Genome-wide association study of exercise-induced skeletal muscle hypertrophy and the construction of predictive...

The aim of the current study was to investigate interindividual differences in muscle thickness of the rectus femoris (MTRF) following 12 wk of resistance training (RT) or high-intensity interval training (HIIT) to explore the genetic architecture underlying skeletal muscle hypertrophy and to construct predictive models. We conducted musculoskeletal ultrasound assessments of the MTRF response in 440 physically inactive adults after the 12-wk exercise period. A genome-wide association study was used to identify variants associated with the MTRF response, separately for RT and HIIT. Using the polygenic predictor score (PPS), we estimated the genetic contribution to exercise-induced hypertrophy. Predictive models for the MTRF response were constructed using random forest (RF), support vector mac (SVM), and generalized linear model (GLM) in 10 cross-validated approaches. MTRF increased significantly after both RT (8.8%, P < 0.05) and HIIT (5.3%, P < 0.05), but with considerable interindividual differences (RT: -13.5 to 38.4%, HIIT: -14.2 to 30.7%). Eleven lead single-nucleotide polymorphisms in RT and eight lead single-nucleotide polymorphisms in HIIT were identified at a significance level of P < 1 × 10^-5. The PPS was associated with the MTRF response, explaining 47.2% of the variation in response to RT and 38.3% of the variation in response to HIIT. Notably, the GLM and SVM predictive models exhibited superior performance compared with RF models (P < 0.05), and the GLM demonstrated optimal performance with an area under curve of 0.809 (95% confidence interval: 0.669-0.949). Factors such as PPS, baseline MTRF, and exercise protocol exerted influence on the MTRF response to exercise, with PPS being the primary contributor. The GLM and SVM predictive model, incorporating both genetic and phenotypic factors, emerged as promising tools for predicting exercise-induced skeletal muscle hypertrophy.NEW & NOTEWORTHY The interindividual variability induced muscle hypertrophy by resistance training (RT) or high-intensity interval training (HIIT) and the associated genetic architecture remain uncertain. We identified genetic variants that underlie RT- or HIIT-induced muscle hypertrophy and established them as pivotal factors influencing the response regardless of the training type. The genetic-phenotype predictive model developed has the potential to identify nonresponders or individuals with low responsiveness before engaging in exercise training.