Objective This study explored the potentially modifiable factors for depression and major depressive disorder(MDD)from the MR-Base database and further evaluated the associations between drug targets with MDD.Methods ...Objective This study explored the potentially modifiable factors for depression and major depressive disorder(MDD)from the MR-Base database and further evaluated the associations between drug targets with MDD.Methods We analyzed two-sample of Mendelian randomization(2SMR)using genetic variant depression(n=113,154)and MDD(n=208,811)from Genome-Wide Association Studies(GWAS).Separate calculations were performed with modifiable risk factors from MR-Base for 1,001 genomes.The MR analysis was performed by screening drug targets with MDD in the DrugBank database to explore the therapeutic targets for MDD.Inverse variance weighted(IVW),fixed-effect inverse variance weighted(FE-IVW),MR-Egger,weighted median,and weighted mode were used for complementary calculation.Results The potential causal relationship between modifiable risk factors and depression contained 459 results for depression and 424 for MDD.Also,the associations between drug targets and MDD showed that SLC6A4,GRIN2A,GRIN2C,SCN10A,and IL1B expression are associated with an increased risk of depression.In contrast,ADRB1,CHRNA3,HTR3A,GSTP1,and GABRG2 genes are candidate protective factors against depression.Conclusion This study identified the risk factors causally associated with depression and MDD,and estimated 10 drug targets with significant impact on MDD,providing essential information for formulating strategies to prevent and treat depression.展开更多
AIM:To explore the causal relationship between several possible behavioral factors and high myopia(HM)using multivariable Mendelian randomization(MVMR)approach and to find the mediators among them with mediation analy...AIM:To explore the causal relationship between several possible behavioral factors and high myopia(HM)using multivariable Mendelian randomization(MVMR)approach and to find the mediators among them with mediation analysis.METHODS:The causal effects of several behavioral factors,including screen time,education time,time spent outdoors,and physical activity,on the risk of HM using univariable Mendelian randomization(MR)and MVMR analyses were first assessed.Genome-wide association study summary statistics of serum metabolites were also used in mediation analysis to determine the extent to which serum metabolites mediate the effects of behavioral factors on HM.RESULTS:MR analyses indicated that both increased time spent outdoors and a higher frequency of moderate physical activity significantly reduced the risk of HM.Further MVMR analysis confirmed that moderate physical activity independently contributed to a lower risk of HM.Additionally,MR analyses identified 13 serum metabolites significantly associated with HM,of which 12 were lipids and one was an amino acid derivative.Mediation analysis revealed that six lipid metabolites mediated the protective effects of moderate physical activity on HM,with the highest mediation proportion observed for 1-(1-enyl-palmitoyl)-GPC(p-16:0;30.83%).CONCLUSION:This study suggests that in addition to outdoor time,moderate physical activity habits may have an independent protective effect against HM and pointed to lipid metabolites as priority targets for the prevention due to low physical activity.These results emphasize the importance of physical activity and metabolic health in HM and underscore the need for further study of these complex associations.展开更多
Emerging evidence highlights the role of thyroid hormones in cancer,although findings are controversial.Research on thyroid-related traits in lung carcinogenesis is limited.Using UK Biobank data,we performed bidirecti...Emerging evidence highlights the role of thyroid hormones in cancer,although findings are controversial.Research on thyroid-related traits in lung carcinogenesis is limited.Using UK Biobank data,we performed bidirectional Mendelian randomization(MR)to assess causal associations between lung cancer risk and thyroid dysfunction(hypothyroidism and hyperthyroidism)or functional traits(free thyroxine[FT4]and normal-range thyroid-stimulating hormone[TSH]).Furthermore,in the smoking-behavior-stratified MR analysis,we evaluated the mediating effect of thyroid-related phenotypes on the association between smoking behaviors and lung cancer.We demonstrated significant associations between lung cancer risk and hypothyroidism(hazard ratio[HR]=1.14,95%confidence interval[CI]=1.03–1.26,P=0.009)and hyperthyroidism(HR=1.55,95%CI=1.29–1.87,P=1.90×10^(-6))in the UKB.Moreover,the MR analysis indicated a causal effect of thyroid dysfunction on lung cancer risk(ORinverse variance weighted[IVW]=1.09,95%CI=1.05–1.13,P=3.12×10^(-6)for hypothyroidism;ORIVW=1.08,95%CI=1.04–1.12,P=8.14×10^(-5)for hyperthyroidism).We found that FT4 levels were protective against lung cancer risk(ORIVW=0.93,95%CI=0.87–0.99,P=0.030).Additionally,the stratified MR analysis demonstrated distinct causal effects of thyroid dysfunction on lung cancer risk among smokers.Hyperthyroidism mediated the effect of smoking behaviors,especially the age of smoking initiation(17.66%mediated),on lung cancer risk.Thus,thyroid dysfunction phenotypes play causal roles in lung cancer development exclusively among smokers and act as mediators in the causal pathway from smoking to lung cancer.展开更多
BACKGROUND Some studies have directed towards an association between diabetes mellitus(DM)and prostate cancer(PCa);however,this specific relationship remains inconclusive.In recent years,Mendelian randomization(MR)has...BACKGROUND Some studies have directed towards an association between diabetes mellitus(DM)and prostate cancer(PCa);however,this specific relationship remains inconclusive.In recent years,Mendelian randomization(MR)has become a widely used analytical method for inferring epidemiological causes.AIM To investigated the potential relationship between DM and PCa using MR.METHODS We downloaded relevant data on"diabetes"and"PCa"from the IEU OpenGWAS project database,performed three different methods to conduct MR,and carried out sensitivity analysis for verification.RESULTS The results indicated that DM was an independent risk factor for PCa.The odds ratio(OR)values obtained using the inverse variance weighted method in this study were as follows:OR=1.018(95%confidence interval:1.004-1.032),P=0.014.CONCLUSION We found that DM could increase the incidence rate of PCa.展开更多
AIM:To assess whether there is a possible causal link between the intake of cheese and the risk of diabetic retinopathy(DR)utilizing a two-sample Mendelian randomization(MR)analysis.METHODS:The research data were obta...AIM:To assess whether there is a possible causal link between the intake of cheese and the risk of diabetic retinopathy(DR)utilizing a two-sample Mendelian randomization(MR)analysis.METHODS:The research data were obtained from summary statistics of genome-wide association studies(GWAS).Genetic loci closely related to cheese intake were extracted as instrumental variables(IVs),and DR was the outcome variable.The data were extracted from individuals of European ethnicity.The data of cheese intake consisted of 451486 samples with 9851867 single nucleotide polymorphisms(SNPs),while the DR data consisted of 206234 samples with 16380446 SNPs.Sixty-one genetic loci closely related to cheese intake were selected as IVs.MR analysis was performed by inverse-variance weighted(IVW)method and MR-Egger regression respectively.The causal relationship between cheese intake and DR was evaluated using odds ratios(ORs)and 95%confidence intervals(CIs).Egger-intercept test was used to test horizontal pleiotropy and sensitivity analysis was performed by leave-one-out test.RESULTS:The P value of the IVW method was less than 0.05,indicating a significant negative correlation between cheese intake and DR.MR-Egger regression showed that the intercept was 0.01 with a standard error of 0.022,and a P-value of 0.634,indicating no evidence of horizontal pleiotropy affecting the IVs related to the exposure factors.Besides,heterogeneity tests confirmed the absence of heterogeneity,and the“leave-one-out”sensitivity analysis demonstrated that the results were stable.CONCLUSION:Cheese intake is causally negatively correlated with the occurrence of DR,and cheese intake could reduce the risk of DR.展开更多
Mendelian randomization(MR)is widely used in causal mediation analysis to control unmeasured confounding effects,which is valid under some strong assumptions.It is thus of great interest to assess the impact of violat...Mendelian randomization(MR)is widely used in causal mediation analysis to control unmeasured confounding effects,which is valid under some strong assumptions.It is thus of great interest to assess the impact of violations of these MR assumptions through sensitivity analysis.Sensitivity analyses have been conducted for simple MR-based causal average effect analyses,but they are not available for MR-based mediation analysis studies,and we aim to fill this gap in this paper.We propose to use two sensitivity parameters to quantify the effect due to the deviation of the IV assumptions.With these two sensitivity parameters,we derive consistent indirect causal effect estimators and establish their asymptotic propersties.Our theoretical results can be used in MR-based mediation analysis to study the impact of violations of MR as-sumptions.The finite sample performance of the proposed method is illustrated through simulation studies,sensitivity ana-lysis,and application to a real genome-wide association study.展开更多
BACKGROUND The identification of specific gene expression patterns is crucial for understanding the mechanisms underlying primary biliary cholangitis(PBC)and finding relevant biomarkers for diagnosis and therapeutic e...BACKGROUND The identification of specific gene expression patterns is crucial for understanding the mechanisms underlying primary biliary cholangitis(PBC)and finding relevant biomarkers for diagnosis and therapeutic evaluation.AIM To determine PBC-associated hub genes and assess their clinical utility for disease prediction.METHODS PBC expression data were obtained from the Gene Expression Omnibus database.Overlapping genes from differential expression analysis and weighted gene coexpression network analysis(WGCNA)were identified as key genes for PBC.Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses were performed to explore the potential roles of key genes.Hub genes were identified in protein-protein interaction(PPI)networks using the Degree algorithm in Cytoscape software.The relationship between hub genes and immune cells was investigated.Finally,a Mendelian randomization study was conducted to determine the causal effects of hub genes on PBC.RESULTS We identified 71 overlapping key genes using differential expression analysis and WGCNA.These genes were primarily enriched in pathways related to cytokinecytokine receptor interaction,and Th1,Th2,and Th17 cell differentiation.We utilized Cytoscape software and identified five hub genes(CD247,IL10,CCL5,CCL3,and STAT3)in PPI networks.These hub genes showed a strong correlation with immune cell infiltration in PBC.However,inverse variance weighting analysis did not indicate the causal effects of hub genes on PBC risk.CONCLUSION Hub genes can potentially serve as valuable biomarkers for PBC prediction and treatment,thereby offering significant clinical utility.展开更多
Background Lung squamous cell carcinoma(LUSC)is a major subtype of non-small cell lung cancer with a high mortality rate.Identifying causal plasma proteins associated with LUSC could provide new insights into the path...Background Lung squamous cell carcinoma(LUSC)is a major subtype of non-small cell lung cancer with a high mortality rate.Identifying causal plasma proteins associated with LUSC could provide new insights into the pathophysiology of the disease and potential therapeutic targets.This study aimed to identify plasma proteins causally linked to LUSC risk using proteome-wide Mendelian randomization(MR)and colocalization analyses.Methods Proteome-wide MR analysis was conducted using data from the UK Biobank Pharma Proteomics Project and deCODE genetics.Summary-level data for LUSC were obtained from the ILCCO Consortium,the FinnGen study,and a separate GWAS study.A total of 1,046 shared protein quantitative trait loci(pQTLs)were analyzed.Sensitivity analyses included the HEIDI test for horizontal pleiotropy and colocalization analysis to validate the causal associations.Results MR analysis identified six plasma proteins associated with LUSC risk:HSPA1L,PCSK7,POLI,SPINK2,TCL1A,and VARS.HSPA1L(OR=0.47;95%CI:0.34–0.65;P=4.89×10^(–6)),SPINK2(OR=0.68;95%CI:0.58–0.80;P=3.17×10^(–6)),and VARS(OR=0.44;95%CI:0.31–0.63;P=5.94×10^(–6))were associated with a decreased risk of LUSC.Conversely,PCSK7(OR=1.37;95%CI:1.21–1.56;P=1.40×10^(–6)),POLI(OR=4.50;95%CI:2.25–9.00;P=2.13×10–5),and TCL1A(OR=1.72;95%CI:1.34–2.21;P=1.89×10–5)were associated with an increased risk.The SMR analysis and HEIDI test confirmed the robustness of these associations.HSPA1L,SPINK2,and VARS showed significant inverse associations,with strong colocalization evidence for TCL1A(PPH4=0.817).Conclusions This study identified six plasma proteins potentially causal for LUSC risk.HSPA1L,SPINK2,and VARS are associated with decreased risk,while PCSK7,POLI,and TCL1A are linked to increased risk.These findings provide new insights into LUSC pathogenesis and highlight potential targets for therapeutic intervention.展开更多
Objective:Gut microbiota(GM)and blood metabolites are associated with the development of urticaria,yet their specific causal relationships in East Asian populations remain unclear.This study aims to elucidate the caus...Objective:Gut microbiota(GM)and blood metabolites are associated with the development of urticaria,yet their specific causal relationships in East Asian populations remain unclear.This study aims to elucidate the causal and mediating relationships among GM,blood metabolites,and urticaria in East Asians using Mendelian randomization(MR)analysis.Methods:Summary-level statistics for 500 GM taxa,112 blood metabolites,and urticaria were obtained from publicly available Genome-Wide Association Studies(GWAS)datasets.Bidirectional MR analyses were performed to examine causal associations among the GM,blood metabolites,and urticaria.The inverse variance weighted(IVW)method served as the primary analytical approach,supplemented by MR-Egger,weighted median,simple mode,and weighted mode methods.Sensitivity analyses included heterogeneity tests,horizontal pleiotropy assessments,and leave-one-out analyses.Mediation analysis was conducted to evaluate the potential mediating effects of blood metabolites on the causal pathways between GM and urticaria.Results:MR analyses identified 12 GM taxa exhibiting significant causal effects on urticaria susceptibility.Nine taxa,such as MF0017_galactose_degradation(OR=1.461,95%CI 1.098 to 1.944,P=0.009),were associated with increased urticaria risk.Three taxa,such as MF0001_arabinoxylan_degradation(OR=0.846,95%CI 0.737 to 0.973,P=0.019),showed protective effects with increased abundance.Additionally,6 blood metabolites demonstrated causal associations with urticaria.Notably,the risk of developing urticaria increases with rising fasting plasma glucose(FPG)levels(OR=1.971,95%CI 1.089 to 3.567,P=0.025).Mediation analysis further demonstrated that FPG partially mediated the protective effect of MF0001_arabinoxylan_degradation on urticaria,accounting for 11.30%of the total effect.Conclusion:This study has delineated specific GM taxa and blood metabolites that hold causal relevance to urticaria in East Asian populations.Notably,arabinogalactan degradation potentially mitigates urticaria risk via reducing FPG concentrations,offering genetic evidence to support therapeutic strategies targeting GM modulation and glucose regulation.展开更多
AIM:To investigate the causal relationship between dietary intake and myopia using Mendelian randomization(MR)analysis.METHODS:Genome-wide association study(GWAS)data from the IEU Open GWAS database were utilized to e...AIM:To investigate the causal relationship between dietary intake and myopia using Mendelian randomization(MR)analysis.METHODS:Genome-wide association study(GWAS)data from the IEU Open GWAS database were utilized to examine associations between myopia and various dietary factors.MR analysis,incorporating both univariable and multivariable approaches,assessed the impact of food intake on myopia risk through five analytical methods,with inverse variance weighted(IVW)serving as the primary reference.Sensitivity analyses,including heterogeneity assessment,horizontal pleiotropy evaluation,and leave-oneout analysis,were conducted to validate the MR findings.RESULTS:Univariable MR analysis identified a causal link between food intake and myopia.Consumption of breaded fish,canned soup,sweet biscuits,and certain fruits correlated with a lower risk of myopia,whereas intake of low-calorie hot chocolate and cereal was associated with an increased risk.Multivariable MR analysis further confirmed that breaded fish consumption exerted a direct protective effect against myopia,particularly when consumed alongside other dietary components.These findings highlight the intricate interplay between specific dietary factors and myopia development,offering valuable insights for further research.CONCLUSION:MR analysis provides evidence supporting a potential causal relationship between breaded fish intake and myopia,underscoring its relevance in targeted myopia prevention strategies.展开更多
BACKGROUND The mucosal barrier's immune-brain interactions,pivotal for neural development and function,are increasingly recognized for their potential causal and therapeutic relevance to irritable bowel syndrome(I...BACKGROUND The mucosal barrier's immune-brain interactions,pivotal for neural development and function,are increasingly recognized for their potential causal and therapeutic relevance to irritable bowel syndrome(IBS).Prior studies linking immune inflammation with IBS have been inconsistent.To further elucidate this relationship,we conducted a Mendelian randomization(MR)analysis of 731 immune cell markers to dissect the influence of various immune phenotypes on IBS.Our goal was to deepen our understanding of the disrupted brain-gut axis in IBS and to identify novel therapeutic targets.AIM To leverage publicly available data to perform MR analysis on 731 immune cell markers and explore their impact on IBS.We aimed to uncover immunophenotypic associations with IBS that could inform future drug development and therapeutic strategies.METHODS We performed a comprehensive two-sample MR analysis to evaluate the causal relationship between immune cell markers and IBS.By utilizing genetic data from public databases,we examined the causal associations between 731 immune cell markers,encompassing median fluorescence intensity,relative cell abundance,absolute cell count,and morphological parameters,with IBS susceptibility.Sensitivity analyses were conducted to validate our findings and address potential heterogeneity and pleiotropy.RESULTS Bidirectional false discovery rate correction indicated no significant influence of IBS on immunophenotypes.However,our analysis revealed a causal impact of IBS on 30 out of 731 immune phenotypes(P<0.05).Nine immune phenotypes demonstrated a protective effect against IBS[inverse variance weighting(IVW)<0.05,odd ratio(OR)<1],while 21 others were associated with an increased risk of IBS onset(IVW≥0.05,OR≥1).CONCLUSION Our findings underscore a substantial genetic correlation between immune cell phenotypes and IBS,providing valuable insights into the pathophysiology of the condition.These results pave the way for the development of more precise biomarkers and targeted therapies for IBS.Furthermore,this research enriches our comprehension of immune cell roles in IBS pathogenesis,offering a foundation for more effective,personalized treatment approaches.These advancements hold promise for improving IBS patient quality of life and reducing the disease burden on individuals and their families.展开更多
Background:Prostate cancer(PCa)patients are at risk of developing second primary malignancies(SPMs),which can significantly shorten their survival.Understanding the risk of SPMs and associated factors is crucial to th...Background:Prostate cancer(PCa)patients are at risk of developing second primary malignancies(SPMs),which can significantly shorten their survival.Understanding the risk of SPMs and associated factors is crucial to the optimization of patient follow-up.Methods:This study focuses on PCa patients who were later diagnosed with SPMs using data from the Surveillance,Epidemiology,and End Results(SEER)database.Variables were carefully selected,and the data were analyzed using machine learning techniques combined with mul-tivariate Cox proportional hazards modeling.Subsequently,a nomogram was generated to predict the 1-,3-,and 5-year survival rates for SPMs patients.Additionally,a two-sample Mendelian randomization(TSMR)analysis was conducted to investigate the causal relationships between PCa and its top ten SPMs.Results:Among the variables,age,marital status,SPM site,M stage,American Joint Committee on Cancer(AJCC)stage,PCa surgery,and prostate-specific antigen(PSA)levels were identified as key prognostic factors through least absolute shrinkage and selection operator(LASSO)and backward stepwise regression.Based on these factors,a nomogram was developed to visually represent survival predictions,complemented by a web-based calculator for easy application.This nomogram,which serves as a supplement to traditional AJCC staging,demonstrated strong predictive power for 1-,3-,and 5-year survival,with area under the curve(AUC)values exceeding 0.85.Additionally,TSMR analysis revealed a causal link between PCa and urothelial carcinoma(UC).Conclusion:This study developed a nomogram for predicting survival in prostate cancer patients with secondary primary malignancies,enhancing prognosis accuracy.TSMR identified a causal link between PCa and UC.展开更多
AIM:To study the causal relationship between obesityrelated anthropometric traits and myopia and the mediating role of educational attainment(EA).METHODS:Univariable Mendelian randomization(UVMR)was performed to evalu...AIM:To study the causal relationship between obesityrelated anthropometric traits and myopia and the mediating role of educational attainment(EA).METHODS:Univariable Mendelian randomization(UVMR)was performed to evaluate the causal association between body mass index(BMI),height,waist-hip ratio(WHR,adjusted for BMI),and mean spherical equivalent(MSE).BMI was divided into fat and fat-free mass and included in multivariable Mendelian randomization(MVMR)to explore the roles of different BMI components in the causal relationship between BMI and MSE.A mediation analysis based on two-step Mendelian randomization(MR)was carried out.Specifically,UVMR was conducted to estimate the causal effect of BMI on EA.The direct effect of EA on MSE was estimated from MVMR.The mediation effect of EA in the BMI-EA-MSE model was calculated by the product of coefficients method.Expression quantitative trait loci(eQTL)-MR,reverse MR,and Linkage Disequilibrium Score Regression(LDSC)were performed to assess the robustness.RESULTS:Genetically predicted higher BMI had a positive total effect on MSE(βIVW=0.26 D,95%CI=0.14 to 0.37 D,P<0.001),whereas there was no significant association between height,WHR,and MSE.Fat mass was found to play a significant role in the effect of body mass on MSE(βIVW=0.50 D,95%CI=0.21 to 0.78 D,P=0.001),but there was no significant association between fat-free mass and MSE.The causal effect of BMI on EA was-0.14(95%CI=-0.16 to-0.11,P<0.001),and the direct effect of EA on MSE was-0.63 D(95%CI=-0.81 to-0.44 D,P<0.001).The mediating effect of EA in the BMI-EA-MSE model was 0.09 D(95%CI=0.06 to 0.12 D),with a mediation proportion of 33%(95%CI=22.1%to 44.6%).No reverse causal associations were detected except for BMI on EA.The results of eQTL-MR and LDSC were consistent with each MR analysis.CONCLUSION:Genetically predicted higher BMI decreases the degree of myopia with a 33%mediation proportion by EA,and fat mass provides a dominant protective role in body mass-myopia.As a supplement to previous observational studies,it provides strong evidence for the relationship between anthropometric traits and refractive errors and offers a theoretical basis for future measures to prevent and control myopia.展开更多
BACKGROUND Education,cognition,and intelligence are associated with cholelithiasis occurrence,yet which one has a prominent effect on cholelithiasis and which cardiometabolic risk factors mediate the causal relationsh...BACKGROUND Education,cognition,and intelligence are associated with cholelithiasis occurrence,yet which one has a prominent effect on cholelithiasis and which cardiometabolic risk factors mediate the causal relationship remain unelucidated.AIM To explore the causal associations between education,cognition,and intelligence and cholelithiasis,and the cardiometabolic risk factors that mediate the associations.METHODS Applying genome-wide association study summary statistics of primarily European individuals,we utilized two-sample multivariable Mendelian randomization to estimate the independent effects of education,intelligence,and cognition on cholelithiasis and cholecystitis(FinnGen study,37041 and 11632 patients,respectively;n=486484 participants)and performed two-step Mendelian randomization to evaluate 21 potential mediators and their mediating effects on the relationships between each exposure and cholelithiasis.RESULTS Inverse variance weighted Mendelian randomization results from the FinnGen consortium showed that genetically higher education,cognition,or intelligence were not independently associated with cholelithiasis and cholecystitis;when adjusted for cholelithiasis,higher education still presented an inverse effect on cholecystitis[odds ratio:0.292(95%CI:0.171-0.501)],which could not be induced by cognition or intelligence.Five out of 21 cardiometabolic risk factors were perceived as mediators of the association between education and cholelithiasis,including body mass index(20.84%),body fat percentage(40.3%),waist circumference(44.4%),waist-to-hip ratio(32.9%),and time spent watching television(41.6%),while time spent watching television was also a mediator from cognition(20.4%)and intelligence to cholelithiasis(28.4%).All results were robust to sensitivity analyses.CONCLUSION Education,cognition,and intelligence all play crucial roles in the development of cholelithiasis,and several cardiometabolic mediators have been identified for prevention of cholelithiasis due to defects in each exposure.展开更多
BACKGROUND Although there is currently a wealth of evidence to indicate that maternal educational attainment is associated with gestational diabetes mellitus(GDM),the specific modifiable risk factors that mediate the ...BACKGROUND Although there is currently a wealth of evidence to indicate that maternal educational attainment is associated with gestational diabetes mellitus(GDM),the specific modifiable risk factors that mediate the causal relationship between these two variables have yet to be identified.AIM To identify the specific modifiable risk factors that mediate the causal relationship between the level of maternal education and GDM.METHODS Mendelian randomization(MR)was conducted using data from genome-wide association studies of European populations.We initially performed a two-sample MR analysis using data on genetic variants associated with the duration of education as instruments,and subsequently adopted a two-step MR approach using metabolic and lifestyle factors as mediators to examine the mechanisms underlying the relationship between the level of maternal education and risk of developing GDM.In addition,we calculated the proportions of total causal effects mediated by identified metabolic and lifestyle factors.RESULTS A genetically predicted higher educational attainment was found to be associated with a lower risk of developing GDM(OR:0.71,95%CI:0.60-0.84).Among the metabolic factors assessed,four emerged as potential mediators of the education-GDM association,which,ranked by mediated proportions,were as follows:Waist-to-hip-ratio(31.56%,95%CI:12.38%-50.70%),body mass index(19.20%,95%CI:12.03%-26.42%),high-density lipoprotein cholesterol(12.81%,95%CI:8.65%-17.05%),and apolipoprotein A-1(7.70%,95%CI:4.32%-11.05%).These findings proved to be robust to sensitivity analyses.CONCLUSION Our findings indicate a causal relationship between lower levels of maternal education and the risk of developing GDM can be partly explained by adverse metabolic profiles.展开更多
BACKGROUND While the impact of depression on cognition is well-documented,the relationship between feelings and cognition has received limited attention.AIM To explore the potential association between feelings and co...BACKGROUND While the impact of depression on cognition is well-documented,the relationship between feelings and cognition has received limited attention.AIM To explore the potential association between feelings and cognition with a twosample Mendelian randomization(MR)analysis.METHODS Our analysis utilized genome-wide association data on various feelings(fed-up feelings,n=453071;worrier/anxious feelings,n=450765;guilty feelings,n=45-0704;nervous feelings,n=450700;sensitivity/hurt feelings,n=449419;miserableness,n=454982;loneliness/isolation,n=455364;happiness,n=152348)in the European population and their impact on cognitive functions(intelligence,n=269867).Conducting a univariable MR(UVMR)analysis to assess the relationship between feelings and cognition.In this analysis,we applied the inverse variance weighting(IVW),weighted median,and MR Egger methods.Additionally,we performed sensitivity analysis(leave-one-out analysis),assessed heterogeneity(using MR-PRESSO and Cochran’s Q test),and conducted multiple validity test(employing MR-Egger regression).Subsequently,a multivariable MR(MVMR)analysis was employed to examine the impact of feelings on cognition.IVW served as the primary method in the multivariable analysis,complemented by median-based and MR-Egger methods.RESULTS In this study,UVMR indicated that sensitivity/hurt feelings may have a negative causal effect on cognition(OR=0.63,95%CI:0.43-0.92,P=0.017).After adjustment of other feelings using MVMR,a direct adverse causal effect on cognition was observed(OR_(MVMR)=0.39,95%CI:0.17-0.90,P_(MVMR)=0.027).While a potential increased risk of cognitive decline was observed for fed-up feelings in the UVMR analysis(ORUVMR=0.64,95%CI:0.42-0.97,PUVMR=0.037),this effect disappeared after adjusting for other feelings(OR_(MVMR)=1.42,95%CI:0.43-4.74,P_(MVMR)=0.569).These findings were generally consistent across MV-IVW,median-based,and MR-Egger analyses.MR-Egger regression revealed pleiotropy in the impact of worrier/anxious feelings on cognition,presenting a challenge in identifying the effect.Notably,this study did not demonstrate any significant impact of guilty feelings,nervous feelings,miserableness,or loneliness/isolation on cognition.Due to a limited number of instrumental variables for happiness,this study was unable to analyze the relationship between happiness and cognition.CONCLUSION This MR study finds that sensitivity/hurt feelings are associated with cognitive decline,while the link between worrier/anxious feelings and cognition remains inconclusive.Insufficient evidence supports direct associations between happiness,guilty feelings,nervous feelings,miserableness,loneliness/isolation,and cognition.展开更多
Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel tar...Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases,but no systematic screening for DR has been performed.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.DR data were sourced from the largest FinnGen study,comprising 10,413 DR cases and 308,633 European controls.Genetic instrumental variables were identified using multiple filters.In the two-sample MR analysis,Wald ratio and inverse variance-weighted(IVW)MR were utilized to investigate the causality of plasma proteins with DR.Bidirectional MR,Bayesian Co-localization,and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR analyses.By systemically searching druggable gene lists,the ChEMBL database,DrugBank,and Gene Ontology database,the druggability and relevant functional pathways of the identified proteins were systematically evaluated.Results:Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate<0.05 including 11 with positive associations and 13 with negative associations.For each standard deviation increase in plasm protein levels,the odds ratios(ORs)for DR varied from 0.51(95%CI:0.36-0.73;P=2.22×10-5)for tubulin polymerization-promoting protein family member 3(TPPP3)to 2.02(95%CI:1.44-2.83;P=5.01×10-5)for olfactomedin like 3(OLFML3).Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR analyses.Four proteins exhibited strong co-localization evidence(PH4≥0.8):cytoplasmic tRNA synthetase(WARS),acrosin binding protein(ACRBP),and intercellular adhesion molecule 1(ICAM1)were negatively associated with DR risk,while neurogenic locus notch homolog protein 2(NOTCH2)showed a positive association.No confounding factors were detected between pQTLs and DR according to the phenotypic scan.Drugability assessments highlighted 6 proteins already in drug development endeavor and 18 novel drug targets,with metalloproteinase inhibitor 3(TIMP)currently in phase I clinical trials for DR.GO analysis identified 18 of 24 plasma proteins enriching 22 pathways related to cell differentiation and proliferation regulation.Conclusions:Twenty-four promising drug targets for DR were identified,including four plasma proteins with particular co-localization evidence.These findings offer new insights into DR's etiology and therapeutic targeting,exemplifying the value of genomic and proteomic data in drug target discovery.展开更多
Dear Editor,We extend our academic appreciation to the contributors of this pioneering study,1 which leverages Mendelian Randomization(MR)to investigate the causal relationship between immune cell phenotypes and intra...Dear Editor,We extend our academic appreciation to the contributors of this pioneering study,1 which leverages Mendelian Randomization(MR)to investigate the causal relationship between immune cell phenotypes and intracranial aneurysms(IAs),demonstrating a certain level of innovation.By extracting 731 immunophenotypes from publicly available genetic databases and conducting large-scale analyses,the study comprehensively evaluates the impact of immune cell traits on IAs.Moreover,multivariable MR analysis was employed to adjust for interactions between different immune phenotypes,providing a novel perspective on the interplay between the immune system and IAs.展开更多
Urolithiasis,a disease characterized by the formation of urinary stones,is influenced by immune system dysregulation and metabolic factors.This study investigated the interplay between specific immune cell characteris...Urolithiasis,a disease characterized by the formation of urinary stones,is influenced by immune system dysregulation and metabolic factors.This study investigated the interplay between specific immune cell characteristics and blood metabolites in urolithiasis based on Mendelian randomization.We further explored the potential mediating effects of genetically predicted blood metabolites based on mediation analysis.We employed a two-sample Mendelian randomization analysis to examine the association between immune cell properties,blood metabolites,and urolithiasis risk.Genetic instruments for immune cell characteristics and blood metabolites were used to assess causal relationships and mediating pathways.Our results indicate that 10 immune cell characteristics had a unidirectional causal association with urolithiasis risk.We also detected 13 blood metabolites associated with urolithiasis.We identified 4 pathways through which genetically predicted blood metabolites partly mediated the association between specific immune cell characteristics and urolithiasis risk.This suggests potential mechanistic links where altered blood metabolites may play a role in developing urolithiasis through immune system modulation.This Mendelian randomization study highlights the complex relationship between immune responses,blood metabolites,and urolithiasis.The findings underscore the importance of considering both immune cell features and metabolic factors in understanding the pathogenesis of urolithiasis,offering insights into novel therapeutic targets and diagnostic strategies for this disorder.展开更多
Background:This study aimed to explore the causal link between cervical spondylosis(CS)and major depression(MD)using a bidirectional Mendelian randomization(MR)analysis.Methods:Bidirectional MR was employed to validat...Background:This study aimed to explore the causal link between cervical spondylosis(CS)and major depression(MD)using a bidirectional Mendelian randomization(MR)analysis.Methods:Bidirectional MR was employed to validate the bidirectional causal relationship between CS and MD using pooled data obtained from the Integrated Epidemiology Unit Open Genome Wide Association Study(GWAS)database.MR Egger,weighted median,inverse-variance weighted(IVW),and simple mode methods were used,with priority given to IVW results.Sensitivity analyses,including heterogeneity tests,horizontal pleiotropy tests,and leave-one-out methods,were performed to confirm the stability of the MR results.Results:In a forward MR analysis,a causal effect was found between MD and CS(IVW:OR>1,p<0.05).However,a reverse MR analysis indicated no causal relationship between CS and MD(p>0.05).Sensitivity analyses revealed no sample heterogeneity,no horizontal pleiotropy effect,and no significant bias,thus supporting the reliability of the MR analysis results.Conclusion:This study provides evidence demonstrating that MD is causally associated with CS,whereas CS is not causally linked to MD.Thesefindings offer novel insights into the pathogenesis of these two prevalent diseases.展开更多
基金supported by Natural Science Foundation of Shandong ProvinceChina[ZR2022MH115]the National Natural Science Foundation of China[81301479,82202593]。
文摘Objective This study explored the potentially modifiable factors for depression and major depressive disorder(MDD)from the MR-Base database and further evaluated the associations between drug targets with MDD.Methods We analyzed two-sample of Mendelian randomization(2SMR)using genetic variant depression(n=113,154)and MDD(n=208,811)from Genome-Wide Association Studies(GWAS).Separate calculations were performed with modifiable risk factors from MR-Base for 1,001 genomes.The MR analysis was performed by screening drug targets with MDD in the DrugBank database to explore the therapeutic targets for MDD.Inverse variance weighted(IVW),fixed-effect inverse variance weighted(FE-IVW),MR-Egger,weighted median,and weighted mode were used for complementary calculation.Results The potential causal relationship between modifiable risk factors and depression contained 459 results for depression and 424 for MDD.Also,the associations between drug targets and MDD showed that SLC6A4,GRIN2A,GRIN2C,SCN10A,and IL1B expression are associated with an increased risk of depression.In contrast,ADRB1,CHRNA3,HTR3A,GSTP1,and GABRG2 genes are candidate protective factors against depression.Conclusion This study identified the risk factors causally associated with depression and MDD,and estimated 10 drug targets with significant impact on MDD,providing essential information for formulating strategies to prevent and treat depression.
基金Supported by the Central High Level Hospital Clinical Research Funding(No.BJ-2024-089).
文摘AIM:To explore the causal relationship between several possible behavioral factors and high myopia(HM)using multivariable Mendelian randomization(MVMR)approach and to find the mediators among them with mediation analysis.METHODS:The causal effects of several behavioral factors,including screen time,education time,time spent outdoors,and physical activity,on the risk of HM using univariable Mendelian randomization(MR)and MVMR analyses were first assessed.Genome-wide association study summary statistics of serum metabolites were also used in mediation analysis to determine the extent to which serum metabolites mediate the effects of behavioral factors on HM.RESULTS:MR analyses indicated that both increased time spent outdoors and a higher frequency of moderate physical activity significantly reduced the risk of HM.Further MVMR analysis confirmed that moderate physical activity independently contributed to a lower risk of HM.Additionally,MR analyses identified 13 serum metabolites significantly associated with HM,of which 12 were lipids and one was an amino acid derivative.Mediation analysis revealed that six lipid metabolites mediated the protective effects of moderate physical activity on HM,with the highest mediation proportion observed for 1-(1-enyl-palmitoyl)-GPC(p-16:0;30.83%).CONCLUSION:This study suggests that in addition to outdoor time,moderate physical activity habits may have an independent protective effect against HM and pointed to lipid metabolites as priority targets for the prevention due to low physical activity.These results emphasize the importance of physical activity and metabolic health in HM and underscore the need for further study of these complex associations.
基金funded by the National Natural Science Foundation of China(Grant Nos.82220108002 to F.C.,82273737 to R.Z.,82473728 to Y.W.)the US National Institutes of Health(Grant Nos.CA209414,HL060710,ES000002 to D.C.C.,CA209414,CA249096 to Y.L.)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).R.Z.was partially supported by the Qing Lan Project of the Higher Education Institutions of Jiangsu Province and the Outstanding Young-Level Academic Leadership Training Program of Nanjing Medical University.
文摘Emerging evidence highlights the role of thyroid hormones in cancer,although findings are controversial.Research on thyroid-related traits in lung carcinogenesis is limited.Using UK Biobank data,we performed bidirectional Mendelian randomization(MR)to assess causal associations between lung cancer risk and thyroid dysfunction(hypothyroidism and hyperthyroidism)or functional traits(free thyroxine[FT4]and normal-range thyroid-stimulating hormone[TSH]).Furthermore,in the smoking-behavior-stratified MR analysis,we evaluated the mediating effect of thyroid-related phenotypes on the association between smoking behaviors and lung cancer.We demonstrated significant associations between lung cancer risk and hypothyroidism(hazard ratio[HR]=1.14,95%confidence interval[CI]=1.03–1.26,P=0.009)and hyperthyroidism(HR=1.55,95%CI=1.29–1.87,P=1.90×10^(-6))in the UKB.Moreover,the MR analysis indicated a causal effect of thyroid dysfunction on lung cancer risk(ORinverse variance weighted[IVW]=1.09,95%CI=1.05–1.13,P=3.12×10^(-6)for hypothyroidism;ORIVW=1.08,95%CI=1.04–1.12,P=8.14×10^(-5)for hyperthyroidism).We found that FT4 levels were protective against lung cancer risk(ORIVW=0.93,95%CI=0.87–0.99,P=0.030).Additionally,the stratified MR analysis demonstrated distinct causal effects of thyroid dysfunction on lung cancer risk among smokers.Hyperthyroidism mediated the effect of smoking behaviors,especially the age of smoking initiation(17.66%mediated),on lung cancer risk.Thus,thyroid dysfunction phenotypes play causal roles in lung cancer development exclusively among smokers and act as mediators in the causal pathway from smoking to lung cancer.
文摘BACKGROUND Some studies have directed towards an association between diabetes mellitus(DM)and prostate cancer(PCa);however,this specific relationship remains inconclusive.In recent years,Mendelian randomization(MR)has become a widely used analytical method for inferring epidemiological causes.AIM To investigated the potential relationship between DM and PCa using MR.METHODS We downloaded relevant data on"diabetes"and"PCa"from the IEU OpenGWAS project database,performed three different methods to conduct MR,and carried out sensitivity analysis for verification.RESULTS The results indicated that DM was an independent risk factor for PCa.The odds ratio(OR)values obtained using the inverse variance weighted method in this study were as follows:OR=1.018(95%confidence interval:1.004-1.032),P=0.014.CONCLUSION We found that DM could increase the incidence rate of PCa.
基金Supported by the National Natural Science Foundation of China(No.81960174)the Natural Science Foundation of Guangxi Zhuang Autonomous Region(No.2023GXNSFAA026154)the Youth Science Foundation of Guangxi Medical University(No.GXMUYSF201912).
文摘AIM:To assess whether there is a possible causal link between the intake of cheese and the risk of diabetic retinopathy(DR)utilizing a two-sample Mendelian randomization(MR)analysis.METHODS:The research data were obtained from summary statistics of genome-wide association studies(GWAS).Genetic loci closely related to cheese intake were extracted as instrumental variables(IVs),and DR was the outcome variable.The data were extracted from individuals of European ethnicity.The data of cheese intake consisted of 451486 samples with 9851867 single nucleotide polymorphisms(SNPs),while the DR data consisted of 206234 samples with 16380446 SNPs.Sixty-one genetic loci closely related to cheese intake were selected as IVs.MR analysis was performed by inverse-variance weighted(IVW)method and MR-Egger regression respectively.The causal relationship between cheese intake and DR was evaluated using odds ratios(ORs)and 95%confidence intervals(CIs).Egger-intercept test was used to test horizontal pleiotropy and sensitivity analysis was performed by leave-one-out test.RESULTS:The P value of the IVW method was less than 0.05,indicating a significant negative correlation between cheese intake and DR.MR-Egger regression showed that the intercept was 0.01 with a standard error of 0.022,and a P-value of 0.634,indicating no evidence of horizontal pleiotropy affecting the IVs related to the exposure factors.Besides,heterogeneity tests confirmed the absence of heterogeneity,and the“leave-one-out”sensitivity analysis demonstrated that the results were stable.CONCLUSION:Cheese intake is causally negatively correlated with the occurrence of DR,and cheese intake could reduce the risk of DR.
基金This work was supported by the National Natural Science Foundation of China(12171451,72091212).
文摘Mendelian randomization(MR)is widely used in causal mediation analysis to control unmeasured confounding effects,which is valid under some strong assumptions.It is thus of great interest to assess the impact of violations of these MR assumptions through sensitivity analysis.Sensitivity analyses have been conducted for simple MR-based causal average effect analyses,but they are not available for MR-based mediation analysis studies,and we aim to fill this gap in this paper.We propose to use two sensitivity parameters to quantify the effect due to the deviation of the IV assumptions.With these two sensitivity parameters,we derive consistent indirect causal effect estimators and establish their asymptotic propersties.Our theoretical results can be used in MR-based mediation analysis to study the impact of violations of MR as-sumptions.The finite sample performance of the proposed method is illustrated through simulation studies,sensitivity ana-lysis,and application to a real genome-wide association study.
基金Supported by School-Level Key Projects at Bengbu Medical College,No.2021byzd109。
文摘BACKGROUND The identification of specific gene expression patterns is crucial for understanding the mechanisms underlying primary biliary cholangitis(PBC)and finding relevant biomarkers for diagnosis and therapeutic evaluation.AIM To determine PBC-associated hub genes and assess their clinical utility for disease prediction.METHODS PBC expression data were obtained from the Gene Expression Omnibus database.Overlapping genes from differential expression analysis and weighted gene coexpression network analysis(WGCNA)were identified as key genes for PBC.Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses were performed to explore the potential roles of key genes.Hub genes were identified in protein-protein interaction(PPI)networks using the Degree algorithm in Cytoscape software.The relationship between hub genes and immune cells was investigated.Finally,a Mendelian randomization study was conducted to determine the causal effects of hub genes on PBC.RESULTS We identified 71 overlapping key genes using differential expression analysis and WGCNA.These genes were primarily enriched in pathways related to cytokinecytokine receptor interaction,and Th1,Th2,and Th17 cell differentiation.We utilized Cytoscape software and identified five hub genes(CD247,IL10,CCL5,CCL3,and STAT3)in PPI networks.These hub genes showed a strong correlation with immune cell infiltration in PBC.However,inverse variance weighting analysis did not indicate the causal effects of hub genes on PBC risk.CONCLUSION Hub genes can potentially serve as valuable biomarkers for PBC prediction and treatment,thereby offering significant clinical utility.
基金supported by The Medical Engineering Cross Research Funding of Shanghai Jiaotong University"Star of Jiaotong University"Program(24X010301595).
文摘Background Lung squamous cell carcinoma(LUSC)is a major subtype of non-small cell lung cancer with a high mortality rate.Identifying causal plasma proteins associated with LUSC could provide new insights into the pathophysiology of the disease and potential therapeutic targets.This study aimed to identify plasma proteins causally linked to LUSC risk using proteome-wide Mendelian randomization(MR)and colocalization analyses.Methods Proteome-wide MR analysis was conducted using data from the UK Biobank Pharma Proteomics Project and deCODE genetics.Summary-level data for LUSC were obtained from the ILCCO Consortium,the FinnGen study,and a separate GWAS study.A total of 1,046 shared protein quantitative trait loci(pQTLs)were analyzed.Sensitivity analyses included the HEIDI test for horizontal pleiotropy and colocalization analysis to validate the causal associations.Results MR analysis identified six plasma proteins associated with LUSC risk:HSPA1L,PCSK7,POLI,SPINK2,TCL1A,and VARS.HSPA1L(OR=0.47;95%CI:0.34–0.65;P=4.89×10^(–6)),SPINK2(OR=0.68;95%CI:0.58–0.80;P=3.17×10^(–6)),and VARS(OR=0.44;95%CI:0.31–0.63;P=5.94×10^(–6))were associated with a decreased risk of LUSC.Conversely,PCSK7(OR=1.37;95%CI:1.21–1.56;P=1.40×10^(–6)),POLI(OR=4.50;95%CI:2.25–9.00;P=2.13×10–5),and TCL1A(OR=1.72;95%CI:1.34–2.21;P=1.89×10–5)were associated with an increased risk.The SMR analysis and HEIDI test confirmed the robustness of these associations.HSPA1L,SPINK2,and VARS showed significant inverse associations,with strong colocalization evidence for TCL1A(PPH4=0.817).Conclusions This study identified six plasma proteins potentially causal for LUSC risk.HSPA1L,SPINK2,and VARS are associated with decreased risk,while PCSK7,POLI,and TCL1A are linked to increased risk.These findings provide new insights into LUSC pathogenesis and highlight potential targets for therapeutic intervention.
基金supported by the Natural Science Foundation of Hunan Province,China(2024JJ7627).
文摘Objective:Gut microbiota(GM)and blood metabolites are associated with the development of urticaria,yet their specific causal relationships in East Asian populations remain unclear.This study aims to elucidate the causal and mediating relationships among GM,blood metabolites,and urticaria in East Asians using Mendelian randomization(MR)analysis.Methods:Summary-level statistics for 500 GM taxa,112 blood metabolites,and urticaria were obtained from publicly available Genome-Wide Association Studies(GWAS)datasets.Bidirectional MR analyses were performed to examine causal associations among the GM,blood metabolites,and urticaria.The inverse variance weighted(IVW)method served as the primary analytical approach,supplemented by MR-Egger,weighted median,simple mode,and weighted mode methods.Sensitivity analyses included heterogeneity tests,horizontal pleiotropy assessments,and leave-one-out analyses.Mediation analysis was conducted to evaluate the potential mediating effects of blood metabolites on the causal pathways between GM and urticaria.Results:MR analyses identified 12 GM taxa exhibiting significant causal effects on urticaria susceptibility.Nine taxa,such as MF0017_galactose_degradation(OR=1.461,95%CI 1.098 to 1.944,P=0.009),were associated with increased urticaria risk.Three taxa,such as MF0001_arabinoxylan_degradation(OR=0.846,95%CI 0.737 to 0.973,P=0.019),showed protective effects with increased abundance.Additionally,6 blood metabolites demonstrated causal associations with urticaria.Notably,the risk of developing urticaria increases with rising fasting plasma glucose(FPG)levels(OR=1.971,95%CI 1.089 to 3.567,P=0.025).Mediation analysis further demonstrated that FPG partially mediated the protective effect of MF0001_arabinoxylan_degradation on urticaria,accounting for 11.30%of the total effect.Conclusion:This study has delineated specific GM taxa and blood metabolites that hold causal relevance to urticaria in East Asian populations.Notably,arabinogalactan degradation potentially mitigates urticaria risk via reducing FPG concentrations,offering genetic evidence to support therapeutic strategies targeting GM modulation and glucose regulation.
基金Supported by Xi’an Science and Technology Program Project(No.24YXYJ0108)Support Projects of Xi’an Children’s Hospital(No.2024I07).
文摘AIM:To investigate the causal relationship between dietary intake and myopia using Mendelian randomization(MR)analysis.METHODS:Genome-wide association study(GWAS)data from the IEU Open GWAS database were utilized to examine associations between myopia and various dietary factors.MR analysis,incorporating both univariable and multivariable approaches,assessed the impact of food intake on myopia risk through five analytical methods,with inverse variance weighted(IVW)serving as the primary reference.Sensitivity analyses,including heterogeneity assessment,horizontal pleiotropy evaluation,and leave-oneout analysis,were conducted to validate the MR findings.RESULTS:Univariable MR analysis identified a causal link between food intake and myopia.Consumption of breaded fish,canned soup,sweet biscuits,and certain fruits correlated with a lower risk of myopia,whereas intake of low-calorie hot chocolate and cereal was associated with an increased risk.Multivariable MR analysis further confirmed that breaded fish consumption exerted a direct protective effect against myopia,particularly when consumed alongside other dietary components.These findings highlight the intricate interplay between specific dietary factors and myopia development,offering valuable insights for further research.CONCLUSION:MR analysis provides evidence supporting a potential causal relationship between breaded fish intake and myopia,underscoring its relevance in targeted myopia prevention strategies.
文摘BACKGROUND The mucosal barrier's immune-brain interactions,pivotal for neural development and function,are increasingly recognized for their potential causal and therapeutic relevance to irritable bowel syndrome(IBS).Prior studies linking immune inflammation with IBS have been inconsistent.To further elucidate this relationship,we conducted a Mendelian randomization(MR)analysis of 731 immune cell markers to dissect the influence of various immune phenotypes on IBS.Our goal was to deepen our understanding of the disrupted brain-gut axis in IBS and to identify novel therapeutic targets.AIM To leverage publicly available data to perform MR analysis on 731 immune cell markers and explore their impact on IBS.We aimed to uncover immunophenotypic associations with IBS that could inform future drug development and therapeutic strategies.METHODS We performed a comprehensive two-sample MR analysis to evaluate the causal relationship between immune cell markers and IBS.By utilizing genetic data from public databases,we examined the causal associations between 731 immune cell markers,encompassing median fluorescence intensity,relative cell abundance,absolute cell count,and morphological parameters,with IBS susceptibility.Sensitivity analyses were conducted to validate our findings and address potential heterogeneity and pleiotropy.RESULTS Bidirectional false discovery rate correction indicated no significant influence of IBS on immunophenotypes.However,our analysis revealed a causal impact of IBS on 30 out of 731 immune phenotypes(P<0.05).Nine immune phenotypes demonstrated a protective effect against IBS[inverse variance weighting(IVW)<0.05,odd ratio(OR)<1],while 21 others were associated with an increased risk of IBS onset(IVW≥0.05,OR≥1).CONCLUSION Our findings underscore a substantial genetic correlation between immune cell phenotypes and IBS,providing valuable insights into the pathophysiology of the condition.These results pave the way for the development of more precise biomarkers and targeted therapies for IBS.Furthermore,this research enriches our comprehension of immune cell roles in IBS pathogenesis,offering a foundation for more effective,personalized treatment approaches.These advancements hold promise for improving IBS patient quality of life and reducing the disease burden on individuals and their families.
基金Student Innovation Capability Enhancement Program of Guangzhou Medical University,Grant/Award Numbers:2022 NO.67,2023 NO.7Special Funds for the Cultivation of Guangdong College Students'Scientific and Technological Innovation(“Climbing Program”Special Funds),Grant/Award Number:pdjh2023b0431。
文摘Background:Prostate cancer(PCa)patients are at risk of developing second primary malignancies(SPMs),which can significantly shorten their survival.Understanding the risk of SPMs and associated factors is crucial to the optimization of patient follow-up.Methods:This study focuses on PCa patients who were later diagnosed with SPMs using data from the Surveillance,Epidemiology,and End Results(SEER)database.Variables were carefully selected,and the data were analyzed using machine learning techniques combined with mul-tivariate Cox proportional hazards modeling.Subsequently,a nomogram was generated to predict the 1-,3-,and 5-year survival rates for SPMs patients.Additionally,a two-sample Mendelian randomization(TSMR)analysis was conducted to investigate the causal relationships between PCa and its top ten SPMs.Results:Among the variables,age,marital status,SPM site,M stage,American Joint Committee on Cancer(AJCC)stage,PCa surgery,and prostate-specific antigen(PSA)levels were identified as key prognostic factors through least absolute shrinkage and selection operator(LASSO)and backward stepwise regression.Based on these factors,a nomogram was developed to visually represent survival predictions,complemented by a web-based calculator for easy application.This nomogram,which serves as a supplement to traditional AJCC staging,demonstrated strong predictive power for 1-,3-,and 5-year survival,with area under the curve(AUC)values exceeding 0.85.Additionally,TSMR analysis revealed a causal link between PCa and urothelial carcinoma(UC).Conclusion:This study developed a nomogram for predicting survival in prostate cancer patients with secondary primary malignancies,enhancing prognosis accuracy.TSMR identified a causal link between PCa and UC.
基金Supported by Hubei Province Key Research and Development Program Project,Hubei Provincial Department of Science and Technology(No.2022BCA044)Key Scientific Research Projects of Health Commission of Hubei Province in 2023-2024,Health Commission of Hubei Province(No.WJ2023Z006).
文摘AIM:To study the causal relationship between obesityrelated anthropometric traits and myopia and the mediating role of educational attainment(EA).METHODS:Univariable Mendelian randomization(UVMR)was performed to evaluate the causal association between body mass index(BMI),height,waist-hip ratio(WHR,adjusted for BMI),and mean spherical equivalent(MSE).BMI was divided into fat and fat-free mass and included in multivariable Mendelian randomization(MVMR)to explore the roles of different BMI components in the causal relationship between BMI and MSE.A mediation analysis based on two-step Mendelian randomization(MR)was carried out.Specifically,UVMR was conducted to estimate the causal effect of BMI on EA.The direct effect of EA on MSE was estimated from MVMR.The mediation effect of EA in the BMI-EA-MSE model was calculated by the product of coefficients method.Expression quantitative trait loci(eQTL)-MR,reverse MR,and Linkage Disequilibrium Score Regression(LDSC)were performed to assess the robustness.RESULTS:Genetically predicted higher BMI had a positive total effect on MSE(βIVW=0.26 D,95%CI=0.14 to 0.37 D,P<0.001),whereas there was no significant association between height,WHR,and MSE.Fat mass was found to play a significant role in the effect of body mass on MSE(βIVW=0.50 D,95%CI=0.21 to 0.78 D,P=0.001),but there was no significant association between fat-free mass and MSE.The causal effect of BMI on EA was-0.14(95%CI=-0.16 to-0.11,P<0.001),and the direct effect of EA on MSE was-0.63 D(95%CI=-0.81 to-0.44 D,P<0.001).The mediating effect of EA in the BMI-EA-MSE model was 0.09 D(95%CI=0.06 to 0.12 D),with a mediation proportion of 33%(95%CI=22.1%to 44.6%).No reverse causal associations were detected except for BMI on EA.The results of eQTL-MR and LDSC were consistent with each MR analysis.CONCLUSION:Genetically predicted higher BMI decreases the degree of myopia with a 33%mediation proportion by EA,and fat mass provides a dominant protective role in body mass-myopia.As a supplement to previous observational studies,it provides strong evidence for the relationship between anthropometric traits and refractive errors and offers a theoretical basis for future measures to prevent and control myopia.
文摘BACKGROUND Education,cognition,and intelligence are associated with cholelithiasis occurrence,yet which one has a prominent effect on cholelithiasis and which cardiometabolic risk factors mediate the causal relationship remain unelucidated.AIM To explore the causal associations between education,cognition,and intelligence and cholelithiasis,and the cardiometabolic risk factors that mediate the associations.METHODS Applying genome-wide association study summary statistics of primarily European individuals,we utilized two-sample multivariable Mendelian randomization to estimate the independent effects of education,intelligence,and cognition on cholelithiasis and cholecystitis(FinnGen study,37041 and 11632 patients,respectively;n=486484 participants)and performed two-step Mendelian randomization to evaluate 21 potential mediators and their mediating effects on the relationships between each exposure and cholelithiasis.RESULTS Inverse variance weighted Mendelian randomization results from the FinnGen consortium showed that genetically higher education,cognition,or intelligence were not independently associated with cholelithiasis and cholecystitis;when adjusted for cholelithiasis,higher education still presented an inverse effect on cholecystitis[odds ratio:0.292(95%CI:0.171-0.501)],which could not be induced by cognition or intelligence.Five out of 21 cardiometabolic risk factors were perceived as mediators of the association between education and cholelithiasis,including body mass index(20.84%),body fat percentage(40.3%),waist circumference(44.4%),waist-to-hip ratio(32.9%),and time spent watching television(41.6%),while time spent watching television was also a mediator from cognition(20.4%)and intelligence to cholelithiasis(28.4%).All results were robust to sensitivity analyses.CONCLUSION Education,cognition,and intelligence all play crucial roles in the development of cholelithiasis,and several cardiometabolic mediators have been identified for prevention of cholelithiasis due to defects in each exposure.
文摘BACKGROUND Although there is currently a wealth of evidence to indicate that maternal educational attainment is associated with gestational diabetes mellitus(GDM),the specific modifiable risk factors that mediate the causal relationship between these two variables have yet to be identified.AIM To identify the specific modifiable risk factors that mediate the causal relationship between the level of maternal education and GDM.METHODS Mendelian randomization(MR)was conducted using data from genome-wide association studies of European populations.We initially performed a two-sample MR analysis using data on genetic variants associated with the duration of education as instruments,and subsequently adopted a two-step MR approach using metabolic and lifestyle factors as mediators to examine the mechanisms underlying the relationship between the level of maternal education and risk of developing GDM.In addition,we calculated the proportions of total causal effects mediated by identified metabolic and lifestyle factors.RESULTS A genetically predicted higher educational attainment was found to be associated with a lower risk of developing GDM(OR:0.71,95%CI:0.60-0.84).Among the metabolic factors assessed,four emerged as potential mediators of the education-GDM association,which,ranked by mediated proportions,were as follows:Waist-to-hip-ratio(31.56%,95%CI:12.38%-50.70%),body mass index(19.20%,95%CI:12.03%-26.42%),high-density lipoprotein cholesterol(12.81%,95%CI:8.65%-17.05%),and apolipoprotein A-1(7.70%,95%CI:4.32%-11.05%).These findings proved to be robust to sensitivity analyses.CONCLUSION Our findings indicate a causal relationship between lower levels of maternal education and the risk of developing GDM can be partly explained by adverse metabolic profiles.
文摘BACKGROUND While the impact of depression on cognition is well-documented,the relationship between feelings and cognition has received limited attention.AIM To explore the potential association between feelings and cognition with a twosample Mendelian randomization(MR)analysis.METHODS Our analysis utilized genome-wide association data on various feelings(fed-up feelings,n=453071;worrier/anxious feelings,n=450765;guilty feelings,n=45-0704;nervous feelings,n=450700;sensitivity/hurt feelings,n=449419;miserableness,n=454982;loneliness/isolation,n=455364;happiness,n=152348)in the European population and their impact on cognitive functions(intelligence,n=269867).Conducting a univariable MR(UVMR)analysis to assess the relationship between feelings and cognition.In this analysis,we applied the inverse variance weighting(IVW),weighted median,and MR Egger methods.Additionally,we performed sensitivity analysis(leave-one-out analysis),assessed heterogeneity(using MR-PRESSO and Cochran’s Q test),and conducted multiple validity test(employing MR-Egger regression).Subsequently,a multivariable MR(MVMR)analysis was employed to examine the impact of feelings on cognition.IVW served as the primary method in the multivariable analysis,complemented by median-based and MR-Egger methods.RESULTS In this study,UVMR indicated that sensitivity/hurt feelings may have a negative causal effect on cognition(OR=0.63,95%CI:0.43-0.92,P=0.017).After adjustment of other feelings using MVMR,a direct adverse causal effect on cognition was observed(OR_(MVMR)=0.39,95%CI:0.17-0.90,P_(MVMR)=0.027).While a potential increased risk of cognitive decline was observed for fed-up feelings in the UVMR analysis(ORUVMR=0.64,95%CI:0.42-0.97,PUVMR=0.037),this effect disappeared after adjusting for other feelings(OR_(MVMR)=1.42,95%CI:0.43-4.74,P_(MVMR)=0.569).These findings were generally consistent across MV-IVW,median-based,and MR-Egger analyses.MR-Egger regression revealed pleiotropy in the impact of worrier/anxious feelings on cognition,presenting a challenge in identifying the effect.Notably,this study did not demonstrate any significant impact of guilty feelings,nervous feelings,miserableness,or loneliness/isolation on cognition.Due to a limited number of instrumental variables for happiness,this study was unable to analyze the relationship between happiness and cognition.CONCLUSION This MR study finds that sensitivity/hurt feelings are associated with cognitive decline,while the link between worrier/anxious feelings and cognition remains inconclusive.Insufficient evidence supports direct associations between happiness,guilty feelings,nervous feelings,miserableness,loneliness/isolation,and cognition.
基金funded by the Hainan Province Clinical Medical Center(82171084)the National Natural Science Foundation of China(82371086).
文摘Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases,but no systematic screening for DR has been performed.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.DR data were sourced from the largest FinnGen study,comprising 10,413 DR cases and 308,633 European controls.Genetic instrumental variables were identified using multiple filters.In the two-sample MR analysis,Wald ratio and inverse variance-weighted(IVW)MR were utilized to investigate the causality of plasma proteins with DR.Bidirectional MR,Bayesian Co-localization,and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR analyses.By systemically searching druggable gene lists,the ChEMBL database,DrugBank,and Gene Ontology database,the druggability and relevant functional pathways of the identified proteins were systematically evaluated.Results:Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate<0.05 including 11 with positive associations and 13 with negative associations.For each standard deviation increase in plasm protein levels,the odds ratios(ORs)for DR varied from 0.51(95%CI:0.36-0.73;P=2.22×10-5)for tubulin polymerization-promoting protein family member 3(TPPP3)to 2.02(95%CI:1.44-2.83;P=5.01×10-5)for olfactomedin like 3(OLFML3).Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR analyses.Four proteins exhibited strong co-localization evidence(PH4≥0.8):cytoplasmic tRNA synthetase(WARS),acrosin binding protein(ACRBP),and intercellular adhesion molecule 1(ICAM1)were negatively associated with DR risk,while neurogenic locus notch homolog protein 2(NOTCH2)showed a positive association.No confounding factors were detected between pQTLs and DR according to the phenotypic scan.Drugability assessments highlighted 6 proteins already in drug development endeavor and 18 novel drug targets,with metalloproteinase inhibitor 3(TIMP)currently in phase I clinical trials for DR.GO analysis identified 18 of 24 plasma proteins enriching 22 pathways related to cell differentiation and proliferation regulation.Conclusions:Twenty-four promising drug targets for DR were identified,including four plasma proteins with particular co-localization evidence.These findings offer new insights into DR's etiology and therapeutic targeting,exemplifying the value of genomic and proteomic data in drug target discovery.
文摘Dear Editor,We extend our academic appreciation to the contributors of this pioneering study,1 which leverages Mendelian Randomization(MR)to investigate the causal relationship between immune cell phenotypes and intracranial aneurysms(IAs),demonstrating a certain level of innovation.By extracting 731 immunophenotypes from publicly available genetic databases and conducting large-scale analyses,the study comprehensively evaluates the impact of immune cell traits on IAs.Moreover,multivariable MR analysis was employed to adjust for interactions between different immune phenotypes,providing a novel perspective on the interplay between the immune system and IAs.
基金support from various sources including the Innovation and Development Joint Fund of Chongqing Natural Science Foundation of China(No.CST-B2023NSCQ-LZX0099)Chongqing Science and Health Joint Medical High-end Talent Project(China)(No.2022GDRC012)+3 种基金Science and Technology Research Program of Chongqing Municipal Education Commission of China(No.KJZD-K202100402)CQMU Program for Youth Innovation in Future Medicine(Chongqing,China)(No.W0073)National Natural Science Foundation of China(82401866)Special Grants for Postdoctoral Research Projects in Chongqing in 2023(2023CQBSHTB3134).
文摘Urolithiasis,a disease characterized by the formation of urinary stones,is influenced by immune system dysregulation and metabolic factors.This study investigated the interplay between specific immune cell characteristics and blood metabolites in urolithiasis based on Mendelian randomization.We further explored the potential mediating effects of genetically predicted blood metabolites based on mediation analysis.We employed a two-sample Mendelian randomization analysis to examine the association between immune cell properties,blood metabolites,and urolithiasis risk.Genetic instruments for immune cell characteristics and blood metabolites were used to assess causal relationships and mediating pathways.Our results indicate that 10 immune cell characteristics had a unidirectional causal association with urolithiasis risk.We also detected 13 blood metabolites associated with urolithiasis.We identified 4 pathways through which genetically predicted blood metabolites partly mediated the association between specific immune cell characteristics and urolithiasis risk.This suggests potential mechanistic links where altered blood metabolites may play a role in developing urolithiasis through immune system modulation.This Mendelian randomization study highlights the complex relationship between immune responses,blood metabolites,and urolithiasis.The findings underscore the importance of considering both immune cell features and metabolic factors in understanding the pathogenesis of urolithiasis,offering insights into novel therapeutic targets and diagnostic strategies for this disorder.
文摘Background:This study aimed to explore the causal link between cervical spondylosis(CS)and major depression(MD)using a bidirectional Mendelian randomization(MR)analysis.Methods:Bidirectional MR was employed to validate the bidirectional causal relationship between CS and MD using pooled data obtained from the Integrated Epidemiology Unit Open Genome Wide Association Study(GWAS)database.MR Egger,weighted median,inverse-variance weighted(IVW),and simple mode methods were used,with priority given to IVW results.Sensitivity analyses,including heterogeneity tests,horizontal pleiotropy tests,and leave-one-out methods,were performed to confirm the stability of the MR results.Results:In a forward MR analysis,a causal effect was found between MD and CS(IVW:OR>1,p<0.05).However,a reverse MR analysis indicated no causal relationship between CS and MD(p>0.05).Sensitivity analyses revealed no sample heterogeneity,no horizontal pleiotropy effect,and no significant bias,thus supporting the reliability of the MR analysis results.Conclusion:This study provides evidence demonstrating that MD is causally associated with CS,whereas CS is not causally linked to MD.Thesefindings offer novel insights into the pathogenesis of these two prevalent diseases.
