Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study

Abstract

Background: Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity.

Methods: We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent.

Findings: We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects.

Interpretation: Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.

Funding: arcOGEN was funded by a special purpose grant from Arthritis Research UK.

Figure

Regional association plots of replicating signals Case–control association results (–log₁₀ [p value]) for genotyped SNPs in the discovery set are plotted against genomic position (National Center for Biotechnology Information build 36) for the stratum in which the most significant meta-analysis p value occurred. The index SNP is denoted by a purple diamond in the discovery set and by a purple square in the final meta-analysis. The circles indicate association results of genotyped SNPs in the region; the colour reflects the correlation coefficient (r²) of each genotyped SNP with the index SNP estimated with the CEU HapMap II panel. Estimated recombination rates (in cM/Mb) are plotted in red. The region shown in the plots extends to either 500 kb upstream and downstream of the index SNP or until the next recombination hotspot if this lies further than a distance of 500 kb. (A) Chromosome 3 signal centred on rs6976 in total joint replacement. (B) Chromosome 9 signal centred on rs4836732 in female total hip replacement. (C) Chromosome 6 signal centred on rs9350591 in hip osteoarthritis. (D) Chromosome 12 signal centred on rs10492367 in hip osteoarthritis. (E) Chromosome 12 signal centred on rs835487 in total hip replacement. SNP=single nucleotide polymorphism. CEU=Utah residents with ancestry from northern and western Europe.