Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data

Abstract

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.

Figure 1. Genetic correlations between osteoarthritis and other traits and diseases.

Genetic correlations (rg) between osteoarthritis and other publicly available GWAS results, based on LD score regression as implemented in LDHub. The diagram shows traits with significant correlation (P<0.05) and 95% confidence intervals across all osteoarthritis definitions. The red outline of the bars denotes negative correlation and the blue outline denotes positive correlation. The upper right legend shows the categories of the traits. OA: osteoarthritis; OA_hip: Hip osteoarthritis; OA_knee: Knee osteoarthritis; OA_kneehip: Knee and/or hip osteoarthritis. Lumbar spine bone mineral density 1 and 2 relate to two different published studies.

Figure 2. Allelic architecture of index variants.

Meta-analysis based odds ratio with its 95% confidence interval of 99 variants (previously-reported denoted as circles and newly-reported denoted as diamonds) with UK Biobank and arcOGEN meta-analysis P<3.0x10^-8 (two-sided) as a function of their weighted allele frequency. The curves indicate 80% power at the genome-wide significance threshold of P≤3.0x10^-8, for the four sample sizes of the meta-analyses. We have 80% power to detect an association at genome-wide significance for a variant with 1% MAF and allelic odds ratio of 1.19, 1.40, 1.32 and 1.25 for all osteoarthritis, hip osteoarthritis, knee osteoarthritis and knee and/or hip osteoarthritis, respectively. For 0.1% MAF the corresponding odds ratios are 1.66, 2.43, 2.12 and 1.90.