J Rheum Dis.  2019 Apr;26(2):104-110. 10.4078/jrd.2019.26.2.104.

Causal Association between Bone Mineral Density and Osteoarthritis: A Mendelian Randomization Study

• Song GG
• Lee YH

• KMID: 2442020
• DOI: http://doi.org/10.4078/jrd.2019.26.2.104

Abstract

OBJECTIVE
To examine whether bone mineral density (BMD) is causally associated with osteoarthritis (OA).
METHODS
We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighting (IVW), weighted median, and MR-Egger regression methods. We used publicly available summary statistics datasets of a genome-wide association study (GWAS) on femur neck (FN) BMD of individuals of European ancestry as the exposure and a GWAS for non-cancer illness code self-reported: OA from the individuals included in the UK Biobank as the outcome.
RESULTS
We selected 21 independent single-nucleotide polymorphisms with genome-wide significance (p<5.00E-08) from GWAS on FN BMD as the instrumental variables. The IVW method (beta=0.010, standard error [SE]=0.003, p=0.002) and the weighted median approach (beta=0.011, SE=0.004, p=0.006) yielded evidence of a causal association between FN BMD and OA. However, the MR-Egger analysis showed no causal association between FN BMD and OA (beta=0.005, SE=0.017, p=0.753). Since MR-Egger regression suffers from a lack of power and a susceptibility to weak instrument bias, the MR analysis results may support a causal association between FN BMD and OA.
CONCLUSION
The results of MR analysis by IVW and weighted median, but not MR-Egger regression indicate that FN BMD is likely to be causally associated with an increased risk of OA incidence The current findings may provide an opportunity to elucidate the underlying mechanisms of the effects of BMD on the OA incidence.

Keyword

Bone density; Osteoarthritis; Mendelian randomization

MeSH Terms

Bias (Epidemiology)
Bone Density*
Dataset
Femur Neck
Genome-Wide Association Study
Incidence
Methods
Osteoarthritis*
Random Allocation*

Figure

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  Figure 1. Forest plot of the causal effects of BMD-associated SNPs on OA. BMD: bone mineral density, SNP: single nucleotide polymorphism, OA: osteoarthritis, IVW: inverse-variance weighting, MR: Mendelian randomization.

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  Figure 2. Scatter plots of genetic associations with BMD against the genetic associations with OA. The slopes of each line represent the causal association for each method. The blue line represents the inverse-variance weighting estimate, the green line represents the weighted median estimate, and the dark blue line represents the Mendelian randomization‐ Egger estimate. BMD: bone mineral density, OA: osteoarthritis, SNP: single nucleotide polymorphism.

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  Figure 3. “Leave-one-out” analysis to investigate the possibility that the causal association was driven by a unique SNP. SNP: single nucleotide polymorphism, MR: Mendelian randomization.

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