Osteoarthritis (OA) is the most prevalent form of arthritis and is characterised by deterioration of the articular cartilage within a joint. Abnormal remodelling of the subchondral bone underlying this cartilage is thought to have a major role in the disease. OA has a significant genetic component, with twin studies suggesting the heritability of radiographic knee and hip OA to be around 39% and 60% respectively. Genome-wide association studies (GWAS) have identified at least 64 genetic loci associated with the disease.
We have generated a unique expression quantitative trait locus (eQTL) resource for mapping genetic regulatory regions in osteoclasts using cells differentiated in vitro from 158 patients undergoing bone mineral density scanning at Sir Charles Gairdner Hospital in Western Australia. Considering the role of subchondral bone remodelling in OA, we used this resource to investigate the 64 OA GWAS loci for evidence of genetic regulatory effects relevant to osteoclasts.
After correction for multiple testing, in the osteoclast dataset we observed significant associations between the OA GWAS variants rs11732213 (4p16.3), rs2953013 (17q11.2) and rs143384 (20q11.22) and expression of the genes FAM53A, OMG and UQCC1 respectively (P=5.6×10-5– 1.4×10-6). Strong evidence for co-localisation (>75% posterior probability) of OA GWAS and osteoclast genetic regulatory association signals was observed for all 3 loci. In each instance, the OA GWAS variant was in close proximity (within 150kb) to the eQTL-gene transcription start site. UQCC1 presents strongly as an OA-risk gene, encoding a growth regulator and having previously been implicated in developmental dysplasia of the hip.
We have identified regulatory effects for the OA GWAS variants rs11732213 (FAM53A), rs2953013 (OMG) and rs143384 (UQCC1) in human osteoclasts. This study highlights the value of using genetic regulatory data to determine which genes are relevant to GWAS loci.