Dataset Information

Non-steroidal anti-inflammatory drug target gene associations with major depressive disorders: a Mendelian randomisation study integrating GWAS, eQTL and mQTL Data.

ABSTRACT: Previous observational studies reported associations between non-steroidal anti-inflammatory drugs (NSAIDs) and major depressive disorder (MDD), however, these associations are often inconsistent and underlying biological mechanisms are still poorly understood. We conducted a two-sample Mendelian randomisation (MR) study to examine relationships between genetic variants and NSAID target gene expression or DNA methylation (DNAm) using publicly available expression, methylation quantitative trait loci (eQTL or mQTL) data and genetic variant-disease associations from genome-wide association studies (GWAS of MDD). We also assessed drug exposure using gene expression and DNAm levels of NSAID targets as proxies. Genetic variants were robustly adjusted for multiple comparisons related to gene expression, DNAm was used as MR instrumental variables and GWAS statistics of MDD as the outcome. A 1-standard deviation (SD) lower expression of NEU1 in blood was related to lower C-reactive protein (CRP) levels of -0.215 mg/L (95% confidence interval (CI): 0.128-0.426) and a decreased risk of MDD (odds ratio [OR] = 0.806; 95% CI: 0.735-0.885; p = 5.36 × 10^-6). A concordant direction of association was also observed for NEU1 DNAm levels in blood and a risk of MDD (OR = 0.886; 95% CI: 0.836-0.939; p = 4.71 × 10^-5). Further, the genetic variants associated with MDD were mediated by NEU1 expression via DNAm (β = -0.519; 95% CI: -0.717 to -0.320256; p = 3.16 × 10^-7). We did not observe causal relationships between inflammatory genetic marker estimations and MDD risk. Yet, we identified a concordant association of NEU1 messenger RNA and an adverse direction of association of higher NEU1 DNAm with MDD risk. These results warrant increased pharmacovigilance and further in vivo or in vitro studies to investigate NEU1 inhibitors or supplements for MDD.

SUBMITTER: He Q

PROVIDER: S-EPMC10382318 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Non-steroidal anti-inflammatory drug target gene associations with major depressive disorders: a Mendelian randomisation study integrating GWAS, eQTL and mQTL Data.

He Qian Q Wu Kevin Chun Hei KCH Bennett Adam N AN Fan Beifang B Liu Jundong J Huang Ruixuan R Kong Alice P S APS Tian Xiaoyu X Kwok Man Ki Maggie MKM Chan Kei Hang Katie KHK

The pharmacogenomics journal 20230325 4

Previous observational studies reported associations between non-steroidal anti-inflammatory drugs (NSAIDs) and major depressive disorder (MDD), however, these associations are often inconsistent and underlying biological mechanisms are still poorly understood. We conducted a two-sample Mendelian randomisation (MR) study to examine relationships between genetic variants and NSAID target gene expression or DNA methylation (DNAm) using publicly available expression, methylation quantitative trait ...[more]

PMID: 36966195

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Project description:BackgroundIncreasing evidence suggests a potential causal association between lipid levels and facial aging. The aim of this study was to investigate the relationship between levels of specific lipids and facial aging via Mendelian randomization methods. Additionally, this study aimed to identify mediators and explore relevant genes and drug targets.MethodsIn this study, genome-wide association data on plasma lipids from 7,174 Finnish individuals in the UK Biobank were used. Two-sample Mendelian randomization was applied to assess the causal effects of specific lipids on facial aging. Sensitivity and pleiotropy analyses were conducted to ensure the robustness and reliability of the results. Multivariate Mendelian randomization was conducted to account for the potential impact of confounding factors. Furthermore, summary-data-based Mendelian randomization was used to identify relevant genes, which were validated through multiomics data. Finally, drug‒gene interactions were explored via molecular docking techniques.ResultsTwo-sample Mendelian randomization analysis revealed a causal relationship between lipid levels and facial aging. According to the multivariate Mendelian randomization results, smoking was found to mediate this association, and these lipids remained significantly associated with facial aging, even after accounting for environmental confounders. Using summary-data-based Mendelian randomization, CYP21A2, CCND1, PSMA4, and MED1 were identified as potential gene targets, with MED1 further validated through pQTL and mQTL data. Additionally, the MED1 protein was found to bind spontaneously with astragalin, fenofibrate, and ginsenoside.ConclusionsThe results revealed a causal relationship between lipid levels and facial aging, revealing key gene targets that were still significantly associated with facial aging after controlling for environmental confounders. Additionally, the interactions between MED1 and certain drugs may indicate potential pathways for therapeutic interventions related to facial aging.

Project description:Aims/hypothesisObservational studies have shown a bidirectional association between major depressive disorder (MDD) and cardiometabolic diseases. We conducted a two-sample bidirectional Mendelian randomisation (MR) study to assess the causal associations of MDD with type 2 diabetes, coronary artery disease (CAD) and heart failure and vice versa.MethodsWe extracted summary-level data for MDD, type 2 diabetes, CAD and heart failure from corresponding published large genome-wide association studies of individuals mainly of European-descent. In total, 96 SNPs for MDD, 202 SNPs for type 2 diabetes, 44 SNPs for CAD and 12 SNPs for heart failure were proposed as instrumental variables at the genome-wide significance level (p < 5 × 10-8). The random-effects inverse-variance weighted method was used for the main analyses.ResultsGenetic liability to MDD was significantly associated with type 2 diabetes and CAD at the Bonferroni-corrected significance level. The ORs of type 2 diabetes and CAD were respectively 1.26 (95% CI 1.10, 1.43; p = 6 × 10-4) and 1.16 (95% CI 1.05, 1.29; p = 0.0047) per one-unit increase in loge odds of MDD. There was a suggestive association between MDD and heart failure (OR 1.11 [95% CI 1.01, 1.21]; p = 0.033). We found limited evidence supporting causal effects of cardiometabolic diseases on MDD risk in the reverse MR analyses.Conclusions/interpretationThe present study strengthened the evidence that MDD is a potential risk factor for type 2 diabetes and CAD. Whether MDD is causally related to heart failure needs further study.Data availabilityAll data included in this study were uploaded as supplements and are also publicly available through published GWASs and open GWAS datasets (UK Biobank, 23andMe and Psychiatric Genomics: https://datashare.is.ed.ac.uk/handle/10283/3203; DIAGRAM: http://diagram-consortium.org/downloads.html; CARDIoGRAMplusCD4: www.cardiogramplusc4d.org/; HERMES: http://www.kp4cd.org/datasets/mi). Graphical abstract.

Dataset Information

Non-steroidal anti-inflammatory drug target gene associations with major depressive disorders: a Mendelian randomisation study integrating GWAS, eQTL and mQTL Data.

Publications

Non-steroidal anti-inflammatory drug target gene associations with major depressive disorders: a Mendelian randomisation study integrating GWAS, eQTL and mQTL Data.

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