Exploring potential plasma drug targets for cholelithiasis through multiancestry Mendelian randomization.

BACKGROUND: Cholelithiasis poses significant health and economic burdens, necessitating novel pharmacological targets to enhance treatment efficacy. METHOD: Based on genome-wide association analysis (GWAS) studies, we performed two-sample Mendelian randomization (MR) analysis based on plasma proteomics to explore potential drug targets in European (nCase=40,191 and nControl=361,641) and Asian (nCase=9,305 and nControl=168,253) populations. We confirmed the directionality and robust correlation of the drug targets with the results through reverse MR analysis, Steiger filtering, Bayesian colocalization, phenotype scanning and replication in multiple databases. Further exploration of the safety and possible mechanisms of action of phenome-wide MR analysis and protein‒protein interactions (PPIs) as individual drug targets was performed. RESULTS: Our proteomics-based MR analyses suggested that FUT3 (OR=0.87; 95% CI, 0.84-0.89; P=4.70×10-32), NOE1 (OR=0.58; 95% CI, 0.52-0.66; P=4.21×10-23), UGT1A6 (OR=0.68; 95% CI, 0.64-0.73; P=9.58×10-30) and FKBP52 (OR=1.75; 95% CI, 1.37-2.24; P=8.61×10-6) were potential drug targets in Europeans, whereas KLB (OR=1.11; 95% CI, 1.07-1.16; P=7.59×10-7) and FGFR4 (OR=0.94; 95% CI, 0.91-0.96; P=4.07×10-6) were valid targets in East Asians. There was no reverse causality for these drug targets. Evidence from Bayesian colocalization analyses supported that exposure and outcome shared consistent genetic variables. Phenome-wide MR analysis suggested the potential deleterious effects of NOE1 and FGFR4. PPI analysis confirmed the pathways associated with the potential targets involved in bile acid metabolism. CONCLUSIONS: Genetically predicted levels of the plasma proteins FUT3, NOE1, UGT1A6 and FKBP52 have potential as prospective targets in Europeans. Moreover, the plasma levels of KLB and FGFR4 may serve as potential targets for the treatment of cholelithiasis in East Asians.

Association of lipid-lowering drugs with gut microbiota: A Mendelian randomization study.

BACKGROUND: The gut microbiota can be influenced by lipid metabolism. We aimed to evaluate the impact of lipid-lowering medications, such as proproteinconvertase subtilisin/kexin type 9 (PCSK9) inhibitors, Niemann-Pick C1-like protein (NPC1L1) inhibitors, and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors, on gut microbiota through drug target Mendelian randomization (MR) investigation. METHODS: We used genetic variants that were associated with low-density lipoprotein cholesterol (LDL-C) in genome-wide association studies and located within or near drug target genes as proxies for lipid-lowering drug exposure. In addition, expression trait loci in drug target genes were used as complementary genetic tools. We used effect estimates calculated using inverse variance weighted MR (IVW-MR) and summary data-based MR (SMR). Multiple sensitivity analyses were performed. RESULTS: Genetic proxies for lipid-lowering drugs broadly affected the abundance of gut microbiota. High expression of NPC1L1 was significantly associated with an increase in the genus Eggerthella (ß = 1.357, SE = 0.337, P = 5.615 × 10-5). An HMGCR-mediated increase in LDL-C was significantly associated with the order Pasteurellales (ß = 0.489, SE = 0.123, P = 6.955 × 10-5) and the genus Haemophilus (ß = 0.491, SE = 0.125, P = 8.379 × 10-5), whereas a PCSK9-mediated increase in LDL-C was associated with the genus Terrisporobacter (ß = 0.666, SE = 0.127, P = 1.649 × 10-5). No pleiotropy was detected. CONCLUSIONS: This drug target MR highlighted the potential interventional effects of lipid-lowering drugs on the gut microbiota and separately revealed the possible effects of different types of lipid-lowering drugs on specific gut microbiota.

Associations of hearing loss and structural changes in specific cortical regions: a Mendelian randomization study.

INTRODUCTION: Previous studies have suggested a correlation between hearing loss (HL) and cortical alterations, but the specific brain regions that may be affected are unknown. METHODS: Genome-wide association study (GWAS) data for 3 subtypes of HL phenotypes, sensorineural hearing loss (SNHL), conductive hearing loss, and mixed hearing loss, were selected as exposures, and GWAS data for brain structure-related traits were selected as outcomes. The inverse variance weighted method was used as the main estimation method. RESULTS: Negative associations were identified between genetically predicted SNHL and brain morphometric indicators (cortical surface area, cortical thickness, or volume of subcortical structures) in specific brain regions, including the bankssts (ß = -0.006 mm, P = 0.016), entorhinal cortex (ß = -4.856 mm2, P = 0.029), and hippocampus (ß = -24.819 cm3, P = 0.045), as well as in brain regions functionally associated with visual perception, including the pericalcarine (ß = -10.009 cm3, P = 0.013). CONCLUSION: Adaptive changes and functional remodeling of brain structures occur in patients with genetically predicted HL. Brain regions functionally associated with auditory perception, visual perception, and memory function are the main brain regions vulnerable in HL.

Association of gut microbiota with cerebral cortical thickness: A Mendelian randomization study.

BACKGROUND: The causal relationship between gut microbiota and cerebral cortex development remains unclear. We aimed to scrutinize the plausible causal impact of gut microbiota on cortical thickness via Mendelian randomization (MR) study. METHODS: Genome-wide association study (GWAS) data for 196 gut microbiota phenotypes (N = 18,340) were obtained as exposures, and GWAS data for cortical thickness-related traits (N = 51,665) were selected as outcomes. Inverse variance weighted was used as the main estimate method. A series of sensitivity analyses was used to test the robustness of the estimates including Cochran's Q test, MR-Egger intercept analysis, Steiger filtering, scatter plot funnel plot and leave-one-out analysis. RESULTS: Genetic prediction of high Bacillales (ß = 0.005, P = 0.032) and Lactobacillales (ß = 0.010, P = 0.012) abundance was associated with a potential increase in global cortical thickness. For specific functional brain subdivisions, genetically predicted order Lactobacillales would potentially increase the thickness of the fusiform (ß = 0.014, P = 0.016) and supramarginal (ß = 0.017, P = 0.003). Meanwhile, order Bacillales would increase the thickness of fusiform (ß = 0.007, P = 0.039), insula (ß = 0.011, P = 0.003), rostralanteriorcingulate (ß = 0.014, P = 0.002) and supramarginal (ß = 0.006, P = 0.043). No significant estimates of heterogeneity or pleiotropy were found. CONCLUSIONS: Through MR studies, we discovered genetic prediction of the Lactobacillales and Bacillales orders potentially linked to cortical thickness, affirming gut microbiota may enhance brain structure. Genetically predicted supramarginal and fusiform may be potential targets.

Causal relationship between gastroesophageal reflux disease, Barrett's esophagus, and epilepsy: A bidirectional Mendelian randomization study.

BACKGROUND: The incidence of gastroesophageal reflux disease (GERD) has been shown to be elevated in individuals with epilepsy. Traditional observational studies have led to a limited understanding of the effects of GERD and BE on epilepsy due to the interference of reverse causation and potential confounders. METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to determine whether GERD and BE can increase the risk of epilepsy. Genome-wide association study data on epilepsy and its subgroups were obtained from the International League Against Epilepsy consortium for primary analysis using three MR approaches and the FinnGen consortium for replication and meta-analysis. We calculated causal estimates between the two esophageal diseases and epilepsy using the inverse-variance weighted method. Sensitivity analysis was conducted to detect heterogeneity and pleiotropy. RESULTS: We found a potential effect of genetically predicted GERD on the risk of epilepsy (odds ratio [OR] = 1.078; 95% confidence interval [CI], 1.014-1.146, p = .016). Specifically, GERD showed an effect on the risk of generalized epilepsy (OR = 1.163; 95% CI, 1.048-1.290, p = .004) but not focal epilepsy (OR = 1.059, 95% CI, 0.992-1.131, p = .084). Notably, BE did not show a significant causal relationship with the risks of generalized and focal epilepsy. CONCLUSIONS: Under MR assumptions, our findings suggest a potential risk-increasing effect of GERD on epilepsy, especially generalized epilepsy. Considering the exploratory nature of our study, the association between GERD and epilepsy needs to be confirmed by future prospective studies.