Genetic modifiers of Huntington’s disease differentially influence motor and cognitive domains

Abstract

Genome-wide association studies (GWAS) of Huntington’s disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals with a rater-estimated age at motor onset. To capitalize on the wealth of phenotypic data in several large HD natural history studies, we have performed algorithmic prediction using common motor and cognitive measures to predict age at other disease landmarks as additional phenotypes for GWAS. Combined with imputation using the Trans-Omics for Precision Medicine reference panel, predictions using integrated measures provided objective landmark phenotypes with greater power to detect most modifier loci. Importantly, substantial differences in the relative modifier signal across loci, highlighted by comparing common modifiers at MSH3 and FAN1, revealed that individual modifier effects can act preferentially in the motor or cognitive domains. Individual components of the DNA maintenance modifier mechanisms may therefore act differentially on the neuronal circuits underlying the corresponding clinical measures. In addition, we identified new modifier effects at the PMS1 and PMS2 loci and implicated a potential new locus on chromosome 7. These findings indicate that broadened discovery and characterization of HD genetic modifiers based on additional quantitative or qualitative phenotypes offers not only the promise of in-human validated therapeutic targets, but also a route to dissecting the mechanisms and cell types involved in both the somatic instability and toxicity components of HD pathogenesis.

Intellectual enrichment and genetic modifiers of cognitive function in Huntington’s disease

“…We did not find a significant association between FAN1, MAPT, BDNF and COMT variants and global cognitive function at baseline or change over time after Bonferroni correction for five multiple comparisons (all pbon > 0.068; Table 3). In agreement with previous analyses of disease progression in the same cohort 25 and recent research 15 , MSH3 was a significant predictor of global cognitive function at baseline and change (both pbon = 0.045; Table 3 and Supplementary Table 9). More specifically, participants with one or more 3a alleles in MSH3 had better cognitive function at baseline and slower cognitive decline compared to non-carriers of 3a alleles (for average age and DBS slope (95% CI) = -0.329 (-0.434, -0.223) and -0.118 (-0.241, 0.004) for non-carriers and carriers respectively; contrast estimate (SE) non-carriers vs carriers = -0.21 (0.081), t-value(213) = -2.587, p-value = 0.010; Figure 2A and Supplementary Figure 4).…”

“…Intellectual enrichment did not interact with any of the other genetic polymorphisms we examined, whereas the only genetic predictor with a significant effect on cognitive function was variation in MSH3. A recent study 15 has identified MSH3 as a modifier of cognitive function in HD, while we have previously shown in this cohort that variation in MSH3, specifically carrying a 3a allele, has a protective effect on a composite score of disease progression which included cognitive and psychomotor function 22,25 . It is currently hypothesized that MSH3 is introducing an expansion of the HTT CAG repeat in the process of repair.…”

“…To understand the mechanism by which BDNF interacts with intellectual enrichment to impact cognitive function, we examined the interaction between BDNF and intellectual enrichment on brain volume. The effect of the interaction of BDNF with intellectual enrichment was significant, but small, on both caudate and total GM volume rate of change (both pbon < 0.03 corrected for two tests; Supplementary Table [13][14][15]. The difference in rate of volume change between individuals with high and low intellectual enrichment was positive in Met66 allele carriers, but negative for non-carriers.…”

“…Because the main outcome measure was cognitive function, we focused on SNPs that had been previously associated with cognitive and psychomotor function in Huntington's disease. Based on previous literature we therefore selected the following SNPs: rs4680 on chromosome 22 14 in COMT, which relates to dopamine metabolism, rs9468 on chromosome 17 16 in MAPT, which relates to tau protein production, rs2140734 on chromosome 15 near FAN1 13,24 , which is involved in DNA repair, and a polymorphic repeat expansion in exon 1 on chromosome 5 of MSH3 15,22,25,26 , which is involved in DNA mismatch repair. In addition, we tested another polymorphism, rs6265 (Val66Met) on chromosome 11 in BDNF, which encodes the Val66Met polymorphism and regulates BDNF expression.…”

“…In Huntington's disease, a small number of studies have so far examined the role of genetic polymorphisms and lifestyle factors on individual differences in cognitive function. More specifically, education and participation in lifelong intellectual activities [10][11][12] , as well as a number of genes, including FAN1 13 , COMT 14 , MSH3 15 and MAPT 16 , predict cognitive function. Two of these studies have also provided preliminary evidence that intellectual enrichment is associated with less striatal atrophy 11,12 , suggesting that it supports greater brain maintenance.…”