Exercise-Related Heart Rate Response Traits and Parkinson’s Disease: Genetic Correlation, Gene-Based Analysis, and Bidirectional Mendelian Randomization

Background: Recent observational studies suggest that impaired exercise-related heart rate responses may precede the clinical diagnosis of Parkinson’s disease (PD). However, it remains unclear whether this association reflects shared common-variant genetic architecture, bidirectional causal effects, or other mechanisms. Methods: We analyzed genome-wide association study (GWAS) summary statistics for post-exercise heart rate recovery at 50 s (N = 54,137), heart rate increase during exercise (N = 54,137), and PD (N = 482,730). Linkage disequilibrium score regression (LDSC) estimated genetic correlations (rg). Gene-based, gene-set, and gene-property analyses were conducted using Multi-marker Analysis of GenoMic Annotation (MAGMA) via Functional Mapping and Annotation (FUMA). Bidirectional Mendelian randomization (MR) was used to assess potential causal effects. Results: LDSC revealed no significant genetic correlation between PD and post-exercise heart rate recovery at 50 s (rg = −0.006, P = 0.903) or heart rate increase during exercise (rg = −0.021, P = 0.694). No overlap was observed between the sets of genes reaching Bonferroni-corrected significance for PD and either exercise-related heart rate response trait. Likewise, no overlap was observed among significant gene sets or tissue-specific enrichment results after FDR or Bonferroni correction. Bidirectional MR analyses did not identify statistically supported associations within the precision of the available data, with a limited number of instruments and wide confidence intervals. Conclusions: These findings do not support strong shared common-variant genetic architecture or statistically supported bidirectional causal associations between PD and exercise-related heart rate response traits. They refine the interpretation of prior observational associations. Other mechanisms cannot be excluded.