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GWAS identifies 8 novel genetic loci linked to osteoarthritis


In an effort to discover human susceptibility loci for osteoarthritis, beyond the three already identified (MCF2L, GDF5 and chromosome 7q22), a new genome-wide association study (GWAS) was performed using samples collected by the Arthritis Research UK Osteoarthritis Genetics (arcOGEN) consortium.

Of the 7410 unrelated northern European patients who were prospectively and retrospectively selected for inclusion and compared with 11 009 unrelated controls, 80% had received a total joint replacement of the hip or knee. The signals identified were replicated in a second group of 7473 cases and 42 938 controls, again from northern Europe.

Eight novel genetic loci that appear to be strong candidates for osteoarthritis risk factors were identified. Five of these showed genome-wide significance while the three others were just below the significance threshold. The strongest signal was the SNP on chromosome 3 that codes for a missense polymorphism within GNL3, the nucleostemin gene. Functional studies have revealed higher levels of nucleostemin in patients with osteoarthritis. Another association, within the FTO gene, highlights the close relationship between osteoarthritis and obesity.

Editor’s comment: Most susceptibility loci identified were associated with hip OA rather than knee OA, supporting epidemiological observations that hip OA is predominantly due to bone abnormalities (genetic factors) while knee OA is more commonly associated with joint injury and obesity (environmental factors). This study also highlights the GWAS trade-off: huge sample sizes are necessary to discover susceptibility loci but focusing on a specific phenotype (therefore using smaller sample sizes) results in stronger signals and less misclassification error.

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