Insights from human genetic studies into the pathways involved in osteoarthritis

Genetic studies have revealed that most loci associated with osteoarthritis (OA) show ethnic stratification, with limited overlap between Asian and European populations. Consequently, such studies have often focused on particular ethnic groups, with those performed in European cohorts yielding the most replicated associations. As for other common diseases, the OA susceptibility loci mapped to date account for only a fraction of disease heritability. Nevertheless, analysis of these loci could identify biological pathways related to OA pathogenesis. Such an approach is taken in this Review and provides valuable insights into OA aetiology. For example, several of the loci associated with OA contain genes encoding key regulators of skeletogenesis and endochondral ossification. Furthermore, direct and indirect regulation of gene transcription is highlighted as an important factor in this disease. Interestingly, genes encoding structural proteins of the cartilage extracellular matrix do not seem to be a repository for OA susceptibility. Therefore, susceptibility might operate at a regulatory rather than a structural level, which is a potentially promising finding, as the activities of regulators are amenable to therapeutic modulation. Greater clarity will emerge as more association signals are identified; nonetheless, patterns of aetiology are clearly discernible, from a molecular perspective, even with the relatively small number currently available.