From Genes to Trajectories: Mapping Genetic Influences on Huntington’s Disease Progression

Background There are many diseases with established genetic factors, such as Huntington’s disease (HD), that are characterized by variable rates of progression. However, beyond the contribution of the known genetic factors—in this case the Huntingtin (HTT) gene—the impact of the full human genome on the natural progression of such diseases throughout a patient’s life remains largely unknown. Motivation The increased availability of genome wide association (GWA) data in HD gene expansion carriers (HDGECs), combined with the clinical assessment scores on the same set of patients, has provided a perfect opportunity to assess the potentially broader genetic impact on the natural progression of HD. As increasing amounts of GWA data becomes available more generally, it is our expectation that the methodology developed for HD will be applicable to other diseases with a strong genetic component. Method A genetics driven, probabilistic disease progression model was built to identify and investigate the ways in which a range of genetic factors affect the natural progression of HD. Results Several SNPs were discovered to have previously undocumented affects at different stages of disease progression for HD. This discovery may shed light on the potential mechanistic impact of previously unidentified genes on HD that may have implications for clinical management. This result also establishes the potential application of this methodology to other genetic diseases.