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

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


Title: Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independently of body mass index
Author: Hartley, April
Sanderson, Eleanor
Granell, Raquel
Paternoster, Lavinia
Zheng, Jie
Smith, George Davey
Southam, Lorraine
Hatzikotoulas, Konstantinos
Boer, Cindy G.
Van Meurs, Joyce
... 52 more authors Show all authors
Date: 2022-08-01
Language: English
Scope: 14
University/Institute: University of Akureyri
Department: Office of Division of Diagnostic and Support Services
Faculty of Medicine
Internal Medicine and Emergency Services
Series: International Journal of Epidemiology; 51(4)
ISSN: 0300-5771
DOI: 10.1093/ije/dyab251
Subject: body mass index; bone mineral density; Mendelian randomization; Osteoarthritis; UK Biobank; Epidemiology
URI: https://hdl.handle.net/20.500.11815/4234

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Citation:

Hartley , A , Sanderson , E , Granell , R , Paternoster , L , Zheng , J , Smith , G D , Southam , L , Hatzikotoulas , K , Boer , C G , Van Meurs , J , Zeggini , E , Gregson , C L , Tobias , J H , Stefánsdóttir , L , Zhang , Y , De Almeida , R C , Wu , T T , Teder-Laving , M , Skogholt , A H , Terao , C , Zengini , E , Alexiadis , G , Barysenka , A , Bjornsdottir , G , Gabrielsen , M E , Gilly , A , Ingvarsson , Þ , Johnsen , M B , Jónsson , H , Kloppenburg , M G , Luetge , A , Mägi , R , Mangino , M , Nelissen , R R G H H , Shivakumar , M , Steinberg , J , Takuwa , H , Thomas , L , Tuerlings , M , Babis , G , Cheung , J P Y , Samartzis , D , Lietman , S A , Slagboom , P E , Stefánsson , K , Uitterlinden , A G , Winsvold , B , Zwart , J A , Sham , P C , Thorleifsson , G , Gaunt , T R , Morris , A P , Valdes , A M , Tsezou , A , Cheah , K S E , Ikegawa , S , Hveem , K , Esko , T , Wilkinson , J M , Meulenbelt , I , Michael Lee , M T & Styrkársdóttir , U 2022 , ' Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independently of body mass index ' , International Journal of Epidemiology , vol. 51 , no. 4 , pp. 1254-1267 . https://doi.org/10.1093/ije/dyab251

Abstract:

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.

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Publisher Copyright: © 2021 The Author(s). Published by Oxford University Press on behalf of the International Epidemiological Association.

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