Association analysis of indel variants and gene expression identifies MDM4 as a novel locus for skeletal muscle hypertrophy and power athlete status

Insertions and deletions (indels) are the second most common type of variation in the human genome, with limited data on their associations with exercise-related phenotypes. The aim of the study was to examine the association between 18,370 indel variants and athletic performance, followed by functional and bioinformatic studies in 356,006 individuals. In a case-control study (n=80), the D allele of the functional (eQTL) rs35493922 I/D polymorphism of the MDM4 gene was over-represented in power athletes (77.4%) compared to controls (32.5%; OR=7.1, p=9.8×10-6) and endurance athletes (48.3%; OR=3.7, p=0.0013). Furthermore, the D allele was positively associated (p=0.0013) with greater whole-body fat-free mass in the UK Biobank cohort (n=354,808). MDM4 encodes a nuclear protein which inhibits the activity of the p53 tumor suppressor protein (induces skeletal muscle fibre atrophy). Accordingly, in a muscle biopsy study of athletes (n=22), we found that MDM4 expression was significantly (p=0.0009) higher in the m. vastus lateralis of power compared to endurance athletes and was positively correlated with the percentage of fast-twitch muscle fibres (r=0.56, p=0.0062) and relative area occupied by fast-twitch muscle fibres (r=0.55, p=0.0086). The association between the MDM4 gene expression and increased proportion of fast-twitch muscle fibres has been confirmed in two additional cohorts (m. vastus lateralis: n=291, p=0.001; m. gastrocnemius: n=791, p=0.003). Furthermore, it was shown that the expression of MDM4 significantly increased (n=14, p=0.0009) in response to strength training (compared to endurance training). In conclusion, MDM4 is suggested as a potential regulator of muscle fibre specification and size, with its indel variant associated with power athlete status.