Davina J Hensman Moss, Antonio F Pardiñas, Prof Douglas Langbehn, Kitty Lo, Prof Blair R Leavitt, Prof Raymund Roos, Prof Alexandra Durr, Prof Simon Mead
Huntington's disease is an autosomal dominant fatal neurodegenerative condition caused by a CAG repeat expansion in huntingtin gene, HTT. 1 It is a movement, cognitive, and psychiatric disorder, but symptoms, age of disease onset, and disease progression vary.2 Age of onset reflects the trajectory of disease pathology up to the point of motor onset. 1 ; 3 However, the transition from premanifest to manifest Huntington's disease is gradual, 4 ; 5 making clinical definition challenging. Furthermore, psychiatric and cognitive changes might not be concurrent with motor onset.6 Despite this imprecision in defining onset, the inverse correlation of HTT CAG repeat length and age at motor onset accounts for 50–70% of the observed variance in onset. 7 Part of the remaining difference in age of onset was also recently shown to be genetically encoded, and genes of the DNA damage response were identified as being likely to modify onset of Huntington's disease.8
The need for clinical trials close to disease onset has motivated a number of observational studies.5; 9 ; 10 These new data provide the opportunity to investigate the association between onset and progression and whether they are influenced by the same biology, and permit the study of individuals before clinical onset. TRACK-HD5 ; 6 was a prospective, observational, biomarker study that represents the most deeply phenotyped cohort of people with premanifest and symptomatic Huntington's disease, with annual visits involving motor, cognitive, psychiatric and imaging assessments. We used TRACK-HD data5 ; 6 to generate a novel unified Huntington's disease progression measure for use in a genetic association analysis. We developed a similar measure in participants from the REGISTRY study9 to replicate our findings. We used these disease progression measures as quantitative variables in genome-wide association analyses of the TRACK-HD and REGISTRY data, and aimed to replicate this finding in a meta-analysis.