Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independently of body mass index
Hartley, April; Sanderson, Eleanor; Granell, Raquel; Paternoster, Lavinia; Zheng, Jie; Smith, George Davey; Southam, Lorraine; Hatzikotoulas, Konstantinos; Boer, Cindy G.; Van Meurs, Joyce; Zeggini, Eleftheria; Gregson, Celia L.; Tobias, Jon H.; Stefánsdóttir, Lilja; Zhang, Yanfei; De Almeida, Rodrigo Coutinho; Wu, Tian T.; Teder-Laving, Maris; Skogholt, Anne Heidi; Terao, Chikashi; Zengini, Eleni; Alexiadis, George; Barysenka, Andrei; Bjornsdottir, Gyda; Gabrielsen, Maiken Elvestad; Gilly, Arthur; Ingvarsson, Thorvaldur; Johnsen, Marianne Bakke; Jonsson, Helgi Freyr; Kloppenburg, Margreet G.; Luetge, Almut; Mägi, Reedik; Mangino, Massimo; Nelissen, Rob R.G.H.H.; Shivakumar, Manu; Steinberg, Julia; Takuwa, Hiroshi; Thomas, Laurent; Tuerlings, Margo; Babis, George; Cheung, Jason Pui Yin; Samartzis, Dino; Lietman, Steve A.; Slagboom, P. Eline; Stefansson, Kari; Uitterlinden, André G.; Winsvold, Bendik K S; Zwart, John Anker Henrik; Sham, Pak Chung; Thorleifsson, Gudmar; Gaunt, Tom R.; Morris, Andrew P.; Valdes, Ana M.; Tsezou, Aspasia; Cheah, Kathryn S.E.; Ikegawa, Shiro; Hveem, Kristian; Esko, Tõnu; Wilkinson, J. Mark; Meulenbelt, Ingrid; Michael Lee, Ming Ta; Styrkársdóttir, Unnur
Peer reviewed, Journal article
Published version
![Thumbnail](/ntnu-xmlui/bitstream/handle/11250/3068284/dyab251.pdf.jpg?sequence=6&isAllowed=y)
View/ Open
Date
2022Metadata
Show full item recordCollections
Original version
International Journal of Epidemiology. 2022, 51 (4), 1254-1267. 10.1093/ije/dyab251Abstract
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 random-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 femoral neck (FN)–BMD and hip/knee OA summary statistics, determined whether genetic correlation explained the causal effect of BMD on OA.
Results
1SMR provided strong evidence for a causal effect of BMD estimated from heel ultrasound (eBMD) on hip and knee OA {odds ratio [OR]hip = 1.28 [95% confidence interval (CI) = 1.05, 1.57], p = 0.02, ORknee = 1.40 [95% CI = 1.20, 1.63], p = 3 × 10–5, OR per standard deviation [SD] increase}. 2SMR effect sizes were consistent in direction. Results suggested that the causal pathways between eBMD and OA were bidirectional (βhip = 1.10 [95% CI = 0.36, 1.84], p = 0.003, βknee = 4.16 [95% CI = 2.74, 5.57], p = 8 × 10–9, β = 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 the 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.