Unpicking Causal Relationships Between Grip Strength and Cardiorespiratory Fitness: A Bidirectional Mendelian...

Understanding the dominant direction of association between cardiorespiratory fitness (CRF) and grip strength could help refine physical activity recommendations. We performed a Mendelian Randomization (MR) analysis to elucidate the bidirectional relationship between CRF and grip strength (GS). Using an inverse-variance weighted (IVW) MR framework, we estimated the strength of the GS (exposure)-CRF (outcome) association using genome-wide association summary data. When examining the CRF (exposure)-GS (outcome) association, the CRF genetic instrument was related to individual-level GS phenotypic data in 367 693 UK Biobank participants. Several sensitivity analyses were performed (e.g., MR-Egger, MR-weighted median estimator and MR-PRESSO) and both measures were scaled by body weight (w). In the direction GS-to-CRF, a 1-unit increase in GSw (i.e., GS/weight) was associated with 1.70 mL/kg/min (95% confidence interval (CI): 1.14,2.27) higher CRFw (IVW model). This finding persisted across most sensitivity analyses. In the reverse direction, there was no evidence supporting an effect of CRFw on GSw, e.g., a 1-unit increase in CRFw led to a 0.00 kg/kg (95% CI: -0.01,0.02) higher GSw (IVW model). Our finding of a dominant direction of association from greater GS to higher CRF is relevant when considering how to promote physical activity guidelines. For example, placing too much emphasis on improving/maintaining CRF is unlikely to result in maximum benefits for other fundamental components of physical fitness, particularly muscle strength.