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 ... -  《-》

Exploring the Association between Serum B Vitamins, Homocysteine and Mental Disorders: Insights from Mendelian Randomization.

Hu Y ，Yu M ，Wang Y ，Wu H ，Yang X ，Chen X ，Wu J ... -  《Nutrients》

Non-causal relationship of polycystic ovarian syndrome with homocysteine and B vitamins: evidence from a two-sample Mendelian randomization.

Previous observational studies have identified a correlation between elevated plasma homocysteine (Hcy) levels and polycystic ovary syndrome (PCOS). This study aimed to determine whether a causal relationship exists between Hcy and PCOS at the genetic level. A two-sample Mendelian Randomization (TSMR) study was implemented to assess the genetic impact of plasma levels of Hcy, folate, vitamin B12, and vitamin B6 on PCOS in individuals of European ancestry. Independent single nucleotide polymorphisms (SNPs) associated with Hcy (n=12), folate (n=2), vitamin B12 (n=10), and vitamin B6 (n=1) at genome-wide significance levels (P<5×10-8) were selected as instrumental variables (IVs). Data concerning PCOS were obtained from the Apollo database. The primary method of causal estimation was inverse variance weighting (IVW), complemented by sensitivity analyses to validate the results. The study found no genetic evidence to suggest a causal association between plasma levels of Hcy, folate, vitamin B12, vitamin B6, and PCOS. The effect sizes, determined through random-effect IVW, were as follows: Hcy per standard deviation increase, OR = 1.117, 95%CI: (0.842, 1.483), P = 0.442; folate per standard deviation increase, OR = 1.008, CI: (0.546, 1.860), P = 0.981; vitamin B12 per standard deviation increase, OR = 0.978, CI: (0.808, 1.185), P = 0.823; and vitamin B6 per standard deviation increase, OR = 0.967, CI: (0.925, 1.012), P = 0.145. The fixed-effect IVW results for each nutrient exposure and PCOS were consistent with the random-effect IVW findings, with additional sensitivity analyses reinforcing these outcomes. Our findings indicate no causal link between Hcy, folate, vitamin B12, vitamin B6 levels, and PCOS.

Su N ，Li J ，Xia Y ，Huang C ，Chen L ... -  《Frontiers in Endocrinology》

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 genetically vitamins and sepsis risk: a two-sample Mendelian randomization study.

In recent years, observational studies have been conducted to investigate the potential impact of vitamins on sepsis. However, many of these studies have produced inconsistent results. Our Mendelian randomization (MR) study aims to evaluate the causality between vitamins and sepsis from a genetic perspective. Our MR study was designed following the STROBE-MR guidelines. Genetic instrumental variables for vitamins including folate, vitamin B12, B6, A (Retinol), C, D, and K were obtained from previous genome-wide association studies (GWAS) and MR studies. Five different sepsis severity levels were included in the analysis. The genetic instrumental variables were screened for potential confounders using PhenoScanner V2. MR analysis was performed using MR-egger, inverse-variance weighted multiplicative random effects (IVW-RE), inverse-variance weighted multiplicative fixed-effects (IVW-FE), and wald ratio methods to assess the relationship between vitamins and sepsis. Sensitivity analysis was performed using the MR-egger_intercept method, and the MR-PRESSO package and Cochran's Q test were used to evaluate the heterogeneity of the instrumental variables. Our MR study found no statistically significant association between vitamins and sepsis risk, regardless of the type of vitamin (P-value > 0.05). The odds ratios (ORs) for folate, vitamin B6, vitamin B12, vitamin A, vitamin D, vitamin K, and vitamin C were 1.164 (95% CI: 0.895-1.514), 0.987 (95% CI: 0.969-1.005), 0.975 (95% CI: 0.914-1.041), 0.993 (95% CI: 0.797-1.238), 0.861 (95% CI: 0.522-1.42), 0.955 (95% CI: 0.86-1.059), and 1.049 (95% CI: 0.911-1.208), respectively. Similar results were observed in subgroups of different sepsis severity levels. Our MR study found no evidence of a causal association between vitamins and sepsis risk from a genetic perspective. Further randomized controlled trials are necessary to confirm these results.

Lou C ，Meng Z ，Shi Y ，Zheng R ，Pan J ，Qian S ... -  《BMC INFECTIOUS DISEASES》