Cindy Boer

68 | Chapter 2.1 Abstract Objective Osteoarthritis is one of the most frequent and disabling diseases of the elder- ly. 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. Methods 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 co- horts. Results We identified five genome-wide significant (GWS, p-value≤5·0*10 −08 ) SNPs an- notated to four distinct loci. In addition, we found two additional loci that were sig- nificantly 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 us- ing 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. Conclusion We identified four novel loci ( TGFA, PIK3R1, FGFR3 and TREH ) and con- firmed two loci known to be associated with cartilage thickness. The identified associ- ations 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.