Dataset Information

Genetically Determined Levels of Serum Metabolites and Risk of Neuroticism: A Mendelian Randomization Study.

ABSTRACT:

Background

Neuroticism is a strong predictor for a variety of social and behavioral outcomes, but the etiology is still unknown. Our study aims to provide a comprehensive investigation of causal effects of serum metabolome phenotypes on risk of neuroticism using Mendelian randomization (MR) approaches.

Methods

Genetic associations with 486 metabolic traits were utilized as exposures, and data from a large genome-wide association study of neuroticism were selected as outcome. For MR analysis, we used the standard inverse-variance weighted (IVW) method for primary MR analysis and 3 additional MR methods (MR-Egger, weighted median, and MR pleiotropy residual sum and outlier) for sensitivity analyses.

Results

Our study identified 31 metabolites that might have causal effects on neuroticism. Of the 31 metabolites, uric acid and paraxanthine showed robustly significant association with neuroticism in all MR methods. Using single nucleotide polymorphisms as instrumental variables, a 1-SD increase in uric acid was associated with approximately 30% lower risk of neuroticism (OR: 0.77; 95% CI: 0.62-0.95; PIVW?=?0.0145), whereas a 1-SD increase in paraxanthine was associated with a 7% higher risk of neuroticism (OR: 1.07; 95% CI: 1.01-1.12; PIVW?=?.0145).

Discussion

Our study suggested an increased level of uric acid was associated with lower risk of neuroticism, whereas paraxanthine showed the contrary effect. Our study provided novel insight by combining metabolomics with genomics to help understand the pathogenesis of neuroticism.

SUBMITTER: Qian L

PROVIDER: S-EPMC7816676 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Genetically Determined Levels of Serum Metabolites and Risk of Neuroticism: A Mendelian Randomization Study.

Qian Li L Fan Yajuan Y Gao Fengjie F Zhao Binbin B Yan Bin B Wang Wei W Yang Jian J Ma Xiancang X

The international journal of neuropsychopharmacology 20210101 1

<h4>Background</h4>Neuroticism is a strong predictor for a variety of social and behavioral outcomes, but the etiology is still unknown. Our study aims to provide a comprehensive investigation of causal effects of serum metabolome phenotypes on risk of neuroticism using Mendelian randomization (MR) approaches.<h4>Methods</h4>Genetic associations with 486 metabolic traits were utilized as exposures, and data from a large genome-wide association study of neuroticism were selected as outcome. For M ...[more]

PMID: 32808022

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Project description:BACKGROUND:The role of urate in cardiovascular diseases (CVDs) has been extensively investigated in observational studies; however, the extent of any causal effect remains unclear, making it difficult to evaluate its clinical relevance. METHODS AND FINDINGS:A phenome-wide association study (PheWAS) together with a Bayesian analysis of tree-structured phenotypic model (TreeWAS) was performed to examine disease outcomes related to genetically determined serum urate levels in 339,256 unrelated White British individuals (54% female) in the UK Biobank who were aged 40-69 years (mean age, 56.87; SD, 7.99) when recruited from 2006 to 2010. Mendelian randomization (MR) analyses were performed to replicate significant findings using various genome-wide association study (GWAS) consortia data. Sensitivity analyses were conducted to examine possible pleiotropic effects on metabolic traits of the genetic variants used as instruments for urate. PheWAS analysis, examining the association with 1,431 disease outcomes, identified 13 distinct phecodes representing 4 disease groups (inflammatory polyarthropathies, hypertensive disease, circulatory disease, and metabolic disorders) and 9 disease outcomes (gout, gouty arthropathy, pyogenic arthritis, essential hypertension, coronary atherosclerosis, ischemic heart disease, chronic ischemic heart disease, myocardial infarction, and hypercholesterolemia) that were associated with genetically determined serum urate levels after multiple testing correction (p < 3.35 × 10-4). TreeWAS analysis, examining 10,750 ICD-10 diagnostic terms, identified more sub-phenotypes of cardiovascular and cerebrovascular diseases (e.g., angina pectoris, heart failure, cerebral infarction). MR analysis successfully replicated the association with gout, hypertension, heart diseases, and blood lipid levels but indicated the existence of genetic pleiotropy. Sensitivity analyses support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observational associations with CVDs. The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and possible misclassification of cases for mild disease that did not require hospitalization. CONCLUSION:In this study, high serum urate levels were found to be associated with increased risk of different types of cardiac events. The finding of genetic pleiotropy indicates the existence of common upstream pathological elements influencing both urate and metabolic traits, and this may suggest new opportunities and challenges for developing drugs targeting a common mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular comorbidities.

Project description:Background: Positive associations between inflammatory biomarkers and the risk of heart failure (HF) have been reported in conventional observational studies. However, the causal effects of inflammatory biomarkers on HF have not been fully elucidated. We conducted a Mendelian randomization (MR) study to examine the possible etiological roles of inflammatory biomarkers in HF. Methods: Summary statistical data for the associations between single nucleotide polymorphisms (SNPs) and C-reactive protein (CRP), fibrinogen, and components of the interleukin-1 (IL-1)-interleukin-6 (IL-6) inflammatory signaling pathway, namely, interleukin-1β (IL-1β), IL-1 receptor antagonist (IL-1ra), IL-6, and soluble IL-6 receptor (sIL-6r), were obtained from genome-wide association studies (GWASs) for individuals of European descent. The GWAS dataset of 977,323 participants of European ancestry, which included 47,309 HF cases and 930,014 controls, was collected to identify genetic variants underlying HF. A two-sample Mendelian randomization framework was implemented to examine the causality of the association between these inflammatory biomarkers and HF. Results: Our MR analyses found that genetically determined CRP and fibrinogen were not causally associated with HF risk (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.84-1.02, p = 0.15; OR = 0.94, 95% CI = 0.55-1.58, p = 0.80, respectively). These findings remained consistent using different Mendelian randomization methods and in sensitivity analyses. For the IL-1-IL-6 pathway, causal estimates for IL-6 (OR = 0.86, 95% CI 0.81-0.91, p < 0.001), but not for IL-1β, IL-1ra, or sIL-6r, were significant. However, the association between genetically determined IL-6 and HF risk became non-significant after excluding SNPs with potential pleiotropy (OR = 0.89, 95% CI = 0.77-1.03, p = 0.12). Conclusion: Our study did not identify convincing evidence to support that CRP and fibrinogen, together with their upstream IL-1-IL-6 signaling pathway, were causally associated with HF risk.

Dataset Information

Genetically Determined Levels of Serum Metabolites and Risk of Neuroticism: A Mendelian Randomization Study.

Background

Methods

Results

Discussion

Publications

Genetically Determined Levels of Serum Metabolites and Risk of Neuroticism: A Mendelian Randomization Study.

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