Genetic studies of elite athlete status

In the past decade, limited progress has been made in identifying genetic associations with performance and health-related fitness phenotypes due to the use primarily of the traditional candidate-gene approach involving small sample sizes and few coordinated research efforts. Much of the genetic data relating to human performance has been generated while exploring the aetiology of lifestyle-related disorders such as obesity and type 2 diabetes mellitus (T2DM). As of 2008, over 200 autosomal gene entries and quantitative trait loci have been reported to be significantly associated with performance and health-related fitness. However, most genetic findings to date have been inconclusive due to studies employing relatively small sample sizes and predominantly single-gene approaches which are especially prone to type I errors. It is widely accepted that there will be many genes involved in sporting performance and health-related fitness phenotypes, and hence it is timely that genetic research has moved to the genomics era with the use of a genome-wide approach (e.g. genotyping a large number of variants simultaneously across the entire human genome) in a well-phenotyped, large cohort. This thesis summarizes the recent findings of genetic predisposition to elite human performance by using the conventional candidate-gene approach as well as the unbiased genome-wide approach (i.e. genome-wide association studies, GWASs). The current candidate gene study focused on investigating whether polymorphisms in the angiotensin-converting enzyme (ACE) and α-actinin-3 (ACTN3) genes are associated with elite swimmer status (stratified by swimming distance) in Caucasians and East Asians. ACE I/D and ACTN3 p.R577X polymorphisms were genotyped for 200 elite Caucasian swimmers (short and middle distance, ≤ 400 m, n = 130; long distance, > 400 m, n = 70) and 326 elite Japanese and Taiwanese swimmers (short distance, ≤ 100 m, n = 166; middle distance, 200–400 m, n = 160). Logistic regression and multiple-testing adjustment were applied to test for these genetic associations. ACE I/D was found to be associated with swimmer status in Caucasians, with the D allele being overrepresented in short-and-middle-distance swimmers with the largest effect being observed for the I-allele-dominant model (odds ratio = 1.90; logistic regression p = 0.001; permutation test p = 0.0005). In East Asians, however, the I allele was overrepresented in the short-distance swimmer group under the D-allele-dominant model (odds ratio = 1.52; logistic regression p = 0.012; permutation test p = 0.0098). The ACE I/D association findings in the elite swimmer cohorts showed that different risk alleles responsible for the associations were observed in swimmers of different ethnicities. ACTN3 p.R577X was not statistically significantly associated with swimmer status in either Caucasian or East Asian population. The lack of associations between the functional ACTN3 p.R577X polymorphism and elite swimmer status in both cohorts were in contrast to many associations with power-/sprint- performance in other sports previously reported. Since current sample size is relatively modest, larger studies will be required to further confirm these results, which, however, have highlighted that it is probable that the genes studied here are not the resulting variants responsible for the phenotypes of interest, despite the associations reported by previous candidate-gene studies in other sports. The present GWAS were conducted in an attempt to identify common polymorphisms associated with elite sprint and endurance status in Jamaicans, African-Americans and Japanese, respectively. These unique athlete cohorts comprised of athletes of the highest standard including world record holders, world champions, Olympians and winners of other international events. Following exclusion of individuals and markers failing the quality control filters, 609,801 autosomal SNPs in 88 Jamaican sprint athletes and 87 Jamaican controls, 637,991 autosomal SNPs in 79 African-American sprint athletes and 391 African-American controls, and 541,179 autosomal SNPs in 114 Japanese athletes (including 60 endurance and 54 sprint athletes) and 116 Japanese controls, were available for association analyses. 17, 7, 36 and 21 SNPs were associated with elite athlete status at a p < 0.00005 threshold of significance in elite Jamaican sprint, African-American sprint, Japanese sprint and Japanese endurance GWAS sets, respectively. Meta-analyses were performed for SNPs with unadjusted association p < 0.00005 across the sprint GWAS sample sets (i.e. Jamaican sprint, African-American sprint, Japanese sprint GWAS cohorts), using the fixed-effects model. The top 17 SNPs (unadjusted p < 0.00005) from the Jamaican sprint cohort were extracted from the association results of African-American sprint, Japanese sprint cohorts, respectively, for the combined effects to be calculated using a meta-analysis method. The same procedure was also applied to the top hits in African-American and Japanese cohorts. The combined odds ratio for the top meta-analysis hit was 2.61 (p = 0.000000466) with the allele G associated with elite sprint status in Jamaicans, African-Americans and Japanese. Although meta-analysis has increased the sample size and power to detect associations in the current GWAS, independent replication of these associations followed by functional studies of replicated SNPs are required. The results of the association studies presented here are the very first positive findings from GWAS involving world-class athletes and these encouraging findings provide further evidence of the importance of genetic predisposition to elite human performance. GWAS of athletes of the highest performance caliber as well as the application of meta-analysis across several initial GWASs seemed to help to circumvent the need for very large cohort of elite athletes and increase the study power. Nevertheless, future GWAS involving large well-funded collaborations using larger cohorts of elite athletes will be necessary in order to explore further the genetic architecture underlying elite human performance. Such initiatives may also allow gene x gene and gene x environment interactions to be explored to some extent, as well as the predictive utility of this genomic research.