Assessment of the relationship between gut microbiota and bone mineral density: a two-sample Mendelian randomization study

Yuan Xue, Xuan Wang, Honglin Liu, Junfeng Kang, Xiaohong Liang, Aina Yao, Zhifang Dou
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Abstract

Emerging evidence from observational studies and clinical trials suggests a connection between the gut microbiota and variations in bone mineral density (BMD). Nonetheless, the specific association between gut microbiota and BMD alterations at different skeletal sites has not been comprehensively explored. To address this, we employed Genome-Wide Association Study (GWAS) summary statistics from a publicly accessible database, conducting a two-sample Mendelian Randomization analysis to elucidate the potential causal relationship between gut microbiota composition and BMD.This study utilized two distinct thresholds for screening instrumental variables (IVs), followed by an extensive series of quality control procedures to identify IVs that were significantly related to exposure. Gut microbiota were classified into two sets based on hierarchical levels: phylum, class, order, family, and genus. Bone mineral density (BMD) data were systematically collected from four skeletal sites: femoral neck, lumbar spine, forearm, and heel. For Mendelian Randomization (MR) analysis, robust methods including Inverse-Variance Weighting (IVW) and the Wald Ratio Test were employed. Additional analytical tests such as the Outlier Test, Heterogeneity Test, ‘Leave-One-Out’ Test, and Pleiotropy Test were conducted to assess the impact of horizontal pleiotropy, heterogeneities, and the genetic variation stability of gut microbiota on BMD causal associations. The MR Steiger Directionality Test was applied to exclude studies with potential directional biases.In this two-sample Mendelian randomization analysis, we utilized five sets of exposure GWAS (Genome-Wide Association Studies) summary statistics and four sets of outcome GWAS summary statistics. The initial analysis, applying a threshold of p < 5 × 10−6, identified 48 significant causal relationships between genetic liability in the gut microbiome and bone mineral density (BMD). A subsequent analysis with a more stringent threshold of p < 5 × 10−8 uncovered 14 additional causal relationships. Upon applying the Bonferroni correction, 9 results from the first analysis and 10 from the second remained statistically significant.Our MR analysis revealed a causal relationship between gut microbiota and bone mineral density at all sites, which could lead to discoveries in future mechanistic and clinical studies of microbiota-associated osteoporosis.
肠道微生物群与骨矿物质密度之间关系的评估:双样本孟德尔随机研究
来自观察性研究和临床试验的新证据表明,肠道微生物群与骨矿物质密度(BMD)的变化之间存在联系。然而,肠道微生物群与不同骨骼部位的骨矿物质密度变化之间的具体关联尚未得到全面探讨。为了解决这个问题,我们采用了来自公开数据库的全基因组关联研究(GWAS)汇总统计数据,并进行了双样本孟德尔随机分析,以阐明肠道微生物群组成与 BMD 之间的潜在因果关系。肠道微生物群根据门、纲、目、科和属的层次分为两组。从股骨颈、腰椎、前臂和足跟四个骨骼部位系统地收集了骨矿物质密度(BMD)数据。在孟德尔随机化(MR)分析中,采用了包括逆方差加权(IVW)和沃尔德比率检验在内的稳健方法。此外,还进行了离群值检验、异质性检验、"留一 "检验和多义性检验等分析检验,以评估肠道微生物群的水平多义性、异质性和遗传变异稳定性对 BMD 因果关系的影响。在这一双样本孟德尔随机分析中,我们使用了五组暴露 GWAS(全基因组关联研究)汇总统计数据和四组结果 GWAS 汇总统计数据。最初的分析采用了 p < 5 × 10-6 的阈值,确定了肠道微生物组中的遗传责任与骨矿物质密度(BMD)之间的 48 个显著因果关系。随后采用更严格的 p < 5 × 10-8 的阈值进行分析,又发现了 14 个因果关系。我们的磁共振分析揭示了肠道微生物群与所有部位的骨矿物质密度之间的因果关系,这可能会在未来微生物群相关骨质疏松症的机理和临床研究中有所发现。
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