Genome-Wide Association Study of Radiographic Knee Osteoarthritis in North American Caucasians.

Objective: A major barrier to genetic studies of OA is the need to obtain large numbers of individuals with standardized radiographic evaluations for OA. To address this gap, we performed a genome-wide association study (GWAS) of radiographically-defined tibiofemoral knee OA in 3,898 cases and 3,168 controls from four well-characterized North American cohorts, and replication analysis of published OA loci. Methods: We performed meta-analysis using a two-stage design. Stage 1 (discovery) consisted of a GWAS meta-analysis of radiographic knee OA carried out in the Osteoarthritis Initiative and the Johnston County Osteoarthritis Project. Knee OA was defined as definitive osteophytes and possible joint space narrowing or total joint replacement in one or both knees. Stage 2 (validation) was performed in the Multicenter Osteoarthritis Study and Genetics of Osteoarthritis Study. We genotyped lead meta-analysis variants (P-value<1 × 10−4) from Stage 1 and tested the association between these variants and knee OA. We then combined results from all cohorts in a meta-analysis. Results: Lead variants from Stage 1, representing 49 unique loci, were analyzed in Stage 2; none met genome-wide significance in the combined analysis of Stage 1 and 2. We validated one locus with nominal significance (P-value<0.05), which was also our top finding in the combined meta-analysis: rs4867568 (LSP1P3, OR[95% CI]=0.84[0.79-0.91], P-value=3.02 × 10−6). We observed nominally significant associations (P-value<0.05) with two published OA loci: rs143383 (GDF5, OR[95% CI]=1.12[1.04-1.21], P-value=2.13 × 10−3) and rs1558902 (FTO, OR[95% CI]=1.10[1.02-1.18], P-value=0.01). Conclusion: These findings provide suggestive evidence for a novel knee OA locus and confirm previously published associations in GDF5 and FTO. This article is protected by copyright. All rights reserved.