Huntington's disease (HD) is caused by a CAG expansion mutation whose length is the primary determinant of the age at which diagnostic motor signs emerge, typically in mid-life. The length of the CAG repeat is also correlated with age of onset of cognitive or psychiatric clinical signs in those who present first with these features. Thus, CAG repeat length influences the rate with which biological changes in HD that begin early, due to the expression of mutant huntingtin, lead much later to motor, cognitive or psychiatric onset, although not all steps in each of these three pathogenic processes are likely to be identical. However, the age at onset of motor signs, and likely the timing of cognitive, psychiatric and imaging abnormalities, is influenced by other as yet unidentified genetic factors, not as independent risk factors but as modifiers, i.e., suppressors or enhancers of phenotypes dependent on the presence of an expanded CAG repeat. PREDICT-HD, which was established as an observational study to investigate the effects of the HD mutation during the decades prior to diagnosis, has accumulated a wealth of data in various domains, including brain imaging, motor signs, cognitive disturbance and psychiatric manifestations, that represent a valuable resource for identifying potential modifiers. Via the Center for Inherited Disease Research (CIDR), we have recently generated genome-wide SNP data for PREDICT-HD, and we have complemented these data with genome-wide SNP data for more than 6,000 HD individuals from the Huntington Study Group COHORT study, the European Huntington Disease Network's Registry study and a collection of banked post-mortem HD brains. A coordinated strategy using PREDICT-HD in combination with these other datasets offers the opportunity to identify genetic modifiers that influence the disease pathway(s) triggered by the HD mutation by enhancing or suppressing its timing and/or modifying its phenotypic expression. To identify genetic factors that alter the course of HD, we will use a combination of genome-wide association (GWA) analysis of common variants to quantitative HD phenotypes and analysis of rare SNPS identified by whole exome sequencing of 'extreme'individuals whose phenotypes differ substantially from those expected from their CAG-length and age. Completion of our aims will advance HD research toward effective therapeutics, as the identification of modifier genes, which alter the rate or expression of the disease in human patients, could provide 'pre-validated'targets for therapeutic development as well as a new tool for stratifying clinical trials to maximie their informativeness.
This grant will use a combination of genetic strategies including comparison of individuals representing opposite extremes of the manifestations of Huntington's disease to identify genetic factors that modify the course of the disorder and therefore provide valid targets for therapeutic development.
|Aylward, Elizabeth H (2014) Magnetic resonance imaging striatal volumes: a biomarker for clinical trials in Huntington's disease. Mov Disord 29:1429-33|