Genetics Modulate Gray Matter Variation Beyond Disease Burden in Prodromal Huntington’s Disease

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.

Dynamic functional network connectivity in Huntington's disease and its associations with motor and cognitive measures

“…The CAP‐Age product (CAP) score is defined as CAP = Age*(CAG − 33.66) (Zhang, et al, ), where age is measured at the time of the scan. CAP scores have been used to estimate time to HD onset and to index HD progression accounting for exposure time to the toxic protein effects of CAG expansion (Ciarochi et al, ; Lee et al, ; Liu et al, ; Paulsen, Long, Ross, et al, ; Ross et al, ; Tabrizi et al, ).…”

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

“…1). MTMR10-tagging single nucleotide polymorphisms (SNPs) identified in individuals with HD or SCA2 may relate to FAN1 expression levels [14][15][16]. MTMR10 transcripts could hypothetically act in an antisense manner to regulate FAN1 mRNA stability and translatability.…”

Genome-wide contribution of common Short-Tandem Repeats to Parkinson’s Disease genetic risk

“…PART1 is a long non-coding RNA that was found to be differentially expressed (downregulated) in a microarray-based analysis of 50 PD patients compared to 22 healthy controls 29 . The ZSWIM7 eSTR was associated with significant effects on gene expression in different genes, such as TRPV2, a cation channel part of the Transient receptor potential family of proteins (TRPs) that are activated by physical and chemical stimuli 30 , and that are known to be involved in the regulation of ionic homeostasis, which is disrupted in PD 31 ; ADORA2B is an adenosine receptor which has been associated with neurodegenerative conditions such as Huntington's disease 32 , however no link to PD has been established so far; lnc-NCOR1-1 and NCOR1 (Nuclear Receptor Corepressor 1) are located within the same chromosomal region (short arm of chromosome 17) and were also influenced by the eSTRs. The former long non-coding gene has not been thoroughly characterized, therefore little is known about its function.…”