Lifestyle, Genetics, and Their Interactions in Determining Parkinson’s Disease Risk

Abstract

Parkinson’s disease is the second most common neurodegenerative disease, afflicting 1-2% of the population over the age of 65, and its prevalence is expected to rise as the population of older adults increases, highlighting the importance of prevention and treatment. In this dissertation, we investigated the associations between dietary, lifestyle, and genetic factors and PD risk, using data from three large prospective cohorts: the Nurses’ Health Study, the Health Professionals Follow-up Study, and the Cancer Prevention Study II Nutrition Cohort. For all analyses, we assessed diet using validated food frequency questionnaires; self-administered biennial questionnaires were used to identify PD cases, who were then confirmed by neurologists specializing in movement disorders via medical records. Cox proportional hazards models and conditional logistic models were used to calculate the relative risks (RR) of PD and 95% confidence intervals (CI). In addition, we assessed multiplicative interactions by conducting likelihood ratio test and additive interaction using three indices: the relative risk due to interaction (RERI), the attributable proportion (AP), and the synergy index (SI). In Chapter 1, we found that total caffeine intake was protective against PD in women who have never used postmenopausal hormone therapy (PMH) and men; the pooled multivariable-adjusted RR comparing the highest to lowest quintile of caffeine intake in men and women with never PMH use was 0.62 (95% CI= 0.39, 0.98; p = 0.04). In addition, as the pathogeneses of many complex diseases involve multiple components, we examined how genetic factors may influence the association between caffeine intake and PD risk in Chapter 3, but we did not find sufficient evidence for the presence of an interaction between caffeine intake and GRIN2A and CYP1A2 polymorphisms. In Chapter 2, we found that risk scores composed of predetermined lifestyle risk factors and family history of PD was strongly associated with overall risk for men and women; we report that factors may combine to influence PD risk by interacting with each other. Our findings show that in addition to individual risk factors, there may be a complex interplay between multiple factors to potentially contribute to the neurodegeneration in Parkinson’s disease.