| Title: | Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independently of body mass index |
| Journal: | International Journal of Epidemiology |
| Published: | 13 Dec 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34897459/ |
| DOI: | https://doi.org/10.1093/ije/dyab251 |
| URL: | https://academic.oup.com/ije/advance-article-pdf/doi/10.1093/ije/dyab251/42209378/dyab251.pdf |
| Citations: | 24 (17 in last 2 years) as of 8 Aug 2024 |
Publication 12642
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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.</p>
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.</p>
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.</p>
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.</p>
8 Keywords
- Body Mass Index
- Bone Density
- Causality
- Genome-Wide Association Study
- Humans
- Mendelian Randomization Analysis
- Osteoarthritis, Knee
- Polymorphism, Single Nucleotide
63 Authors
- April Hartley
- Eleanor Sanderson
- Raquel Granell
- Lavinia Paternoster
- Jie Zheng
- George Davey Smith
- Lorraine Southam
- Konstantinos Hatzikotoulas
- Cindy G Boer
- Joyce van Meurs
- Eleftheria Zeggini
- Lilja Stefánsdóttir
- Yanfei Zhang
- Rodrigo Coutinho de Almeida
- Tian T Wu
- Jie Zheng
- Maris Teder-Laving
- Anne-Heidi Skogholt
- Chikashi Terao
- Eleni Zengini
- George Alexiadis
- Andrei Barysenka
- Gyda Bjornsdottir
- Maiken E Gabrielsen
- Arthur Gilly
- Thorvaldur Ingvarsson
- Marianne B Johnsen
- Helgi Jonsson
- Margreet G Kloppenburg
- Almut Luetge
- Reedik Mägi
- Massimo Mangino
- Rob R G H H Nelissen
- Manu Shivakumar
- Julia Steinberg
- Hiroshi Takuwa
- Laurent Thomas
- Margo Tuerlings
- George Babis
- Jason Pui Yin Cheung
- Dino Samartzis
- Steve A Lietman
- P Eline Slagboom
- Kari Stefansson
- André G Uitterlinden
- Bendik Winsvold
- John-Anker Zwart
- Pak Chung Sham
- Gudmar Thorleifsson
- Tom R Gaunt
- Andrew P Morris
- Ana M Valdes
- Aspasia Tsezou
- Kathryn S E Cheah
- Shiro Ikegawa
- Kristian Hveem
- Tõnu Esko
- J Mark Wilkinson
- Ingrid Meulenbelt
- Ming Ta Michael Lee
- Unnur Styrkársdóttir
- Celia L Gregson
- Jon H Tobias
1 Application
| Application ID | Title |
|---|---|
| 17295 | AUtomated Generation of Musculoskeletal phENotypes from the UK biobank exTended imaging study (AUGMENT Study) |
Enabling scientific discoveries that improve human health