Genetic and Clinical Basis for Inflammatory Bowel Disease and Parkinson's Disease Comorbidity

Study Rationale:
Recent studies have shown that mutations in the LRRK2 gene, known to increase the risk of Parkinson’s disease (PD), are also associated with inflammatory bowel disease (IBD), a chronic disorder of the gut characterized by recurrent abdominal pain, diarrhea, rectal bleeding and weight loss. Subsequently, IBD patients have been found to be at a higher risk of developing PD compared to the general population. Given that onset of IBD proceeds that of PD by ~25-30 years, finding genetic mutations in IBD patients with PD and characterizing the course of their disease could help recognize early signs of PD and design novel therapies to prevent or postpone PD in high-risk individuals.

Hypothesis:
We hypothesize that PD patients with IBD will carry unique mutations in LRRK2 and other genes and display distinct clinical course compared to patients with only IBD or PD and that IBD-directed therapies can reduce the risk of PD later in life.

Study Design:
We are proposing to use medical information from large national registries to determine clinical features in patients with both IBD and PD and explore if certain therapies prescribed to IBD patients could reduce risk of PD. We will also identify changes in the DNA sequence of individuals with both diseases and compare them to the genetic make-up of individuals with IBD only, PD only and unaffected control volunteers.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
The proposed study will help develop early genetic and clinical biomarkers of PD in IBD patients decades before the onset of PD. Genetic mutations found in patients with both IBD and PD may help recognize individuals at high risk of PD early on, understand the pathophysiology of PD, and lead to the development of novel drugs to treat or prevent PD.

Next Steps for Development:
We will validate the effects of newly identified mutations in large cohorts of PD cases and controls. We will also design pre-clinical studies to determine mitigating effects of IBD-directed therapies on the development of neuroinflammation. Lastly, we will conduct in silico studies to identify existing compounds that target the genes associated with IBD-PD comorbidity for drug development and repurposing.