Genome-Wide Association Study Identifies CDKN1A as a Novel Locus Associated with Muscle Fiber Composition.

Muscle fiber composition is associated with physical performance, with endurance athletes having a high proportion of slow-twitch muscle fibers compared to power athletes. Approximately 45% of muscle fiber composition is heritable, however, single nucleotide polymorphisms (SNP) underlying inter-individual differences in muscle fiber types remain largely unknown. Based on three whole genome SNP datasets, we have shown that the rs236448 A allele located near the cyclin-dependent kinase inhibitor 1A ( CDKN1A ) gene was associated with an increased proportion of slow-twitch muscle fibers in Russian ( n = 151; p = 0.039), Finnish ( n = 287; p = 0.03), and Japanese ( n = 207; p = 0.008) cohorts (meta-analysis: p = 7.9 × 10 -5 . Furthermore, the frequency of the rs236448 A allele was significantly higher in Russian ( p = 0.045) and Japanese ( p = 0.038) elite endurance athletes compared to ethnically matched power athletes. On the contrary, the C allele was associated with a greater proportion of fast-twitch muscle fibers and a predisposition to power sports. CDKN1A participates in cell cycle regulation and is suppressed by the miR-208b, which has a prominent role in the activation of the slow myofiber gene program. Bioinformatic analysis revealed that the rs236448 C allele was associated with increased CDKN1A expression in whole blood ( p = 8.5 × 10 -15 ) and with greater appendicular lean mass ( p = 1.2 × 10 -5 ), whereas the A allele was associated with longer durations of exercise ( p = 0.044) reported amongst the UK Biobank cohort. Furthermore, the expression of CDKN1A increased in response to strength ( p < 0.0001) or sprint ( p = 0.00035) training. Accordingly, we found that CDKN1A expression is significantly ( p = 0.002) higher in the m. vastus lateralis of strength athletes compared to endurance athletes and is positively correlated with the percentage of fast-twitch muscle fibers ( p = 0.018). In conclusion, our data suggest that the CDKN1A rs236448 SNP may be implicated in the determination of muscle fiber composition and may affect athletic performance.