Genetic association studies for complex traits: relevance for the sports medicine practitioner

In this issue of BJSM , September et al 1 report DNA variants within the COL5A1 gene among patients with Achilles tendinopathy (the cases) and among controls with no tendinopathy, matched for age and country of origin. Their findings suggest that a common DNA variation in the COL5A1 gene may be a risk factor for Achilles tendinopathy. Replication of their results among larger cohorts will be necessary to validate this finding. It can be a challenge for the busy sports medicine practitioner to distil the clinical relevance of association studies such as this one. Although genetic testing for mendelian (single-gene) disorders is widely available in many countries, genetic testing for single-nucleotide polymorphisms (SNPs) is generally unavailable outside research laboratories. With certain notable exceptions (eg, the link between apoE variants, cardiovascular and neurological disease),2-4 statistical associations between common SNPs and complex diseases have not been borne out by further study. Numerous pitfalls occur in both the design and interpretation of these studies, which has resulted in a poor track record for independent replication. Thus, a brief summary of these pitfalls may be useful to the BJSM ’s readership. By way of background, there are just over 14 million SNPs known to exist in the human genome.5 Most of these exist in two possible forms, reflecting variation in the sequence that arose as a new mutation many generations ago. At some loci, any of three or even all four DNA bases (adenine, guanine, cytosine and thymine; A,G, C and T) may occur at measurable frequency in a population. Once a variant’s frequency reaches 1% of all alleles in the population, such a variant is no longer considered a “mutation,” but rather a “polymorphism.” Recent advances in the rapidity and cost-effectiveness of DNA sequencing technologies have enabled the assessment …