P010 Assessing the effects of cardiorespiratory fitness and grip strength on depression and depression symptoms: a Mendelian randomization study in the UK biobank

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Background Depression is a highly prevalent common psychiatric disorder and a leading global contributor to chronic disability. Evidence regarding the beneficial effects of physical activity in preventing and treating depression has been accumulating for decades. However, little is known about underlying mechanisms, such as those relating to cardiorespiratory fitness (CRF) and muscle strength, and how they impact on depression and specific symptomology. We aimed to determine whether CRF and muscle strength causally effect depression and its individual symptoms. Methods We conducted a Mendelian randomisation (MR) analysis in up to 341,326 participants of European ancestry from UK Biobank (aged 37-73 years). Genetic variants from published genome-wide association studies (GWAS) of CRF and grip strength (to proxy overall muscle strength) were used to instrument exposures. A broad depression phenotype based on self-report and hospital records, as well as individual measures of depression symptoms from the Patient Health Questionnaire-9 (PHQ-9) were used as outcomes. Robustness to violations of instrumental variable assumptions was assessed using three additional methods: MR-Egger, weighted median MR, and MR-PRESSO. Analysis was repeated stratifying by sex. To address potential bias due to sample overlap, we also repeated analyses using summary statistics from a major depressive disorder (MDD) GWAS excluding UK Biobank participants. All analyses were conducted using Stata v18, Plink v1.9, R and RStudio v4.3.2. Results There was no clear evidence for causal effects of CRF on any depression outcome. There was robust evidence for an effect of greater grip on lower odds of broad depression (OR per 0.1kg increase in weight adjusted grip: 0.86, 95% CI:0.80,0.93), as well as the PHQ-9 items appetite changes (OR:0.56, 95% CI:0.49,0.65), and anhedonia (OR:0.79, 95% CI:0.69,0.90). Sensitivity analysis showed consistent effect estimates across MR-Egger, weighted median, and MR-PRESSO methods. In the main analysis, there was some evidence for effects of greater grip on lower odds of depressed mood (OR:0.85, 95% CI:0.74,0.97), psychomotor changes (OR:0.79, 95% CI:0.64,0.97), fatigue (OR:0.83, 95% CI:0.74,0.93) and concentration problems (OR:0.85, 95% CI:0.74,0.98). Effects were mostly driven by stronger associations in females, and, results replicated in the two-sample MR for MDD. Conclusion Muscle strength, especially in females, may represent an important modifiable factor for preventing and treating depression as well as several specific symptoms, including core symptoms such as anhedonia and depressed mood. Although our findings may not be generalisable, for example to non-Europeans, analyses were robust and yielded consistent results across complementary MR methods with differing assumptions.

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