We will investigate the role of environmental factors on likelihood of developing Parkinson’s disease (PD) and the severity of the disease in parkinsonism associated with the LRRK2 gene (LRRK2 PD). The effects of environmental factors have not been systematically investigated in LRRK2 PD. We believe that there is a high probably this project will provide important new knowledge regarding gene-environment interaction in LRRK2 PD.
Using clinical and environmental data already collected on members of two large cohorts of LRRK2 mutation or risk variant carriers (“mutation carriers”), our first aim will investigate the relationship between disease risk and environmental exposures using a time-to-event analysis including both carriers with PD and carriers without PD and time to PD diagnosis as the outcome. Our second aim will investigate the relationship between clinical characteristics of PD and environmental exposures in carriers with PD using a case-control design, where “cases” are those with a particular characteristic.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Mutations and polymorphisms in the LRRK2 gene have been associated with parkinsonism in populations worldwide. However, not all people with these mutations develop PD. These observations suggest that the effect of genetic variation in LRRK2 on disease risk and phenotype depends on co-occurrence of other environmental and genetic factors. Importantly, because many are modifiable, identifying environmental factors can lead to readily applied interventions.
We hypothesize that exposures associated with higher risk of idiopathic PD (e.g. traumatic brain injury, pesticides) will be associated with earlier age at LRRK2 PD onset, and those associated with lower risk of idiopathic PD (e.g. tobacco, caffeine) will be associated with later onset of LRRK2 PD. We also expect that environmental exposures associated with higher risk of idiopathic PD will be directly associated with more severe LRRK2 PD and exposures associated with lower risk will be inversely associated. This project provides a unique opportunity to study the role of environmental factors in LRRK2 PD by combining two well-studied cohorts.