Osteoarthritis (OA), a common skeletal disease, is a leading cause of disability among the elderly populations. OA is characterized by gradual loss of articular cartilage, but the etiology and pathogenesis of OA are largely unknown. Epidemiological and genetic studies have demonstrated that genetic factors play an important role in OA. To identify susceptibility genes for OA, we performed a large-scale, case-control association study using gene-based single nucleotide polymorphisms (SNPs). In two independent case-control populations, we found significant association (P=9.8x10(-7)) between hip OA and a SNP (IVS3-293C>T) located in intron 3 of the calmodulin (CaM) 1 gene (CALM1). CALM1 was expressed in cultured chondrocytes and articular cartilage, and its expression was increased in OA. Subsequent linkage-disequilibrium mapping identified five SNPs showing significant association equivalent to IVS3-293C>T. One of these (-16C>T) is located in the core promoter region of CALM1. Functional analyses indicate that the susceptibility -16T allele decreases CALM1 transcription in vitro and in vivo. Inhibition of CaM in chondrogenic cells reduced the expression of the major cartilage matrix genes Col2a1 and Agc1. These results suggest that the transcriptional level of CALM1 is associated with susceptibility for hip OA through modulation of chondrogenic activity. Our findings reveal the CALM1-mediated signaling pathway in chondrocytes as a novel potential target for treatment of OA.