Causal relationships between anthropometric traits, bone mineral density, osteoarthritis and spinal stenosis: A Mendelian randomisation investigation

ObjectiveSpinal stenosis is a common condition among older individuals, with significant morbidity attached. Little is known about its risk factors but degenerative conditions, such as osteoarthritis (OA) have been identified for their mechanistic role. This study aims to explore causal relationships between anthropometric risk factors, osteoarthritis, and spinal stenosis using Mendelian randomization (MR) techniques.DesignWe applied two-sample MR to investigate the causal relationships between genetic liability for select risk factors and spinal stenosis. Next, we examined the genetic relationship between osteoarthritis and spinal stenosis with LD score regression and CAUSE MR method. Finally, we used multivariable MR to explore whether osteoarthritis and BMI mediate the causal pathways identified.ResultsOur analysis revealed strong evidence for the effect of higher BMI (OR=1.54, 95%CI:1.41-1.69, p-value=2.7 x 10-21), waist (OR=1.43, 95%CI:1.15-1.79, p-value=1.5x10-3) and hip (OR=1.50, 95%CI:1.27-1.78, p-value=3.3x10-6) circumference on spinal stenosis. Strong evidence of causality was also observed for higher bone mineral density (BMD): total body (OR=1.21, 95%CI:1.12-1.29, p-value=1.6x10-7), femoral neck (OR=1.35, 95%CI:1.09-1.37, p-value=7.5x10-7), and lumbar spine (OR=1.38, 95%CI:1.25-1.52, p-value=4.4x10-11). We detected high genetic correlations between spinal stenosis and osteoarthritis (rg range: 0.47-0.66), with CAUSE results supporting a causal effect of osteoarthritis on spinal stenosis (ORallOA=1.6, 95%CI:1.41-1.79). Direct effects of BMI, BMD on spinal stenosis remained after adjusting for osteoarthritis in the multivariable MR.ConclusionsGenetic susceptibility to anthropometric risk factors, particularly higher BMI and BMD can increase the risk of spinal stenosis, independent of osteoarthritis status. These results may inform preventative strategies and treatments.