Assessment of causal effects of physical activity on neurodegenerative diseases: A Mendelian randomization study

Abstract

Background: Physical activity has been hypothesized to play a protective role in neurodegenerative diseases. However, effect estimates previously derived from observational studies were prone to confounding or reverse causation.

Methods: We performed a two-sample Mendelian randomization (MR) analysis to explore the causal association of accelerometer-measured physical activity with 3 common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We selected genetic instrumental variants reaching genome-wide significance (p < 5 × 10^-8) from 2 largest meta-analyses of about 91,100 UK Biobank participants. Summary statistics for AD, PD, and ALS were retrieved from the up-to-date studies in European ancestry led by the international consortia. The random-effect, inverse-variance weighted MR was employed as the primary method, while MR pleiotropy residual sum and outlier (MR-PRESSO), weighted median, and MR-Egger were implemented as sensitivity tests. All statistical analyses were performed using the R programming language (Version 3.6.1; R Foundation for Statistical Computing, Vienna, Austria).

Results: Primary MR analysis and replication analysis utilized 5 and 8 instrumental variables, which explained 0.2% and 0.4% variance in physical activity, respectively. In each set, one variant at 17q21 was significantly associated with PD, and MR sensitivity analyses indicated them it as an outlier and source of heterogeneity and pleiotropy. Primary results with the removal of outlier variants suggested odds ratios (ORs) of neurodegenerative diseases per unit increase in objectively measured physical activity were 1.52 for AD (95% confidence interval (95%CI): 0.88-2.63, p = 0.13) and 3.35 for PD (95%CI: 1.32-8.48, p = 0.01), while inconsistent results were shown in the replication set for AD (OR = 1.06, 95%CI: 1.01-1.12, p = 0.02) and PD (OR = 0.99, 95%CI: 0.88-0.12, p = 0.97). Similarly, the beneficial effect of physical activity on ALS (OR = 0.51, 95%CI: 0.29-0.91, p = 0.02) was not confirmed in the replication analysis (OR = 0.96, 95%CI: 0.91-1.02, p = 0.22).

Conclusion: Genetically predicted physical activity was not robustly associated with risk of neurodegenerative disorders. Triangulating evidence across other studies is necessary in order to elucidate whether enhancing physical activity is an effective approach in preventing the onset of AD, PD, or ALS.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Genetic epidemiology; Mendelian randomization; Parkinson's disease; Physical activity.

Graphical abstract

Fig. 1

Schematic of the Mendelian randomization study and key assumptions. First, genetic instrumental variants associated with accelerometer-measured physical activity at genome-wide significance (p < 5 × 10⁻⁸) all satisfied the relevance assumption. Second, there scarcely existed any factors confounding the natural randomization in gamete formation to violate the independence assumption. Lastly, potential horizontal pleiotropic effects violating the exclusion-restriction assumption were inspected. AD = Alzheimer's disease; ALS = amyotrophic lateral sclerosis; PD = Parkinson's disease; SNPs = single-nucleotide polymorphisms.

Fig. 2

Mendelian randomization analysis of the effect of physical activity on AD. Scatter plots depict the genetic variant−physical activity effect (point and horizontal line) vs. the genetic variant−AD effect (point and horizontal line). The fitted line denotes the overall estimate given by the IVW method with all instrumental variants included (solid line) or after the removal of certain variant (dashed line). Regarding the 2 variants significantly associated with Parkinson's disease, rs2696625 in the primary analysis (A) showed significant heterogeneity (Cook's D = 62.10; Cochran's p_Het = 0.04), while rs55657917 in the replication set (B) presented minimal heterogeneity (Cook's D = 0.95; Cochran's p_Het = 0.08). AD = Alzheimer's disease; Cook's D = Cook's distance; IVW = inverse-variance weighted; OR = odds ratio; SNP = single-nucleotide polymorphism.

Fig. 3

Mendelian randomization analysis of the effect of physical activity on PD. Scatter plots depict the genetic variant−physical activity effect (point and horizontal line) vs. the genetic variant−PD effect (point and horizontal line). The fitted line denotes the overall estimate given by the IVW method with all instrumental variants included (solid line) or after the removal of certain variant (dashed line). Both in the primary (A) and replication (B) analysis, each variant at 17q21.3 manifested significant heterogeneity (rs2696625, Cook's D = 42.36; Cochran's p_Het < 0.001; and rs55657917, Cook's D = 0.53; Cochran's p_Het < 0.001). Cook's D = Cook's distance; IVW = inverse-variance weighted; OR = odds ratio; PD = Parkinson's disease; SNP = single-nucleotide polymorphism.

Fig. 4

Mendelian randomization analysis of the effect of physical activity on ALS. Scatter plots depict the genetic variant−physical activity effect (point and horizontal line) vs. the genetic variant−ALS effect (point and horizontal line). The fitted line denotes the overall estimate given by the IVW method with all instrumental variants included (solid line) or after the removal of certain variant (dashed line). Either in the primary (A) or replication (B) instrumental set, the 17q21.3 variant showed negligible heterogeneity (rs2696625, Cook's D = 0.33; Cochran's p_Het = 0.55; and rs55657917, Cook's D = 0.32; Cochran's p_Het = 0.29). ALS = amyotrophic lateral sclerosis; Cook's D = Cook's distance; IVW = inverse-variance weighted; OR = odds ratio; SNP = single-nucleotide polymorphism.