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Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independent of body mass index

By April E Hartley, Eleanor Sanderson, Raquel Granell, Lavinia Paternoster, Jie Zheng, George Davey Smith, Lorraine Southam, Konstantinos Hatzikotoulas, Cindy G Boer, Joyce van Meurs, Eleftheria Zeggini, The Genetics of Osteoarthritis consortium, Celia L Gregson, Jon H Tobias

Posted 26 Mar 2021
medRxiv DOI: 10.1101/2021.03.22.21253803

OBJECTIVES: Observational analyses suggest that high Bone Mineral Density (BMD) is a risk factor for osteoarthritis (OA); it is unclear whether this represents a causal effect or shared aetiology and whether these relationships are body mass index (BMI)-independent. We performed bidirectional Mendelian randomization (MR) to uncover the causal pathways between BMD, BMI and OA. METHODS: One-sample (1S)MR estimates were generated by two-stage least-squares regression. Unweighted allele scores instrumented each exposure. Two-sample (2S)MR estimates were generated using inverse-variance weighted fixed-effects meta-analysis. Multivariable MR (MVMR), including BMD and BMI instruments in the same model, determined the BMI-independent causal pathway from BMD to OA. Latent causal variable (LCV) analysis, using weight-adjusted FN-BMD and hip/knee OA summary statistics, determined if genetic correlation explained the causal effect of BMD on OA. RESULTS: 1SMR provided strong evidence for a causal effect of eBMD on hip and knee OA (ORhip=1.28[1.05,1.57],p=0.02, ORknee=1.40[1.20,1.63],p=3x10-5, OR per SD increase). 2SMR effect sizes were consistent in direction. Results suggested that the causal pathways between eBMD and OA were bidirectional ({beta}hip=1.10[0.36,1.84],p=0.003, {beta}knee=4.16[2.74,5.57],p=8x10-9, {beta}=SD increase per doubling in risk). MVMR identified a BMI-independent causal pathway between eBMD and hip/knee OA. LCV suggested that genetic correlation (i.e. shared genetic aetiology) did not fully explain causal effects of BMD on hip/knee OA. CONCLUSIONS: These results provide evidence for a BMI-independent causal effect of eBMD on OA. Despite evidence of bidirectional effects, the effect of BMD on OA did not appear to be fully explained by shared genetic aetiology, suggesting a direct action of bone on joint deterioration.

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