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

Abstract

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we perform the largest genome-wide association study for osteoarthritis to date (77,052 cases and 378,169 controls), analysing 4 phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discover 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine map to a single variant. We identify putative effector genes by integrating eQTL colocalization, finemapping, human rare disease, animal model, and osteoarthritis tissue expression data. We find enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organisation biological pathways. Ten of the likely effector genes, including TGFB1, FGF18, CTSK and IL11 have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.Osteoarthritis affects 40% of individuals over the age of 70 1 , is a major cause of pain, comorbidity and mortality 2 . Ten million people in the UK alone suffer from osteoarthritis, with a total indirect cost to the economy of £14.8 billion per annum 2 . Disease management targets the main symptom (pain) and culminates in joint replacement surgery (1.76 million per year in the EU) with variable outcomes 3 . There is a clear and urgent need to translate genomic evidence into druggable DATA AVAILABILITY

Zebrafish as an Emerging Model for Osteoporosis: A Primary Testing Platform for Screening New Osteo-Active Compounds

“…Further mechanistic data generated in model systems showed that SOST acts negatively on the WNT signaling pathway and led to the development of a novel antibody treatment Romosozumab (approved in 2018 for clinical use), which blocks SOST activity (11–13). With the advent of genome-wide association studies (GWAS), and efficient whole-genome/exome sequencing (WGS/WES) data mapping there has been a sizeable increase in availability of human genetic data from cohort studies for musculoskeletal conditions including OP, high bone mass (HBM), and osteoarthritis (OA) (14–20). Recent large cohort studies, such as UK-Biobank, have identified many new loci that contain novel osteogenic factors.…”

Discovery and analysis of methylation quantitative trait loci (mQTLs) mapping to novel osteoarthritis genetic risk signals

“…Genome-wide association studies (GWAS) have revealed the polygenic nature of OA and to date over 90 independent risk loci have been identified 3e6 . The largest and most recent OA GWAS was carried out using the full UK Biobank cohort, with a focus on hip and knee OA 6 . This study utilised the genotypes of up to 455,000 individuals across 17.5 million single nucleotide polymorphisms (SNPs).…”

“…In this current study, we focussed on the OA signals that emerged from the analysis of the full UK Biobank cohort 6 and searched our cartilage genetic and epigenetic datasets to identify novel OA mQTLs. We were able to investigate a total of 42 signals and found evidence of mQTLs at ten of these.…”

A low cartilage formation and repair endotype predicts radiographic progression of symptomatic knee osteoarthritis

“…Recent data from the large-scale UK biobank identi ed genetic polymorphisms in eight genes associated with OA [10]. Three of these genes were linked to a cartilage formation/repair endotype, namely Growth Differentiation Factor 5 (GDF5), Fibroblast Growth Factor 18 (FGF18), and Transforming Growth Factorbeta 1 (TGF-β1) [10], suggesting that cartilage formation, when impaired, may be associated with a higher level of OA structural disease progression due to repair attenuation. Thus, cartilage formation by chondrocytes may represent a convergent mechanism with cartilage repair pathways.…”