Physical activity and Parkinson’s disease: a two-sample Mendelian randomisation study

Parkinson’s disease (PD) is the second most common neurodegenerative condition, and the number of people living with PD is projected to double by 2030. Physical activity is known to be protective for a wide range of chronic conditions (such as cardiovascular disease and cancer), and the evidence for protection against PD has strengthened in the past two decades. Meta-analysis of cohort studies has suggested that physical activity lowers the risk of PD.1 However, the causality of this association has not been established because conventional observational studies are susceptible to the effects of confounding and reverse causation. Of particular concern is the potential for reverse causation. Early prodromal disease features may make individuals become less physically active and induce a spurious inverse association. Nonmotor symptoms (hyposmia, constipation, sleep disorders) may precede diagnosis by up to two decades and could lower the propensity to engage in physical activity. We conducted a Mendelian randomisation (MR) study to examine the effect of accelerometer-measured physical activity on the risk of PD. MR exploits genetic variants as instrumental variables that affect the disease outcome through the exposure and allows to determine whether the exposure is a cause of the disease.2 The MR method diminishes confounding by environmental factors because alleles are randomly allocated when passed from parents to offspring at conception and avoids reverse causation because disease cannot affect genotype. We leveraged data from 91 084 UK Biobank participants3 for whom genome-wide …