Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.
Osteoarthritis (OA) is the most common form of arthritis and a leading cause of chronic disability in the western society affecting millions of people. OA is a degenerative joint disease characterized by changes in all joint tissues, including cartilage, bone and synovium, causing chronic pain and loss of function. There are no effective therapeutic treatments available for OA and therefore finding novel biological pathways through genetic association studies can open up new treatment options. The number of known DNA variants associated with OA-risk is limited.
To identify new loci, we have performed a Genome Wide Association Study meta-analysis on cartilage thickness, one of the joint tissues affected in OA in a total sample of more than 20,000 individuals from twelve cohorts. This analysis revealed six variants associated with cartilage thickness, four of these being novel associations, including TGFA as the most prominent one. A systematic prioritization for underlying causal genes, using diverse lines of evidence, highlighted genes underlying the disease associations, including TGFA, RUNX2 and PIK3R1. Large scale exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies