Abstract

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. We aimed to define accurate stable measures of disease progression in Huntington's, and use these to identify genetic modifiers.

Disease progression offers advantages over age-at-motor onset (AAO) as an analytical phenotype. The availability of high quality longitudinal data in TRACK-HD enabled us to define rate of progression accurately. We find AAO and progression are correlated, but no evidence of distinct phenotypic clusters: imaging, cognitive, and quantitative-motor measures progress in parallel.

216 TRACK-HD subjects were genotyped; imputation then QC generated 9,938,174 variants. Using mixed-linear models we tested for association with disease progression and identified two genome-wide significant signals (P=8.5×10−8 and 4.66×10−8), one associated with a gene implicated in HD mouse and cell studies.

To validate these findings we developed a cross-sectional measure of disease progression (“CSP”), andused this to stratify the EHDN Registry cohort. 1,773 subjects with valid phenotype were genotyped. The peak associated with the previously implicated gene was replicated with P=1.4×10−5. Furthermore we found an association (P=2.90×10−7) between the CSP score and a Chromosome 15 locus previously associated with AAO.