THE RELATIONSHIP BETWEEN SLEEP AND PARKINSON'S DISEASE PROGRESSION: A MENDELIAN RANDOMIZATION STUDY

Abstract Introduction Sleep disturbances and disorders are common in Parkinson’s disease and significantly impact quality of life. Often, such sleep disturbances are considered sequelae of neurodegeneration affecting sleep-wake circuitry. However, there is emerging evidence that sleep disturbance may itself play a causal role in neurodegenerative processes via altered clearance of pathological proteins. Whether sleep disturbance affects the pathological progression of Parkinson’s disease is unknown. Recently, a several genetic variants have been discovered for sleep-related parameters through genome-wide association studies (GWAS) providing a unique opportunity to examine the evidence for causal relationships through the use of the Mendelian randomization. Methods To elucidate the causality between sleep disorders and progression of Parkinson’s disease, we performed two sample Mendelian randomization analysis using genetic variants identified from publicly available GWAS data for sleep variables including insomnia, sleep duration, chronotype, napping and daytime sleepiness as exposure variables. Outcome measures were derived from a large collective GWAS of PD progression (N=4093 cases) including the Unified Parkinson’s disease rating scale (UPDRS total and UPDRS- III), motor fluctuations, Age of onset of PD (PD-AOO), Mini-mental state examination (MMSE) and Montreal Cognitive Assessment (MOCA). The robustness of results was examined using conventional Mendelian randomization sensitivity analyses. Results Genetic liability to increased sleep duration was associated with a lower rate of progression of motor symptoms in PD using UPDRS-III score. Meanwhile insomnia was associated with increased rate of motor progression of PD. Predisposition to daytime sleep was associated with lower rates of progression of cognitive decline in PD measured using MMSE. No robust relationships were determined between markers of progression and chronotype or daytime napping. Statistical measures showed significant pleiotropy for the relationships identified. Conclusion Sleep-related variables may have a deterministic role in the clinical progression in Parkinson’s disease and may represent a modifiable target for altering the trajectory of neurodegeneration. Support (If Any)