CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion

Abstract

Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.

Methods: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.

Results: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.

Conclusions: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.

Figures

Figure 1. Relationship of expanded allele CAG repeat length and age at onset of motor manifestations in individuals with Huntington disease

An initial regression model was generated using all 4,068 subjects with Huntington disease (HD), each heterozygous for 1 expanded allele (>35 CAG) and 1 allele in the normal range (35 CAGs) were plotted (filled red circle: longer expanded allele; green: shorter expanded allele) over the heterozygote subsample conforming to statistical assumptions underlying regression analysis (3,674 HD subjects based upon expanded CAGs from 40–53 and statistical exclusion of outliers; see figures e-3, e-4, and e-5). One homozygous subject has 2 equal alleles of 42 CAGs. The minimal adequate model for this heterozygote data set is shown as a red line.