PhD in Dementia Research - Biological dissection of phenotypic heterogeneity in HD

While genetic susceptibility to Huntington’s disease (HD) is determined by the length of the CAG repeat in the HTT gene [1], there is considerable variation in both the age at onset and the psychiatric and cognitive symptoms presented by patients. This variation may indicate genetic heterogeneity, with different biological processes acting in subgroups of patients, indexed by their symptoms. As part of the GeM Consortium, we have implicated DNA repair pathways as modifiers of age at onset [2] and progression [3], and preliminary results indicate shared genetic susceptibility between psychiatric disorders and psychiatric symptoms in HD. This project aims to refine this shared susceptibility into biological processes relevant to specific symptom combinations using novel methods leveraging functional annotations. Genetic overlap between psychiatric and neurological disorders and HD symptoms will be assessed by deriving polygenic risk scores (PRS) [4] using large publically-available GWAS (Psychiatric Genomic Consortium, IGAP) as training sets. These will be tested in approximately 6,000 HD patients from the REGISTRY database for which we have GWAS genotypes, with 4,000 further genotyped individuals expected during the course of the project. Methods will be developed to utilise the shared genetic liability between psychiatric and neurological disorders to derive more powerful PRS [5], and also to deconvolute the shared genetics among these disorders into components unique to particular disorders [6]. These will also be used to investigate whether particular biological pathways relevant to HD and/or psychiatric disorders correlate with particular HD symptoms or symptom clusters. We will develop methods to utilise functional annotations shown to be enriched for association signal to improve the power of both PRS and pathway analysis methods, and also adapt these to analyse rare variation in the exome sequences of 500 REGISTRY HD patients. The methods developed in this project will be applicable to other disorders of interest to the DRI (such as Alzheimer’s disease).

This project will be performed in the UK DRI Cardiff and the MRC Centre for Neuropsychiatric Genetics and Genomics where there is the necessary statistical, biological and clinical expertise.