Genetic Modification of Huntington Disease Acts Early in the Prediagnosis Phase

Abstract

Age at onset of Huntington disease, an inherited neurodegenerative disorder, is influenced by the size of the disease-causing CAG trinucleotide repeat expansion in HTT and by genetic modifier loci on chromosomes 8 and 15. Stratifying by modifier genotype, we have examined putamen volume, total motor score (TMS), and symbol digit modalities test (SDMT) scores, both at study entry and longitudinally, in normal controls and CAG-expansion carriers who were enrolled prior to the emergence of manifest HD in the PREDICT-HD study. The modifiers, which included onset-hastening and onset-delaying alleles on chromosome 15 and an onset-hastening allele on chromosome 8, revealed no major effect in controls but distinct patterns of modification in prediagnosis HD subjects. Putamen volume at study entry showed evidence of reciprocal modification by the chromosome 15 alleles, but the rate of loss of putamen volume was modified only by the deleterious chromosome 15 allele. By contrast, both alleles modified the rate of change of the SDMT score, but neither had an effect on the TMS. The influence of the chromosome 8 modifier was evident only in the rate of TMS increase. The data indicate that (1) modification of pathogenesis can occur early in the prediagnosis phase, (2) the modifier loci act in genetic interaction with the HD mutation rather than through independent additive effects, and (3) HD subclinical phenotypes are differentially influenced by each modifier, implying distinct effects in different cells or tissues. Together, these findings indicate the potential benefit of using genetic modifier strategies for dissecting the prediagnosis pathogenic process in HD.

Keywords: CAG expansion; FAN1; HTT; Huntington disease; RRM2B; age at onset; genetic modifier; symbol digits modalities test; total motor score; trinucleotide repeat.

Figure 1

Age at Motor Diagnosis in PREDICT-HD PREDICT-HD subjects were all enrolled prior to diagnosis, but during the longitudinal study 207 of the subjects in our dataset converted to manifest HD on the basis of motor signs (diagnostic confidence level, DCL = 4 in the UHDRS). The age at diagnosis is plotted relative to CAG repeat size (black circles) on the background of the age at motor onset versus CAG repeat size relationship for the 4,082 HD subjects (gray circles) in our recent GWA study.

Figure 2

Effect of HD Modifier Genotype on Putamen Volume Forest plots are shown for the comparison of putamen volume by modifier genotype within PREDICT-HD controls (subjects with no HD-associated CAG expansion, CAG < 36) and within affected individuals (subjects with CAG expansion, CAG > 35). For each modifier genotype group (see Table 1), the effect of the presence of one or two copies of the modifier-associated SNP allele relative to wild-type (absence of the modifier-associated allele) was assessed at study entry (intercept difference) and longitudinally across multiple clinical visits (slope difference). The point estimate of the difference is shown as box on a line representing the 95% confidence interval (CI) limits (an arrow indicates that the CI limit extends beyond the graph boundary), and a statistically reliable difference between the two genotypes corresponds to an instance where the CI line does not cross 0.

Figure 3

Effect of HD Modifier Genotype on the Symbol Digit Modalities Test Score Forest plots are shown for the comparison of SDMT scores by modifier genotype within PREDICT-HD controls and within affected individuals as detailed in Figure 2.

Figure 4

Effect of HD Modifier Genotype on the Total Motor Score Forest plots are shown for the comparison of TMS by modifier genotype within PREDICT-HD controls and within affected individuals as detailed in Figure 2.