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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 genomewide 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 genomewide 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.
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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.
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.
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.
Table 1.
Instrumental SNPs associated with femur neck BMD and OA GWASs
SNP: single nucleotide polymorphism, BMD: bone mineral density, OA: osteoarthritis, GWAS: genomewide association study, FN: femur neck, Beta: beta coefficient, SE: standard error, CSRNP3: cysteine and serine rich nuclear protein 3, AXIN1: axin 1, CDKAL1: CDK5 regulatory subunit associated protein 1 like 1, C11ORF58: chromosome 11 open reading frame 58, HDAC5: histone deacetylase 5, RSPO3: R-spondin 3, MEF2C: myocyte enhancer factor 2C, COLEC10: collectin subfamily member 10, LRP5: LDL receptor related protein 5, GNG12-AS1: GNG12 antisense RNA 1, WHSC1L2P: Wolf-Hirschhorn syndrome candidate 1-like 2, pseudogene, WNT16: Wnt family member 16, STARD3NL: STARD3 N-terminal like, CTNNB1: catenin beta 1, C7orf76: chromosome 7 open reading frame 76, HOXC4: homeobox C4, SOX6: SRY-box 6, FOXL1: forkhead box L1, SMG6: SMG6, nonsense mediated MRNA decay factor, ZBTB40: zinc finger and BTB domain containing 40, CCDC170: coiled-coil domain containing 170.
Table 2.
The MR estimates from each method of assessing the causal effect of femur neck BMD on the incidence of OA
| MR method | Number of SNPs | Beta | SE | 95 % confidence interval | Association p-value | Cochran's Q statistic | I2 | Heterogeneity p-value |
|---|---|---|---|---|---|---|---|---|
| Inverse variance weighted | 21 | 0.010 | 0.003 | 0.004∼0.016 | 0.002 | 27.39 | 0.262 | 0.125 |
| MR Egger | 21 | 0.005 | 0.017 | −0.028∼0.038 | 0.753 | 27.28 | 0.304 | 0.098 |
| Weighted median | 21 | 0.011 | 0.004 | 0.003∼0.019 | 0.006 | 27.10* | 0.270* | 0.133* |
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