Background Although anxiety disorders are one of the most prevalent mental disorders, their underlying biological mechanisms have not yet been fully elucidated. In recent years, genetically determined metabolites (GDMs) have been used to reveal the biological mechanisms of mental disorders. However, this strategy has not been applied to anxiety disorders. Herein, we explored the causality of GDMs on anxiety disorders through Mendelian randomization study, with the overarching goal of unraveling the biological mechanisms. Methods A two-sample Mendelian randomization (MR) analysis was implemented to assess the causality of GDMs on anxiety disorders. A genome-wide association study (GWAS) of 486 metabolites was used as the exposure, whereas four different GWAS datasets of anxiety disorders were the outcomes. Notably, all datasets were acquired from publicly available databases. A genetic instrumental variable (IV) was used to explore the causality between the metabolite and anxiety disorders for each metabolite. The MR Steiger filtering method was implemented to examine the causality between metabolites and anxiety disorders. The standard inverse variance weighted (IVW) method was first used for the causality analysis, followed by three additional MR methods (the MR-Egger, weighted median, and MR-PRESSO (pleiotropy residual sum and outlier) methods) for sensitivity analyses in MR analysis. MR-Egger intercept, and Cochran’s Q statistical analysis were used to evaluate possible heterogeneity and pleiotropy. Bonferroni correction was used to determine the causative association features (P < 1.03 × 10–4). Furthermore, metabolic pathways analysis was performed using the web-based MetaboAnalyst 5.0 software. All statistical analysis were performed in R software. The STROBE-MR checklist for the reporting of MR studies was used in this study. Results In MR analysis, 85 significant causative relationship GDMs were identified. Among them, 11 metabolites were overlapped in the four different datasets of anxiety disorders. Bonferroni correction showing1-linoleoylglycerophosphoethanolamine (ORfixed-effect IVW = 1.04; 95% CI 1.021–1.06; Pfixed-effect IVW = 4.3 × 10–5) was the most reliable causal metabolite. Our results were robust even without a single SNP because of a “leave-one-out” analysis. The MR-Egger intercept test indicated that genetic pleiotropy had no effect on the results (intercept = − 0.0013, SE = 0.0006, P = 0.06). No heterogeneity was detected by Cochran’s Q test (MR-Egger. Q = 7.68, P = 0.742; IVW. Q = 12.12, P = 0.436). A directionality test conducted by MR Steiger confirmed our estimation of potential causal direction (P < 0.001). In addition, two significant pathways, the “primary bile acid biosynthesis” pathway (P = 0.008) and the “valine, leucine, and isoleucine biosynthesis” pathway (P = 0.03), were identified through metabolic pathway analysis. Conclusion This study provides new insights into the causal effects of GDMs on anxiety disorders by integrating genomics and metabolomics. The metabolites that drive anxiety disorders may be suited to serve as biomarkers and also will help to unravel the biological mechanisms of anxiety disorders.
BackgroundFrailty index and vestibular disorders appear to be associated in observational studies, but causality of the association remains unclear.MethodsA two-sample Mendelian randomization (MR) study was implemented to explore the causal relationship between the frailty index and vestibular disorders in individuals of European descent. A genome-wide association study (GWAS) of frailty index was used as the exposure (n = 175, 226), whereas the GWAS of vestibular disorders was the outcome (n = 462,933). MR Steiger filtering method was conducted to investigate the causal effect of the frailty index on vestibular disorders. An inverse variance weighted (IVW) approach was used as the essential approach to examine the causality. Additionally, the MR-Egger methods, the simple mode analysis, the weighted median analysis, and the weighted mode analysis were used as supplementary methods. The MR-PRESSO analysis, the MR-Egger intercept analysis, and Cochran's Q statistical analysis also were used to detect the possible heterogeneity as well as directional pleiotropy. To evaluate this association, the odds ratio (OR) with 95% confidence intervals (CIs) was used. All statistical analyses were performed in R. The STROBE-MR checklist for the reporting of MR studies was used in this study.ResultsIn total, 14 single nucleotide polymorphisms (SNPs) were identified as effective instrumental variables (IVs) in the two sample MR analyses. The significant causal effect of the frailty index on vestibular disorders was demonstrated by IVW method [OR 1.008 (95% CI 1.003, 1.013), p = 0.001]. Results from the various sensitivity analysis were consistent. The “leave-one-out” analysis indicated that our results were robust even without a single SNP. According to the MR-Egger intercept test [intercept = −0.000151, SE = 0.011, p = 0.544], genetic pleiotropy did not affect the results. No heterogeneity was detected by Cochran's Q test. Results of MR Steiger directionality test indicated the accuracy of our estimate of the potential causal direction (Steiger p < 0.001).ConclusionThe MR study suggested that genetically predicted frailty index may be associated with an increased risk of vestibular disorders. Notably, considering the limitations of this study, the causal effects between frailty index and vestibular disorders need further investigation. These results support the importance of effectively managing frailty which may minimize vestibular disorders and improve the quality of life for those with vestibular disorders.
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