Largest Osteoarthritis GWAS to Date Highlights Opportunities for Drug Repurposing and Novel Targets

New findings from the largest genome-wide association study (GWAS) for osteoarthritis have identified 700 effector genes with high confidence of playing a role in osteoarthritis, 10% of which express proteins targeted by approved drugs across disease fields.1

“This is an exciting set of findings that have identified hundreds of potential new drug targets and opportunities for repurposing drugs already approved and on the market for other conditions,” investigator Marc C. Hochberg, MD, MBA, Professor Emeritus of Medicine at the University of Maryland School of Medicine, said in a statement.2

The investigators performed a GWAS meta-analyses across up to 489,975 cases and 1,472,094 controls and established 962 independent associations, 513 of which had not been previously reported. Refining their search, they used single-cell multiomics data to identify signal enrichment in embryonic skeletal development pathways and integrated orthogonal lines of evidence, including transcriptome, proteome and epigenome profiles of primary joint tissues, to implicate 700 effector genes.1

“With 10 percent of our genetic targets already linked to approved drugs, we are now one step closer to accelerating the development of effective treatments for osteoarthritis," primary investigator Eleftheria Zeggini, PhD, Director of the Institute of Translational Genomics at Helmholtz Munich and Professor of Translational Genomics at the Technical University of Munich, added.2

Within these 700 genes, investigators found find rare coding-variant burden associations with consistently higher effect sizes than common frequency variant associations. These genes often had convergent involvement in 8 biological processes, including the circadian clock, glial-cell-related processes and other pathways with an established role in osteoarthritis such as TGFβ, FGF, WNT, BMP and retinoic acid signaling, and extracellular matrix organization.

Hochberg and colleagues identified 473 approved drugs that target the protein product of 69 effector genes, 5 (7.2%) of which have been previously associated with a pain phenotype. Namely, they noted drugs in early trials that target CYP26B1 of the retinoic pathway and FGF18, a high-affinity ligand for FGFR3 and a member of the FGF pathway, while drugs are currently approved for targeting proteins linked with genes in the TGFβ pathway (TGFB1, COL1A2, COL3A1, i, PRKCZ and ITGB3), WNT signaling genes (PSMB8, TGFB1, PSMC3 and COL6A1), 18 effector genes involved in the extra-cellular matrix, and agonists of the glucocorticoid receptor.1

“In the United States, total costs attributed to osteoarthritis pain and disability average more than $486 billion every year, which is astonishing and points to the need to develop more effective treatments,” Mark T. Gladwin, MD, John Z. and Akiko K. Bowers Distinguished Professor and Dean of University of Maryland School of Medicine, added.2 "In developing new treatments, it is crucial to enhance wider participation in these genome-wide studies so that we can identify novel genetic associations across a broader spectrum of populations."

The investigators encouraged further GWAS meta-analyses with more genetically diverse data from global populations across relevant disease tissues. They stressed that further reinforcing this research can stimulate clinical translation for new drugs and new drug targets for osteoarthritis.1

REFERENCES

1. Hatzikotoulas K, Southam L, Stefansdottir L, et al. Translational genomics of osteoarthritis in 1,962,069 individuals. Nature. Published online April 9, 2025. doi: 10.1038/s41586-025-08771-z

2. Kotz D. Largest Genome-Wide Association Study Uncovers New Drug Targets and Potential Therapies for Osteoarthritis. News release. University of Maryland School of Medicine. April 15, 2025. https://www.medschool.umaryland.edu/news/2025/largest-genome-wide-association-study-uncovers-new-drug-targets-and-potential-therapies-for-osteoarthritis.html