Study Rationale:
Genetic studies looking at differences in DNA have identified key genes that can cause Parkinson's disease (PD) in families and contribute to the overall risk of developing sporadic disease. The most common genetic cause of both inherited and sporadic disease is a specific change in a gene called Leucine-Rich Repeat Kinase 2 (LRRK2). Through our work and others, a portion of the LRRK2 gene which makes the LRRK2 protein contains both rare and common DNA changes that influence the onset of PD. However, the regions within the LRRK2 gene that do not code for protein, but likely regulate the levels produced, have not yet been comprehensively screened for other variations and could play a role in Parkinson's.
Hypothesis:
Genetic variations in the LRRK2 gene change an individual's risk of developing PD. Variation in the regions of the gene that don't make the LRRK2 protein also influence disease risk but are yet to be identified.
Study Design:
We have shown that not all the risk associated with the LRRK2 gene can be accounted for by protein coding variants and, therefore, the goal of our present study is to investigate other types of DNA variations and identify the specific variants driving risk. We will use novel DNA sequencing technologies to extract the region containing the LRRK2 gene from the rest of the genome and sequence this region in both those with PD and healthy participants to look for differences that may affect disease risk.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Clarifying genetic risk factors will help in pre-clinical diagnosis and will help determine which individuals are carrying a genetic risk factor at the LRRK2 gene. These specific genetic variants may provide further insight into the mechanism of how altered levels or dysfunctional LRRK2 leads to the development of Parkinson's; this may identifty therapeutic targets or provide alternative interventional strategies.
Next Steps for Development:
The identification of these variants will not only allow us to better identify those at risk of the disease but will also help define groups of patients who would be best selected for LRRK2-targeted clinical trials.