BackgroundDespite 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.MethodsWe 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.ResultsWe found two novel genome-wide significant loci for OA in the thumb joints. We identifiedWNT9Aas 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,IL11andGDF5loci.ConclusionsWe identified a robust novel genetic locus for hand OA on chromosome 1, of whichWNT9Ais 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.