them for associations with cognitive and motor functioning that cannot be accounted for by CAG-induced disease burden (cumulative effects of CAG expansion and age). Furthermore, we examined genetic associations (at the genomic, HD pathway, and candidate region levels) with the GM components that were related to functional decline. After accounting for disease burden, GM in a component containing cuneus, lingual, and middle occipital regions was positively associated with attention and working memory performance, and the effect size was about a tenth of that of disease burden. Prodromal participants with at least one dystonia sign also had significantly lower GM volume in a bilateral inferior parietal component than participants without dystonia, after controlling for the disease burden. Two single-nucleotide polymorphisms (SNPs: rs71358386 in NCOR1 and rs71358386 in ADORA2B) in the HD pathway were significantly associated with GM volume in the cuneus component, with minor alleles being linked to reduced GM volume. Additionally, homozygous minor allele carriers of SNPs in a candidate region of ch15q13.3 had significantly higher GM volume in the inferior parietal component, and one minor allele copy was associated with a total motor score decrease of 0.14 U. Our findings depict an early genetical GM reduction in prodromal HD that occurs irrespective of disease burden and affects regions important for cognitive and motor functioning.

Original languageEnglish (US)
Article number190
JournalFrontiers in Neurology
Volume9
Issue numberMAR
DOIs
StatePublished - Mar 29 2018
Externally publishedYes

Fingerprint

Huntington Disease
Cytosine
Guanine
Adenine
Occipital Lobe
Single Nucleotide Polymorphism
Dystonia
Alleles
Gray Matter
Short-Term Memory
Tongue
Neurodegenerative Diseases
Disease Progression
Mutation
Genes

Keywords

  • Cognition
  • Genetic modifier
  • Gray matter
  • Huntington's disease
  • Prodromal disease progression

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Genetics modulate gray matter variation beyond disease burden in prodromal Huntington's disease. / PREDICT-HD Investigators and Coordinators of the Huntington Study Group.

In: Frontiers in Neurology, Vol. 9, No. MAR, 190, 29.03.2018.

Research output: Contribution to journalArticle

PREDICT-HD Investigators and Coordinators of the Huntington Study Group 2018, 'Genetics modulate gray matter variation beyond disease burden in prodromal Huntington's disease', Frontiers in Neurology, vol. 9, no. MAR, 190. https://doi.org/10.3389/fneur.2018.00190
PREDICT-HD Investigators and Coordinators of the Huntington Study Group. / Genetics modulate gray matter variation beyond disease burden in prodromal Huntington's disease. In: Frontiers in Neurology. 2018 ; Vol. 9, No. MAR.
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AU - Paulsen, Jane S.

AU - Jeremy Bockholt, H.

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AU - Long, Jeffrey D.

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