Progress and pitfalls in the functional analysis of OA susceptibility alleles

Abstract

Better knowledge of variation in the human genome and the availability of novel technologies allowing the simultaneous assessment of millions of single nucleotide polymorphisms (SNP) using DNA microarrays, have dramatically changed the landscape of genetic research. Genome wide association studies (GWAS) for complex diseases have generated a wave of enthusiasm in the community and lead to substantial progress in understanding many chronic diseases. However, analyzing GWAS studies in osteoarthritis is still a major challenge. Large patient and control cohorts are necessary and phenotype definitions, joints of interest as well as the chronic progressive nature of the diseases have raised enormous challenges for genetic researchers in this field. Nevertheless, different genetic regions have been associated with OA. Identification of regions or even of specific SNPs does not directly demonstrate the involvement of a given gene. Therefore, GWAS studies only provide a starting point to better understand the pathophysiology of disease and the identification of therapeutic targets and strategies. The functional genomics approaches includes different in vitro and in vivo models. The challenges following GWAS are clearly illustrated by the identification of an OA locus on Chromosome 9 that harbors different genes which all could involved in OA. Current evidence suggest that GPR22 and COG5 could play a role in OA but other effects from the C9 cluster cannot be excluded. Moreover, associated regions do not only harbor genes but also other regulators of biological processes such as miRNAs. GWAS studies also will only identify common variants often with limited impact on the heritability of disease, whereas rare variants in genes may have a more profound effect on disease development in an affected individual. Therefore, novel technologies such as next generation sequencing likely will provide additional tools to understand processes that define OA. Again, functional genomic strategies identifying the roles of specific genes and their variants in joint and joint-associated studies will be necessary to provide a full picture.