Inferring causal effects of homocysteine and B-vitamin concentrations on bone mineral density and fractures: Mendelian randomization analyses.

In the progress of bone metabolism, homocysteine (Hcy) and B vitamins play substantial roles. However, the causal associations of homocysteine, B-vitamin concentrations with bone mineral density (BMD), and fractures remain unclear. Therefore, we employed a two-sample Mendelian randomization (MR) design to infer the causal effects of Hcy and B vitamins on BMD and fractures. We selected instrumental variables from large genome-wide association studies (GWASs). Specifically, the exposures mainly included Hcy (sample size: 44,147), vitamin B12 (sample size: 45,576), folate (sample size: 37,465), and vitamin B6 (sample size: 1,864). The outcome variables included total body BMD (sample size: 66,628), heel BMD (sample size: 142,487), femoral neck BMD (sample size: 32,735), lumbar spine BMD (sample size: 28,498), and forearm BMD (sample size: 8143). Additionally, the total body BMD in several age strata was also included. Furthermore, the fractures of the forearm, femoral neck, lumbar spine, heel corresponding with the BMD regions, and femoral neck and lumbar spine BMD in men and women, separately, were added as additional outcomes. Two-sample MR approaches were utilized in this study. Inverse variance weighting (IVW) was adopted as the main analysis. MR-PRESSO, MR-Egger, the weighted median estimate, and multivariable MR were performed as sensitivity methods. In the main analysis, Hcy concentrations have an inverse association with heel BMD (Beta = 0.046, 95% confidence interval (CI) -0.073 to -0.019, P = 9.59E-04) per SD unit. In addition, for one SD increase of vitamin B12, the total body BMD decreased 0.083 unit (95%CI -0.126 to -0.040, P = 1.65E-04). The trend was more obvious in age over 45 years (Beta = -0.135, 95%CI -0.203-0.067, P = 9.86E-05 for age 45-60; Beta = -0.074, 95%CI -0.141 to -0.007, P = 0.031 for age over 60 years). No association of B vitamins and Hcy levels with the risk of fractures and femoral neck and lumbar spine BMD in men and women was found in this study. Other sensitivity MR methods elucidated consistent results. Our findings indicated that there exist the inversely causal effects of Hcy and vitamin B12 on BMD in certain body sites and age strata. These give novel clues for intervening bone-related diseases in public health and nutrition.

Fu L ，Wang Y ，Hu YQ 《Frontiers in Endocrinology》

Causal effects of homocysteine levels on the changes of bone mineral density and risk for bone fracture: A two-sample mendelian randomization study.

Observational studies have demonstrated the relations of homocysteine (HCY) with bone mineral density (BMD) and bone fracture risk, but yielding contradictory results. The present study was conducted to evaluate whether the genetically predicted plasma HCY levels were causally associated with the change of BMD and the risk of bone fracture. Genetic summary statistics were extracted from genome-wide association study (GWAS) meta-analysis of plasma HCY levels (n = 44,147), GWAS meta-analyses of measured forearm (FA), femoral neck (FN) and lumbar spine (LS) BMD (n = up to 32,735), UK Biobank estimated heel BMD (eBMD) (n = 426,824) and fracture (n = 426,795) GWAS data. Two Sample Mendelian Randomization (TSMR) analysis was performed to assess the causal effects of genetically determined plasma HCY on the BMD and bone fractures. The MR analysis indicated that, genetically decreased plasma HCY was associated with the increased FA-BMD based on the inverse variance weighting (IVW) method (standard deviation [SD] = 0.348, 95% CI: 0.146 to 0.550, P = 7 × 10-4). However, there were no significant associations of genetically decreased plasma HCY with FN-BMD, LS-BMD, eBMD and the risk for bone fracture (SD = -0.041, 95% CI: -0.189 to 0.106, P = 0.582; SD = -0.053, 95% CI: -0.238 to 0.131, P = 0.572; SD = -0.030, 95% CI: -0.090 to 0.030, P = 0.328, odds ratio [OR]: 1.03, 95% CI: 0.94 to 1.13, P = 0.562, respectively). Moreover, the results also found that genetically determined HCY increase was not correlated with the changes of BMD and the risk for bone fracture. Our study revealed that genetically decreased plasma HCY was associated with increase of FA-BMD.

Wang P ，Liu L ，Lei SF 《-》

Inferring the genetic effects of serum homocysteine and vitamin B levels on autism spectral disorder through Mendelian randomization.

The previous studies have suggested that serum homocysteine (Hcy) and vitamin B levels are potentially related to autism spectrum disorder (ASD). However, the causality between their concentrations and ASD risk remains unclear. To elucidate this genetic association, we used a Mendelian randomization (MR) design. For this MR analysis, 47 single-nucleotide polymorphisms (SNPs)-13 related to Hcy, 13 to folate, 14 to vitamin B6, and 7 to vitamin B12-were obtained from a large-scale Genome-Wide Association Studies (GWAS) database and employed as instrumental variables (IVs). Our study used three approaches to calculate the MR estimates, including inverse-variance weighted (IVW) method, MR-Egger method, and weighted median (WM) method. Among these, the IVW method served as our primary MR method. False discovery rate (FDR) was implemented to correct for multiple comparisons. We also performed a series of sensitivity analyses, including Cochran's Q test, MR-Egger's intercept, MR-PRESSO, leave-one-out analysis, and the funnel plot. Univariable Mendelian randomization (UVMR) analysis revealed a statistical association between serum vitamin B12 levels and ASD risk (OR = 1.68, 95% CI 1.12-2.52, P = 0.01) using the IVW method. However, neither the WM method (OR = 1.57, 95% CI 0.93-2.66, P = 0.09) nor the MR-Egger method (OR = 2.33, 95% CI 0.48-11.19, P = 0.34) was significantly association with higher levels of serum vitamin B12 and ASD risk. Additionally, we found no evidence of causal relationships between serum levels of vitamin B6, folate, Hcy, and ASD risk. After correcting for the FDR, the causality between serum vitamin B12 levels and ASD risk remained significant (q value = 0.0270). Multivariate Mendelian randomization (MVMR) analysis indicated an independent association between elevated serum vitamin B12 levels and the risk of ASD (OR = 1.74, 95% CI 1.03-2.95, P = 0.03) using the IVW method, but this finding was inconsistent when using the WM method (OR = 1.73, 95% CI 0.89-3.36, P = 0.11) and MR-Egger method (OR = 1.60, 95% CI 0.95-2.71, P = 0.08). Furthermore, no causal associations were observed for serum levels of vitamin B6 and folate in MVMR analysis. Sensitivity analyses confirmed that these results were reliable. Our study indicated that elevated serum vitamin B12 levels might increase the risk of ASD. The potential implications of our results for ASD risk warrant validation in randomized clinical trials.

Jin T ，Huang W ，Pang Q ，He Z ，Yuan L ，Zhang H ，Xing D ，Guo S ，Zhang T ... -  《-》

Causal relationship between bone mineral density and intervertebral disc degeneration: a univariate and multivariable mendelian randomization study.

Although previous studies have suggested a possible association between bone mineral density (BMD) and intervertebral disc degeneration (IDD), the causal relationship between them remains unclear. Evidence from accumulating studies indicates that they might mutually influence one another. However, observational studies may be affected by potential confounders. Meanwhile, Mendelian randomization (MR) study can overcome these confounders to assess causality. This Mendelian randomization (MR) study aimed to explore the causal effect of bone mineral density (BMD) on intervertebral disc degeneration (IDD). Summary data from genome-wide association studies of bone mineral density (BMD) and IDD (the FinnGen biobank) have been acquired. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach. Weighted median, MR-Egger regression, weighted mode, and simple mode were used as supplements. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were performed to assess horizontal pleiotropy. Cochran's Q test evaluated heterogeneity. Leave-one-out sensitivity analysis was further conducted to determine the reliability of the causal relationship. Multivariate MR (MVMR) analyses used multivariable inverse variance-weighted methods to individually and jointly adjust for four potential confounders, body mass index (BMI), Type2 diabetes, hyperthyroidism and smoking. A reverse MR analysis was conducted to assess potential reverse causation. In the univariate MR analysis, femoral neck bone mineral density (FNBMD), heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) had a direct causal effect on intervertebral disc degeneration (IDD) [FNBMD-related analysis: OR(95%CI) = 1.17 (1.04 to 1.31), p = 0.008, eBMD-related analysis: OR(95%CI) = 1.06 (1.01 to 1.12), p = 0.028, LSBMD-related analysis: OR(95%CI) = 1.20 (1.10 to 1.31), p = 3.38E-7,TB BMD-related analysis: OR(95%CI) = 1.20 (1.12 to 1.29), p = 1.0E-8]. In the MVMR analysis, it was revealed that, even after controlling for confounding factors, heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) still maintained an independent and significant causal association with IDD(Adjusting for heel bone mineral density: beta = 0.073, OR95% CI = 1.08(1.02 to 1.14), P = 0.013; Adjusting for lumbar spine bone mineral density: beta = 0.11, OR(95%CI) = 1.12(1.02 to 1.23), P = 0.03; Adjusting for total body bone mineral density: beta = 0.139, OR95% CI = 1.15(1.06 to 1.24), P = 5.53E - 5). In the reverse analysis, no evidence was found to suggest that IDD has an impact on BMD. The findings from our univariate and multivariable Mendelian randomization analysis establish a substantial positive causal association between BMD and IDD, indicating that higher bone mineral density may be a significant risk factor for intervertebral disc degeneration. Notably, no causal effect of IDD on these four measures of bone mineral density was observed. Further research is required to elucidate the underlying mechanisms governing this causal relationship.

Li L ，Li D ，Geng Z ，Huo Z ，Kang Y ，Guo X ，Yuan B ，Xu B ，Wang T ... -  《BMC MUSCULOSKELETAL DISORDERS》

Causal relationship between circulating levels of cytokines and bone mineral density: A mendelian randomization study.

Xu T ，Li C ，Liao Y ，Zhang X ... -  《-》