Background Huntington’s disease is caused by a CAG repeat expansion; ~60% onset variability is accounted for by age and CAG but studies point to ≥40% residual heritability. Disease progression offers advantages over age-at-motor onset (AAO) as an analytical phenotype which include use of multiple variables and time-points, and less inter-rater subjectivity.
Aims To define accurate stable measures of disease progression in Huntington’s, and use these to identify genetic modifiers.
Methods The availability of high quality longitudinal and multivariate data in TRACK-HD enabled us to define rate of progression accurately in 218 subjects. These subjects were then genotyped; imputation then QC generated 9,938,174 variants in 216 subjects. Using mixed-linear models we tested for association with disease progression. To validate our findings we developed a cross-sectional measure of disease progression, and used this to stratify the EHDN REGISTRY cohort. 1,773 subjects with valid phenotype were genotyped, mixed-linear models were used to determine association with cross sectional disease progression.
Results We find AAO and progression are correlated, but no evidence of distinct phenotypic clusters: imaging, cognitive, and quantitative-motor measures progress in parallel. In our TRACK-HD analysis we identify one significant association (P = 1.92 × 10−8) and one association approaching significance in a gene previously implicated in HD mouse and cell studies (P = 5.82 × 10−8). The TRACK-HD peak in a previously HD-implicated gene was replicated with P = 1.39 × 10−5 in the REGISTRY analysis. Furthermore we found an association (P = 2.90 × 10−7) between the cross sectional progression score and a Chromosome 15 locus previously associated with AAO.
- Genetic modifiers GWAS Progression Age at onset