Using multivariable mendelian randomization to estimate the bmi-independent causal effect of bone mineral density on osteoarthritis

AbstractStatin treatment increases bone mineral density (BMD) and reduces fracture risk, but the underlying mechanism is unclear. We used Mendelian randomization (MR) to assess whether this relation is explained by a specific effect in response to statin use, or by a general effect of lipid-lowering. We utilized 400 single nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels and results from a heel BMD GWAS (derived from quantitative ultrasound) in 426,824 individuals from the UK Biobank. We performed univariate and multivariable MR analyses of low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride levels on BMD. To test whether the effect of statins on BMD was mediated by lowering lipid levels, MR was repeated with and without SNPs in theHMGCRregion, the gene targeted by statins. Univariate MR analyses provided evidence for a causal effect of LDL-C on BMD (β= −0.060; −0.084 to −0.036; P = 4×10-6; standard deviation change in BMD per standard deviation change in LDL-C, with 95% CI), but not HDL or triglycerides. Multivariable MR analysis suggested that the effect of LDL-C on BMD was independent of HDL-C and triglycerides, and sensitivity analyses involving MR Egger and weighted median MR approaches suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in theHMGCRregion showed similar effects on BMD(β= −0.083; −0.132 to −0.034; P = 0.001) to those excluding these SNPs (β= −0.063; −0.090 to −0.036; P = 8×10-6). Bidirectional MR analyses provided some evidence for a causal effect of BMD on plasma LDL-C levels. Our results suggest that effects of statins on BMD are at least partly due to their LDL-C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis.

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Parathyroid Hormone and Bone Mineral Density: A Mendelian Randomization Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa579 ◽

2020 ◽

Vol 105 (11) ◽

Author(s):

Zihao Qu ◽

Fangkun Yang ◽

Jianqiao Hong ◽

Wei Wang ◽

Shigui Yan

Keyword(s):

Bone Mineral Density ◽

Parathyroid Hormone ◽

Bone Mineral ◽

Large Scale ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Age Groups ◽

Mineral Density ◽

Serum Pth

Abstract Purpose Accumulating evidence implicates parathyroid hormone (PTH) in the development of osteoporosis. However, the causal effect of PTH on bone mineral density (BMD) remains unclear. Thus, this study is aimed at exploring the association between the concentrations of serum PTH and BMD. Methods The instrumental variables for PTH were selected from a large-scale genome-wide association study (GWAS; n = 29 155). Outcomes included BMD of the forearm (FA; n = 8143), femoral neck (FN; n = 33 297), lumbar spine (LS; n = 32 735), heel (HL; n = 394 929), and risk of fractures in these bones (n = 361 194). Furthermore, the BMD of 5 different age groups: 15 years or younger (n = 11 807), 15–30 (n = 4180), 30–45 (n = 10 062), 45–60 (n = 18 805), and 60 years or older (n = 22 504) were extracted from a GWAS meta-analysis study. The analyses were performed using the 2-sample Mendelian randomization method. Results Mendelian randomization analysis revealed that the level of serum PTH was inversely associated with BMD of FA (95% CI: -0.763 to -0.016), FN (95% CI: -0.669 to -0.304), and LS (95% CI: -0.667 to -0.243). A causal relationship between serum PTH levels and BMD was observed in individuals aged 30–45 (95% CI: -0.888 to -0.166), 45–60 (95% CI: -0.758 to -0.232), and over 60 years (95% CI: -0.649 to -0.163). Main Conclusions This study demonstrated that the concentrations of serum PTH is inversely associated with BMD of several bones. Further analysis revealed site- and age-specific correlations between serum PTH levels and BMD, which implies that the levels of serum PTH contribute to the development of osteoporosis.

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Mendelian Randomization Analysis to Examine for a Causal Effect of Urate on Bone Mineral Density

Journal of Bone and Mineral Research ◽

10.1002/jbmr.2434 ◽

2015 ◽

Vol 30 (6) ◽

pp. 985-991 ◽

Cited By ~ 30

Author(s):

Nicola Dalbeth ◽

Ruth Topless ◽

Tanya Flynn ◽

Murray Cadzow ◽

Mark J Bolland ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Mendelian Randomization ◽

Causal Effect ◽

Mineral Density ◽

Mendelian Randomization Analysis ◽

Randomization Analysis

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Causal Effect of Blood Pressure on Bone Mineral Density and Fracture: A Mendelian Randomization Study

Frontiers in Endocrinology ◽

10.3389/fendo.2021.716681 ◽

2021 ◽

Vol 12 ◽

Author(s):

Bin He ◽

Lifeng Yin ◽

Muzi Zhang ◽

Qiong Lyu ◽

Zhengxue Quan ◽

...

Keyword(s):

Bone Mineral Density ◽

Blood Pressure ◽

Bone Mineral ◽

Mendelian Randomization ◽

Causal Effect ◽

P Value ◽

Positive Finding ◽

Mineral Density ◽

European Descent ◽

Weighted Median

BackgroundHypertension may have some association with osteoporosis. This Mendelian randomization (MR) study aimed to explore the causal effect of blood pressure (BP) on bone mineral density (BMD), fall, and fracture.MethodsWe used the genome-wide association study (GWAS) summary data among 330,956 European-descent individuals to identify 107 single-nucleotide polymorphisms (SNPs) as the instrumental variables of BP. MR analyses of these instruments were performed on 53,236 European individuals for the association with forearm BMD (FA-BMD), femoral neck BMD (FN-BMD), and lumbar spine BMD (LS-BMD); 451,179 European individuals for fall susceptibility; and up to 1.2 million individuals from European descent for fracture. Conventional inverse variance weighted (IVW) method was adopted to obtain the causal estimates of BP on different outcomes, while weighted median, MR-egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) test were used for sensitivity analyses.ResultsGenetically high pulse pressure (PP) could significantly improve FA-BMD (beta-estimate: 0.038, 95% confidence interval [CI]: 0.013 to 0.063, SE:0.013, P-value=0.003<Bonferroni correction P) in the IVW analysis, indicating that 1-SD increase in PP was associated with the improvement in FA-BMD levels by 0.038 g/cm2 (95% CI: 0.013 to 0.063). This positive finding was also confirmed by weighted-median analysis (beta-estimate: 0.034, 95% CI: 0.000 to 0.067, SE:0.017, P-value=0.046) and MR-Egger analysis (beta-estimate: 0.117, 95% CI: 0.026 to 0.208, SE:0.046, P-value=0.011). However, there was no remarkable MR association between BP and other outcomes (i.e., FN-BMD, LS-BMD, fall, and fracture).ConclusionsOur findings reveal a potentially causal relationship between high PP and improved FA-BMD, which may provide new sights for the treatment of osteoporosis.

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Review for "The Effect of Plasma Lipids and Lipid‐Lowering Interventions on Bone Mineral Density: A Mendelian Randomization Study"

10.1002/jbmr.3989/v2/review2 ◽

2020 ◽

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Plasma Lipids ◽

Mendelian Randomization ◽

Lipid Lowering ◽

Mineral Density

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Review for "The Effect of Plasma Lipids and Lipid‐Lowering Interventions on Bone Mineral Density: A Mendelian Randomization Study"

10.1002/jbmr.3989/v1/review1 ◽

2019 ◽

Author(s):

Despoina Manousaki

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Plasma Lipids ◽

Mendelian Randomization ◽

Lipid Lowering ◽

Mineral Density

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Decision letter for "The Effect of Plasma Lipids and Lipid‐Lowering Interventions on Bone Mineral Density: A Mendelian Randomization Study"

10.1002/jbmr.3989/v1/decision1 ◽

2019 ◽

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Plasma Lipids ◽

Mendelian Randomization ◽

Lipid Lowering ◽

Mineral Density

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Circulating Alpha-Tocopherol Levels, Bone Mineral Density, and Fracture: Mendelian Randomization Study

Nutrients ◽

10.3390/nu13061940 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1940

Author(s):

Karl Michaëlsson ◽

Susanna C. Larsson

Keyword(s):

Bone Mineral Density ◽

Confidence Interval ◽

Bone Mineral ◽

Genetic Variants ◽

Mendelian Randomization ◽

Alpha Tocopherol ◽

European Ancestry ◽

Mineral Density ◽

Standard Deviation Increase ◽

A Genome

Recent cohort studies indicate a potential role of the antioxidant α-tocopherol in reducing bone loss and risk of fractures, especially hip fractures. We performed a Mendelian randomization investigation of the associations of circulating α-tocopherol with estimated bone mineral density (eBMD) using heel ultrasound and fractures, identified from hospital records or by self-reports and excluding minor fractures. Circulating α-tocopherol was instrumented by three genetic variants associated with α-tocopherol levels at p < 5 × 10−8 in a genome-wide association meta-analysis of 7781 participants of European ancestry. Summary-level data for the genetic associations with eBMD in 426,824 individuals and with fracture (53,184 cases and 373,611 non-cases) were acquired from the UK Biobank. Two of the three genetic variants were strongly associated with eBMD. In inverse-variance weighted analysis, a genetically predicted one-standard-deviation increase of circulating α-tocopherol was associated with 0.07 (95% confidence interval, 0.05 to 0.09) g/cm2 increase in BMD, which corresponds to a >10% higher BMD. Genetically predicted circulating α-tocopherol was not associated with odds of any fracture (odds ratio 0.97, 95% confidence interval, 0.91 to 1.05). In conclusion, our results strongly strengthen a causal link between increased circulating α-tocopherol and greater BMD. Both an intervention study in those with a low dietary intake of α-tocopherol is warranted and a Mendelian randomization study with fragility fractures as an outcome.

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