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

Abstract

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.

Keywords: DNA; GWAS; athletic performance; endurance; exercise; genetic markers; genotype; muscle fibers; sports; sprinters; talent identification.

Figure 1

A schematic overview of the study design and findings.

Figure 2

Effect of acute endurance (n = 7) and strength (n = 7) exercise on CDKN1A gene expression of m. vastus lateralis of young men. Time points corresponding to Pre, 2.5, and 5 h post-exercise are shown. * p < 0.0001. This figure was generated using publicly available data from Vissing and Schjerling [48].

Figure 3

Differences in the resting CDKN1A gene expression between strength (n = 7) and endurance (n = 11) athletes. * p = 0.002.

Figure 4

Scheme showing the hypothesized mechanism for the association of rs236448 alleles and various factors with muscle fiber composition and exercise-related phenotypes.