Background Despite recent advances in the understanding of the genetic architecture of osteoarthritis (OA), only two genetic loci have been identified for OA of the hand, in part explained by the complexity of the different hand joints and heterogeneity of OA pathology. Methods We used data from the Rotterdam Study (RSI, RSII and RSIII) to create three hand OA phenotypes based on clustering patterns of radiographic OA severity to increase power in our modest discovery genome-wide association studies in the RS (n=8700), and sought replication in an independent cohort, the Framingham Heart Study (n=1203). We used multiple approaches that leverage different levels of information and functional data to further investigate the underlying biological mechanisms and candidate genes for replicated loci. We also attempted to replicate known OA loci at other joint sites, including the hips and knees. Results We found two novel genome-wide significant loci for OA in the thumb joints. We identified WNT9A as a possible novel causal gene involved in OA pathogenesis. Furthermore, several previously identified genetic loci for OA seem to confer risk for OA across multiple joints: TGFa, RUNX2, COL27A1, ASTN2, IL11 and GDF5 loci. Conclusions We identified a robust novel genetic locus for hand OA on chromosome 1, of which WNT9A is the most likely causal gene. In addition, multiple genetic loci were identified to be associated with OA across multiple joints. Our study confirms the potential for novel insight into the genetic architecture of OA by using biologically meaningful stratified phenotypes.
Institut(e)Institute of Translational Genomics (ITG)
FörderungenHarvard University Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA) Research Institute for Diseases in the Elderly Genetic Laboratory of the Department of Internal Medicine, Erasmus MC Netherlands Organisation of Scientific Research NWO Investments Municipality of Rotterdam European Commission (DG XII) Ministry for Health, Welfare and Sports Ministry of Education, Culture and Science Research Institute for Diseases in the Elderly (RIDE) Netherlands Organization for the Health Research and Development (ZonMw) Dutch Arthritis Association European Union Arthritis Research UK as part of the MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA) Medical Research Council Arthritis National Institute on Aging (NIA) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Affymetrix, Inc. National Institutes of Health Erasmus Medical Center and Erasmus University, Rotterdam