Association between obesity and osteoporosis: a two-sample Mendelian randomization analysis

doi:10.12307/2024.579

Abstract

Abstract: BACKGROUND: Numerous clinical studies have suggested a close relationship between obesity and osteoporosis, but whether there is a genetic causal effect between obesity and osteoporosis remains unclear.
OBJECTIVE: To explore the association between obesity and osteoporosis using summary data from a large-scale genome-wide association study (GWAS) through Mendelian randomization analysis.
METHODS: Obesity data were derived from summary statistics of the Genetic Investigation of Anthropometric Traits (GIANT) and the UK Biobank (UKBB). Osteoporosis data were obtained from the Genetic Factors for Osteoporosis (GeFOS) consortium, including two bone density phenotypes: total body bone mineral density (BMD) and heel BMD. The inverse variance-weighted method was the primary analysis, with the Mendelian randomization method based on Egger regression (MR-Egger) and weighted median method as supplementary approaches to calculate the causal association between genetic variations related to obesity and osteoporosis. Sensitivity analyses were conducted to validate the reliability of the results. Heterogeneity was assessed using Cochran’s Q test. Horizontal pleiotropy was assessed through the MR-Egger intercept test. Leave-one-out analysis was performed to evaluate the potential influence of single nucleotide polymorphisms on the combined inverse variance-weighted estimates.
RESULTS AND CONCLUSION: (1) Impact of obesity on osteoporosis: In addition to body mass index and forearm BMD, body mass index, waist-to-hip ratio, body mass index-adjusted waist-to-hip ratio, and whole-body body mass index, heel BMD, forearm BMD, lumbar spine BMD, and femoral neck BMD were causally related to each other. Further Meta-analysis revealed that obesity increased the risk of BMD (odds ratio=1.07, 95% confidence interval: 1.03-1.12, P < 0.01). (2) Impact of osteoporosis on obesity: Apart from arm BMD and lumbar spine BMD as exposure factors showing causal relationships with obesity, other datasets indicated no causal effect between total body BMD, heel BMD, femoral neck BMD, and obesity. Additional meta-analysis demonstrated that BMD did not increase the risk of obesity (odds rate=0.99, 95% confidence interval: 0.98-1.01, P < 0.01 ). There is a causal relationship between obesity and osteoporosis, suggesting that obesity may be a risk factor for osteoporosis. However, no causal association is found between osteoporosis and obesity.

Key words: obesity, osteoporosis, Mendelian randomization, causal relationship, bone mineral density, Meta-analysis, body mass index

CLC Number:

Zhan Qunzhang, Zhang Yuling, Han Yuxin, Lyu Jiazhen, Zheng Xiaoxia, Qu Chongzheng. Association between obesity and osteoporosis: a two-sample Mendelian randomization analysis[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(27): 4319-4324.

Figures/Tables 7

2.1 肥胖对骨质疏松症的影响 2.1.1 工具变量在探索肥胖作为暴露因素对骨质疏松症患病率的因果影响时，在考虑遗传变异作为工具变量的独立性和连锁不平衡后，研究从身体质量指数、腰臀比及经身体质量指数调整的腰臀比的GWAS数据集中分别筛选出了531个SNPs、346个SNPs及322个SNPs，其P值均小于5×10-8，说明这些SNPs与暴露因素高度相关，满足关联性假设。通过Phenoscanner数据库搜索，无剔除SNPs，所有SNPs均符合独立性假设和排他性假设，计算F值均大于10。 2.1.2 孟德尔随机化分析结果逆方差加权法法分析表明，跟骨骨密度作为结局数据集，与身体质量指数(OR=1.111，95%CI：1.071-1.152，P=0.000)、腰臀比(OR=1.163，95%CI：1.104-1.225，P=0.000)、经身体质量指数调整的腰臀比(OR=1.068，95%CI：1.007-1.133，P=0.029)之间呈现正向因果效应，且差异有显著性意义与身体质量指数(OR=1.111， 95%CI：1.071-1.152，P=0.000)、腰臀比(OR=1.163，95%CI：1.104-1.225， P < 0.001)、经身体质量指数调整的腰臀比(OR=1.068，95%CI：1.007-1.133，P=0.029)之间呈现正向因果效应，且差异有显著性意义，与身体质量指数之间无因果关系(P > 0.05)。股骨颈密度作为结局数据集，与身体质量指数、腰臀比之间无因果关系(P > 0.05)，与经身体质量指数调整的腰臀比(OR=1.125，95%CI：1.044-1.214，P=0.002)呈现正向因果效应，差异有显著性意义。与身体质量指数之间无因果关系(P > 0.05)。股骨颈密度作为结局数据集，与身体质量指数、腰臀比之间无因果关系(P > 0.05)，与经身体质量指数调整的腰臀比(OR=1.125，95%CI：1.044-1.214，P=0.002)呈现正向因果效应，差异有显著性意义。具体信息见表2。此外，孟德尔随机化-PRESSO方法在异常值校正前后的因果估计是一致的，散点图同样显示了遗传预测的回归线基本一致，见图1。以上结果表明孟德尔随机化分析的结果是可靠的。"

2.1.3 敏感性分析结果 Cochran’s Q检验结果表明，文章中存在显著的异质性(P < 0.05)，见表2，采用随机效应模型进行分析。利用MR-Egger截距检验水平多效性，结果显示其截距的P值> 0.05，证明水平多效性并不显著，结果较稳健，见表2。留一法检验分析显示没有个别单核苷酸多态性对整体因果估计产生影响。为了进一步检验上述结果的稳定性，绘制的漏斗图中显示的因果效应分布基本对称，不受潜在因素影响而发生偏倚。 2.2 骨质疏松症对肥胖的影响 2.2.1 工具变量在探索骨质疏松症作为暴露因素对肥胖的因果影响时，在考虑遗传变异作为工具变量的独立性和连锁不平衡后，文章从全身骨密度及跟骨骨密度的GWAS数据集中分别筛选出了79个SNPs及229个SNPs，其P值均小于5×10-8，说明这些SNPs与暴露因素高度相关，满足关联性假设。通过Phenoscanner数据库搜索，无剔除SNPs，所有SNPs均符合独立性假设和排他性假设，计算F值均大于10。 2.2.2 孟德尔随机化分析结果逆方差加权法法分析表明，全身骨密度、跟骨骨密度、股骨颈骨密度与肥胖之间不呈现因果效应：全身骨密度与身体质量指数(OR=1.031，95%CI：0.994-1.033，P=0.173)、腰臀比(OR=0.989，95%CI：0.968-1.009，P=0.278)、经身体质量指数调整的腰臀比(OR=0.983，95%CI：0.962-1.005，P=0.122)；跟骨骨密度与肥胖与身体质量指数(OR=1.013，95%CI：0.993-1.034，P=0.212)、腰臀比(OR=1.012，95%CI：0.989-1.035，P=0.302)、经身体质量指数调整的腰臀比(OR=1.008，95%CI：0.983-1.034，P=0.538)；股骨颈骨密度与身体质量指数(OR=0.999，95%CI：0.966-1.033，P=0.949)、腰臀比(OR=0.969，95%CI：0.926-1.013，P=0.164)、经身体质量指数调整的腰臀比(OR=0.968，95%CI：0.921-1.017，P=0.199)。前臂骨密度、腰椎骨密度作为暴露因素对肥胖有因果关系，但因果效应方向性不一致，与身体质量指数呈正向因果关系，与腰臀比、经身体质量指数调整的腰臀比呈负向因果关系。具体结果见表3。此外，散点图同样显示了遗传预测的回归线方向的不一致进一步验证结果是可靠的，见图3。"

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