The role of common DNA variants in Parkinson's disease

Nicholas Wood

Roger Barker, David Burn, Patrick Chinnery, John Hardy, Huw Morris, Karen E Morrison Carl Clarke, Nigel Williams.

PD is common, incurable and severely disabling. Recent studies have estimated the cost in the UK alone to be ~£3bn. Recent epidemiological studies suggest an annual incidence of 10,000 new cases. As the population ages the prevalence is increasing and represents a significant health burden. The available drugs provide only symptomatic relief and there is urgent need for new data to point the way to therapies which modify the course of the disease. Genetic advances in our understanding of familial forms of PD have let to whole new areas of research. However the DNA variants underpinning common 'sporadic' PD remain almost entirely unknown. The field is littered with numerous candidate polymorphism and occasional comprehensive candidate gene studies (on a small scale).

The primary aim is to map common variants which increase the risk of developing PD. However in the process the clinical and pathological dataset we have at our disposal means that we will also be able to study DNA variation which underlies clinical and pathological subtypes of PD. We see this as the first step in identifying novel genes which will require functional follow up. The specific aims are:

• whole genome analysis of PD in 2000 UK cases and controls
• Identification of the strongest association regions through replication in a US/NIH data set
• Preliminary functional characterization of positive association regions using correlation with whole genome brain expression data to infer their possible effects on gene expression
• Preliminary identification of variants that influence sub-phenotypes such as dementia and L-DOPA related dyskinesias.
• Identification of genes and pathways that require further genetic and functional characterization using our resource of PD DNA, PD flash-frozen brain, model organism research and in vitro techniques.