Modification of Huntington's disease by short tandem repeats

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: ATXN3; Huntington’s disease; genetic modification; polyglutamine disease; short tandem repeat.

Graphical Abstract

Figure 1

The lack of modification of HD onset by ATXN3 CAG repeats. To validate the COHORT data analysis of ATXN3 results, we also analyzed the ATXN3 repeat in the REGISTRY samples. Subsequently, we performed linear regression analysis using the combined data to determine whether the longer A, shorter B, or sum of the two repeat alleles C, could explain residual age-at-onset of HD (n = 1388). Twenty-six repeat alleles were observed; the most and second most frequent repeat alleles were 23 and 14 CAGs, accounting for 53% of all repeat alleles. The Y-axis shows residual age-at-onset of HD subjects, representing age-at-onset corrected for individual HTT CAG repeat size (i.e. years). The X-axis represents the length of CAG repeat of ATXN3 (i.e. [CAG]n).

Figure 2

Genome-wide STR association analysis of residual age-at-onset of HD. STRs were imputed based on the typed SNP data and subsequently used as the predictor variable with other covariates to explain residual age-at-onset of HD. For this analysis, we used the sum of two alleles for a given STR (i.e. additive model). Y-axis represents significance levels of association, expressed as –log10(P-value). A dotted horizontal line represents Bonferroni significance (P-value, 8.48E-7 based on 58 894 tests). Triangles mark the polyglutamine disease-causing repeats.