Causal associations of physical activity and leisure sedentary behaviors with age at onset of Huntington's disease: A mendelian randomization study

Abstract

Background: Huntington's disease (HD) is a neurodegenerative disorder for which effective therapies are currently lacking. Studies suggest that increasing physical activity (PA) and reducing leisure sedentary behavior (LSB) mitigate the progression of HD, but their causal relationship with the age at onset (AAO) of HD remains uncertain. To investigate this, we conducted the Two-sample Mendelian Randomization (MR).

Methods: Exposure were retrieved from the UK BioBank's (UKB) Genome-Wide Association Study (GWAS). PA included accelerometer-based average PA, vigorous PA, self-reported moderate-to-vigorous PA (MVPA), and light do-it-yourself activity. LSB included television (TV) time, computer time, and driving time. Outcome came from the GWAS of the GEM-HD Consortium. We applied several MR methods such as inverse variance weighted (IVW), MR-Egger regression, weighted median (WM) for sensitivity analysis.

Results: Increases in light PA (β = 8.53 years, 95 % CI = 10.64 to 44.09, P = 0.001) and accelerometer-based vigorous PA (β = 5.18, 95 % CI = 0.92 to 9.43, P = 0.017) delayed AAO of HD, while longer TV time was associated with earlier AAO of HD (β = -2.88 years, 95 % CI = -4.99 to -0.77, P = 0.007). However, other PA and LSB phenotypes did not significantly affect AAO of HD.

Conclusion: The study revealed a unidirectional causality between PA, LSB and the AAO of HD. Increasing PA and reducing TV time delay HD onset. Therefore, we recommend increasing physical activity and reducing sedentary behavior to delay the occurrence of motor symptoms for premanifest HD individuals.

Keywords: Huntington's disease; Leisure sedentary behaviors; Mendelian randomization; Physical activity.