Using Mendelian randomization analyses in osteoarthritis: state of art and future perspectives

The etiology of osteoarthritis (OA) remains unclear, involving a complex interaction of environmental and genetic factors. Observational studies have contributed substantially to identify modifiable risk factors that were associated with OA risk, but conclusions about the causality are hard to draw as these observed associations are susceptible to be interfered with reverse causality and residual confounding. Mendelian randomization (MR) is a valid approach to provide evidence on causal associations, by using genetic variants as 'proxies' for modifiable exposures to examine the effect of genetic susceptibility to the exposures on the outcomes. Such a method provides an opportunity to elucidate OA pathogenesis and therefore to provide evidence for novel interventions and treatment strategies. In this systematic review, we synthesized evidence from recent studies that applied MR in OA in terms of eight aspects, including lifestyle, nutrition, bone mineral density, reproductive factors, metabolic syndrome, cardiovascular disease, inflammation cytokines and other risk factors. We reflected on the limitations of its current applications in OA, followed by a discussion of our findings and future directions in this field.