Background Physical activities are widely implemented for non–pharmacological intervention to alleviate depressive symptoms. However, there is little evidence supporting their genotype–specific effectiveness in reducing the risk of intentional self–harm in patients with depression. Aims To assess the associations between physical activity and self–harm behavior and determine the recommended level of physical activity across the genotypes. Method We developed the bidirectional analytic model to investigate the genotype–specific effectiveness (BAIGE) on UK Biobank. After the genetic stratification on the depression phenotype cohort using hierarchical clustering, multivariable logistic regression models and Cox proportional hazard models were built to investigate the associations between physical activity and the risk of intentional self–harm behavior. Results A total of 28,923 subjects with depression phenotypes were included in the study. In retrospective cohort analysis, the moderate and highly active groups were at lower risk of self–harm behavior (moderate: adjusted odds ratio [OR], 0.77 [95% CI, 0.61–0.98], high: OR, 0.76 [95% CI, 0.60–0.97]). In the follow–up prospective cohort analysis, light–intensity physical activity (LIPA) was associated with a lower risk of hospitalizations due to self–harm behavior in one genetic cluster (adjusted hazard ratio [HR], 0.26 [95% CI, 0.08 – 0.88]), which was distinguished by three genetic variants: rs1432639, rs4543289, and rs11209948. Compliance with the guideline–level moderate–to–vigorous physical activities was not significantly related to the risk of hospitalizations. Conclusions Physical activities, particularly a certain amount of light–intensity physical activity, mitigate the risk of hospitalizations due to self–harm in depression patients with a specific genotype.

The authors have declared no competing interest.

This study was supported by a Medical Scientist Training Program from the Ministry of Science & ICT of Korea.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All the source data were openly available before the initiation of the study with the approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) approval (REC reference: 21/NW/0157, IRAS project ID: 299116). Please refer to the UK biobank instruction page(https://biobank.ndph.ox.ac.uk/showcase/) for more information.

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The data supporting the findings of this study are available from UK Biobank (https://www.ukbiobank.ac.uk/) and can be requested under license.

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