Unlocking osteoarthritis: what nearly two million genomes can teach us

Potential boosts to drug development and research

Crucially, as many as one out of every ten of effector genes identified in our research encodes proteins that are already being targeted by existing medications approved for other conditions, for instance TGFβ inhibitors. This means that there may be numerous opportunities for drug repurposing, which could considerably shorten the timeline for therapeutic development and potentially deliver the first disease-modifying osteoarthritis treatments to patients much sooner than if we were starting from scratch.

Our findings also reshape OA as a disorder rooted in developmental biology, cellular metabolism, and neural-immune crosstalk—a paradigm shift that could further accelerate the path to precision therapies.

Thirdly, our study reinforces the critical importance of studying osteoarthritis in the right tissues. Chondrocytes (cartilage cells) and primary joint tissues were especially informative in pinpointing the molecular mechanisms at work. For clinicians and researchers designing future translational studies or biomarkers, this offers a strong signal about where to focus attention.

Clinical takeaways for orthopedic surgeons

Our findings have several key implications for orthopedic surgeons. First, they underscore the biological complexity of osteoarthritis—highlighting why structural changes seen on imaging do not always correlate with symptoms, and why some patients progress rapidly while others remain stable for years. A better understanding of each patient’s genetic risk profile may one day help tailor not only surgical timing, but also perioperative management and adjunct therapies.

Furthermore, we found evidence that rare loss-of-function (LOF) variants carry significantly higher effect sizes than common variants. As sequencing technologies become more accessible, these rare variants could help stratify patients—and perhaps even inform decision-making processes on who might benefit from surgery earlier, and who might benefit more from emerging medical therapies.

Thirdly, our study could add clarity on a genetic level in cases of challenging diagnoses such as spinal osteoarthritis, where overlapping symptoms from disc disease or nerve compression regularly make clinical judgement more difficult. We found that genetic signals for spinal OA overlap with those in other joints, suggesting a shared disease biology. More precise genetic and molecular markers may eventually become key features when it comes to differentiating genuine spinal OA from other spinal pathologies, improving diagnosis and patient selection for both surgical and non-surgical interventions.

Benefits for patients and their families

We believe that our research offers hope for those hundreds of millions of patients who live with osteoarthritis as well as for the healthcare providers who support them. In the past decades, OA treatment has almost exclusively consisted of symptom relief: pain management, physical therapy, and ultimately joint replacement. Our study may play a crucial part in addressing the disease at its root.

Better identifying not just risk genes, but biological pathways and potential drug targets, could become key to the development of novel OA therapies that could slow, halt, or even prevent disease progression. Many of the implicated proteins are already being targeted by approved medications, which means that there is a real chance to quickly progress to clinical trials for at least some applications. The more we understand the genetic profiles that drive OA, the closer get to being able to offer personalized treatment plans that are more than just a temporary fix.

However, more work remains. We acknowledge the current limitations in genetic diversity across our study populations, and we are committed to expanding our datasets to reflect the true global burden of OA. As we continue this work, our aim is clear: to translate genetic knowledge into meaningful clinical advances that improve quality of life for patients across every age group, geography, and stage of disease.

Collectively, our study also emphasizes the importance of team science. To make any headway or innovation in today’s age, working together rather than in silos is paramount. Our study underlines the importance of how bringing together a multidisciplinary team from across the globe can make lasting impact by facilitating giants leaps forward rather than baby steps in understanding and treating OA.

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Professors Samartzis and Cheung are authors of the publication Hatzikotoulas, K., Southam, L., Stefansdottir, L. et al. Translational genomics of osteoarthritis in 1,962,069 individuals. Nature 641, 1217–1224 (2025). Full list of authors, contributors, and participating consortia is available online in Nature.