Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis
OBJECTIVE: Osteoarthritis (OA) has a strong genetic component but the success of previous genome-wide association studies (GWAS) has been restricted due to insufficient sample sizes and phenotype heterogeneity. Our aim was to examine the effect of clinically relevant endophenotyping according to site of maximal joint space narrowing (maxJSN) and bone remodelling response on GWAS signal detection in hip OA. METHODS: A stratified GWAS meta-analysis was conducted in 2118 radiographically defined hip OA cases and 6500 population-based controls. Signals were followed up by analysing differential expression of proximal genes for bone remodelling endophenotypes in 33 pairs of macroscopically intact and OA-affected cartilage. RESULTS: We report suggestive evidence (p0.05). STT3B was significantly upregulated in OA-affected versus intact cartilage, particularly in the analysis of hypertrophic and normotrophic compared with atrophic bone remodelling pattern (p=4.2×10-4). CONCLUSIONS: Our findings demonstrate that stratification of OA cases into more homogeneous endophenotypes can identify genes of potential functional importance otherwise obscured by disease heterogeneity. ; This work was supported by Arthritis Research UK (grant 19542, KP and EZ; grant 20308, KP), the Wellcome Trust (grant 098051, KP and EZ), the Joint Action Trust (grant GA1125, British Orthopaedic Association, ST and JMW) and the National Institute for Health Research funded Sheffield Bone Biomedical Research Unit (ST and JMW). This study used genotype data from arcOGEN (http://www.arcogen.org.uk/) funded by a special purpose grant from Arthritis Research UK (grant 18030). This study makes use of data generated by the Wellcome Trust Case-Control Consortium (the 1958 British Birth Cohort collection and the UK Blood Services Collection). A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk and funding for the project was provided by the Wellcome Trust under awards 076113, 085475 and 090355. The Leiden University Medical Center supports the RAAK Study, while research leading to these results has received funding from the Dutch Arthritis Association (DAA 2010_017) and the IDEAL project (European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679)