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
Objective:Based on multistage metabolomic profiling and Mendelian randomization analyses,the current study identified plasma metabolites that predicted the risk of developing gastric cancer(GC)and determined whether k...Objective:Based on multistage metabolomic profiling and Mendelian randomization analyses,the current study identified plasma metabolites that predicted the risk of developing gastric cancer(GC)and determined whether key metabolite levels modified the GC primary prevention effects.Methods:Plasma metabolites associated with GC risk were identified through a case-control study.Bi-directional two-sample Mendelian randomization analyses were performed to determine potential causal relationships utilizing the Shandong Intervention Trial(SIT),a nested case-control study of the Mass Intervention Trial in Linqu,Shandong province(MITS),China,the UK Biobank,and the Finn Gen project.Results:A higher genetic risk score for plasma L-aspartic acid was significantly associated with an increased GC risk in the northern Chinese population(SIT:HR=1.26 per 1 SD change,95%CI:1.07±1.49;MITS:HR=1.07,95%CI:1.00±1.14)and an increased gastric adenocarcinoma risk in Finn Gen(OR=1.68,95%CI:1.16±2.45).Genetically predicted plasma L-aspartic acid levels also modified the GC primary prevention effects with the beneficial effect of Helicobacter pylori eradication notably observed among individuals within the top quartile of L-aspartic acid level(P-interaction=0.098)and the beneficial effect of garlic supplementation only for those within the lowest quartile of L-aspartic acid level(P-interaction=0.02).Conclusions:Elevated plasma L-aspartic acid levels significantly increased the risk of developing GC and modified the effects of GC primary prevention.Further studies from other populations are warranted to validate the modification effect of plasma L-aspartic acid levels on GC prevention and to elucidate the underlying mechanisms.展开更多
Domain randomization is a widely adopted technique in deep reinforcement learning(DRL)to improve agent generalization by exposing policies to diverse environmental conditions.This paper investigates the impact of diff...Domain randomization is a widely adopted technique in deep reinforcement learning(DRL)to improve agent generalization by exposing policies to diverse environmental conditions.This paper investigates the impact of different reset strategies,normal,non-randomized,and randomized,on agent performance using the Deep Deterministic Policy Gradient(DDPG)and Twin Delayed DDPG(TD3)algorithms within the CarRacing-v2 environment.Two experimental setups were conducted:an extended training regime with DDPG for 1000 steps per episode across 1000 episodes,and a fast execution setup comparing DDPG and TD3 for 30 episodes with 50 steps per episode under constrained computational resources.A step-based reward scaling mechanism was applied under the randomized reset condition to promote broader state exploration.Experimental results showthat randomized resets significantly enhance learning efficiency and generalization,with DDPG demonstrating superior performance across all reset strategies.In particular,DDPG combined with randomized resets achieves the highest smoothed rewards(reaching approximately 15),best stability,and fastest convergence.These differences are statistically significant,as confirmed by t-tests:DDPG outperforms TD3 under randomized(t=−101.91,p<0.0001),normal(t=−21.59,p<0.0001),and non-randomized(t=−62.46,p<0.0001)reset conditions.The findings underscore the critical role of reset strategy and reward shaping in enhancing the robustness and adaptability of DRL agents in continuous control tasks,particularly in environments where computational efficiency and training stability are crucial.展开更多
Background:Chronic obstructive pulmonary disease(COPD)is a prevalent respiratory ailment that has risen to become the foremost cause of mortality globally,and statins are a widely used class of lipid-modifying drugs.D...Background:Chronic obstructive pulmonary disease(COPD)is a prevalent respiratory ailment that has risen to become the foremost cause of mortality globally,and statins are a widely used class of lipid-modifying drugs.Data from some observational studies suggest an association between statins use and COPD.Objectives:The main objective of this study was to investigate whether lipids and apolipoproteins are bidirectionally causally associated with COPD at the genetic level using a Mendelian randomization(MR)design,and to determine the potential role of circulating inflammatory proteins as mediators in this association.Methods:The publicly available Genome-Wide Association Study(GWAS)database was utilised for the purposes of the analysis.The data on high-density lipoprotein(HDL-C),low-density lipoprotein(LDL-C),triglycerides(TG),apolipoprotein A-1(ApoA1),and apolipoprotein B(ApoB)were obtained from the UK BioBank,while the COPD dataset was obtained from the FinnGen BioBank R11(number of cases:21,617,number of controls:372,627).Furthermore,data were gathered on genetic variants linked to inflammatory processes,encompassing 91 circulating inflammatory proteins(n=14,823 individuals).A two-sample MR study was conducted using these data to assess the association between HDL-C,LDL-C,TG,ApoA1,and ApoB with the risk of COPD.Furthermore,in order to investigate the potential mediating influence of inflammatory factor alterations between lipids and COPD,a two-step Mendelian randomization(MR)mediation analysis was conducted.Results:The forward MR methods identified two lipids that were found to have a causal relationship with the development of COPD.An elevated level of LDL-C and ApoB was found to be associated with a diminished risk of COPD.Furthermore,the researchers identified circulating inflammatory factors that were determined to be the causal agents in the development of COPD.Mediation analysis indicated that the inflammatory protein S100-A12 may act as a mediator between the LDL-C and COPD pathways.Conclusion:The present MR study provides genetic evidence for a causal relationship between lipids and apolipoproteins and COPD,as well as identifying the inflammatory protein S100-A12 as a potential mediator of the COPD association.The findings offer valuable insights into the mechanistic studies of statins for COPD and potential targets for disease intervention and treatment.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
Objective Observational studies have found associations between inflammatory bowel disease(IBD)and the risk of dementia,including Alzheimer’s dementia(AD)and vascular dementia(VD);however,these findings are inconsist...Objective Observational studies have found associations between inflammatory bowel disease(IBD)and the risk of dementia,including Alzheimer’s dementia(AD)and vascular dementia(VD);however,these findings are inconsistent.It remains unclear whether these associations are causal.Methods We conducted a meta-analysis by systematically searching for observational studies on the association between IBD and dementia.Mendelian randomization(MR)analysis based on summary genome-wide association studies(GWASs)was performed.Genetic correlation and Bayesian colocalization analyses were used to provide robust genetic evidence.Results Ten observational studies involving 80,565,688 participants were included in this metaanalysis.IBD was significantly associated with dementia(risk ratio[RR]=1.36,95%CI=1.04-1.78;I2=84.8%)and VD(RR=2.60,95%CI=1.18-5.70;only one study),but not with AD(RR=2.00,95%CI=0.96-4.13;I^(2)=99.8%).MR analyses did not supported significant causal associations of IBD with dementia(dementia:odds ratio[OR]=1.01,95%CI=0.98-1.03;AD:OR=0.98,95%CI=0.95-1.01;VD:OR=1.02,95%CI=0.97-1.07).In addition,genetic correlation and co-localization analyses did not reveal any genetic associations between IBD and dementia.Conclusion Our study did not provide genetic evidence for a causal association between IBD and dementia risk.The increased risk of dementia observed in observational studies may be attributed to unobserved confounding factors or detection bias.展开更多
Consecutive stresses,such as initial submergence during germination followed by water deficit during the seedling stage,pose significant challenges to direct-seeded rice cultivation.By Linkage disequilibrium analysis,...Consecutive stresses,such as initial submergence during germination followed by water deficit during the seedling stage,pose significant challenges to direct-seeded rice cultivation.By Linkage disequilibrium analysis,Sub1 and Dro1(Δbp:10 Mb),as well as Sub1 and TPP7(Δbp:6 Mb)were identified to exhibit long-range linkage disequilibrium(LRLD).Meta-QTL analysis further revealed that Sub1 and TPP7 co-segregated for tolerance to submergence at the germination and seedling stages.Based on this,we hypothesized that LRLD might influence plant responses to consecutive stresses.To test this hypothesis,we developed a structured recombinant inbred line population from a cross between Bhalum 2 and Nagina 22,with alleles(Sub1 and TPP7)in linkage equilibrium.Mendelian randomization analysis validated that the parental alleles,rather than the recombinant alleles of Sub1 and TPP7,significantly influenced 13 out of 41 traits under consecutive stress conditions.Additionally,16 minor additive effect QTLs were detected between the genomic regions,spanning Sub1 and TPP7 for various traits.A single allele difference between these genomic regions enhanced crown root number,root dry weight,and specific root area by 11.45%,15.69%,and 33.15%,respectively,under flooded germination conditions.Candidate gene analysis identified WAK79 and MRLK59 as regulators of stress responses during flooded germination,recovery,and subsequent water deficit conditions.These findings highlight the critical role of parental allele combinations and genomic regions between Sub1 and TPP7 in regulating the stress responses under consecutive stresses.Favourable haplotypes derived from these alleles can be utilized to improve stress resilience in direct-seeded rice.展开更多
In recent years,Mendelian randomization(MR)has been increasingly utilized,leveraging genetic variants as instrumental variables.This approach significantly mitigates confounder effects and reverse causation,precisely ...In recent years,Mendelian randomization(MR)has been increasingly utilized,leveraging genetic variants as instrumental variables.This approach significantly mitigates confounder effects and reverse causation,precisely clarifying the causal links between exposures and outcomes.MR’s unique advantages have made it instrumental in medicine,especially in elucidating glaucoma’s etiology.It facilitates the identification of potential risk factors,laying the groundwork for developing preventative and therapeutic strategies against glaucoma.Recent MR research has delved into diverse potential glaucoma risk factors,including behavioral habits,metabolic profiles,and their causative linkage to the disease.This review encapsulates MR’s analysis in glaucoma etiology,heralding new avenues for understanding underlying mechanisms and establishing causality.展开更多
Dear Editor,Observational studies in epidemiology have identified a correlation between hypothyroidism and cholelithiasis[1–2].However,the causal relationship between the two diseases remains unclear.To investigate t...Dear Editor,Observational studies in epidemiology have identified a correlation between hypothyroidism and cholelithiasis[1–2].However,the causal relationship between the two diseases remains unclear.To investigate the potential causal relationship,we employed a two-sample bidirectional Mendelian randomization(MR)analysis.展开更多
Chronotype is determined by circadian rhythms,influenced by polygenic variations and environmental factors. Typically, chronotypes are categorized into morning-, intermediate-, and evening-types^([1]). Most cognitive ...Chronotype is determined by circadian rhythms,influenced by polygenic variations and environmental factors. Typically, chronotypes are categorized into morning-, intermediate-, and evening-types^([1]). Most cognitive functions follow daily and circadian rhythms, with the “synchronization effect” reflecting performance variations between optimal and non-optimal times based on an individual's chronotype.展开更多
Objective Observational studies have shown inconsistent associations of loneliness or social isolation(SI)with ischemic heart disease(IHD),with unknown mediators.Methods Using data from genome-wide association studies...Objective Observational studies have shown inconsistent associations of loneliness or social isolation(SI)with ischemic heart disease(IHD),with unknown mediators.Methods Using data from genome-wide association studies of predominantly European ancestry,we performed a bidirectional two-sample Mendelian Randomization(MR)study to estimate causal effects of loneliness(N=487,647)and SI traits on IHD(N=184,305).SI traits included whether individuals lived alone,participated in various types of social activities,and how often they had contact with friends or family(N=459,830 to 461,369).A network MR study was conducted to evaluate the mediating roles of 20 candidate mediators,including metabolic,behavioral and psychological factors.Results Loneliness increased IHD risk(OR=2.129;95%confidence interval[CI]:1.380 to 3.285),mediated by body fat percentage,waist-hip ratio,total cholesterol,and low-density lipoprotein cholesterol.For SI traits,only fewer social activities increased IHD risk(OR=1.815;95%CI:1.189 to 2.772),mediated by hypertension,high-density lipoprotein cholesterol,triglycerides,fasting insulin,and smoking cessation.No reverse causality of IHD with loneliness and SI was found.Conclusion These findings suggested more attention should be paid to individuals who feel lonely and have fewer social activities to prevent IHD,with several mediators as prioritized targets for intervention.展开更多
AIM:To elucidate causal pathways between oxidative biomarkers and age-related macular degeneration(AMD)phenotypes.METHODS:A bidirectional Mendelian randomization(MR)analytical protocol was implemented,which utilized g...AIM:To elucidate causal pathways between oxidative biomarkers and age-related macular degeneration(AMD)phenotypes.METHODS:A bidirectional Mendelian randomization(MR)analytical protocol was implemented,which utilized genome-wide association study(GWAS)summary statistics derived from the IEU OpenGWAS repositories.The investigation focused on 11 oxidative stress markers and AMD phenotypes,encompassing both wet and dry subtypes.The MR methodology incorporated inverse-variance weighted(IVW)calculations,MR-Egger statistical regression,weighted median approximation,and weighted mode assessments to estimate causative relationships.Sensitivity evaluations were conducted to verify result robustness and identify potential pleiotropy.RESULTS:Genetically predicted elevated catalase(CAT)concentrations demonstrated significant associations with heightened risks of overall AMD(IVW OR=1.084,95%CI:1.021-1.151,P=0.008)and wet AMD phenotype(IVW OR=1.113,95%CI:1.047-1.247,P=0.007).Higher genetically predicted albumin concentrations corresponded with reduced AMD risk(IVW OR=0.827,95%CI:0.715-0.957,P=0.013)but increased wet AMD risk(IVW OR=1.229,95%CI:1.036-1.458,P=0.018).Reverse MR analysis revealed that genetically predicted dry AMD exhibited significant association with reduced albumin levels(IVW OR=0.987,95%CI:0.979-0.996,P=0.004),while wet AMD corresponded with decreased total bilirubin(TBIL)and paraoxonase(PON)activity.CONCLUSION:The results offer strong support for a causal link between markers of oxidative stress and the development of AMD,indicating that oxidative processes play a role in driving the disease progression.展开更多
BACKGROUND:This study aims to explore the causal relationship of body weight,body mass index(BMI),and waist circumference (WC) with the risk of cardiac arrest (CA) using two-sample Mendelian randomization (MR).METHODS...BACKGROUND:This study aims to explore the causal relationship of body weight,body mass index(BMI),and waist circumference (WC) with the risk of cardiac arrest (CA) using two-sample Mendelian randomization (MR).METHODS:Data were summarized using genome-wide association studies (GWAS).Twosample MR analyses were performed using the inverse variance weighting (IVW) method,the weighted median method,and the MR-Egger analysis.Heterogeneity test and sensitivity analysis were performed using Cochran’s Q test and the leave-one-out method,respectively.The Steiger test was used to detect reverse causality.Bayesian model-averaged MR was used to identify the most influential risk factors.RESULTS:A total of 13 GWAS data were collected for BMI,body weight and WC.IVW analyses showed a positive correlation of body weight,BMI,and WC with CA (all OR>1 and P<0.05),with MR-Egger and weighted median methods confirming the IVW findings.No horizontal pleiotropy or heterogeneity was observed.Sensitivity analysis indicated that no single nucleotide polymorphism(SNP) caused significant changes in overall causality.Bayesian model-averaged MR was also used to rank causality based on marginal inclusion probability (MIP),and the corresponding modelaveraged causal estimate (MACE) were confirmed,which indicated that WC (GWAS ID:ukb-b-9405)was the highest-ranked risk factor (MIP=0.119,MACE=0.011);its posterior probability was 0.057.A total of 14 sex-specific GWAS data on weight,BMI,and WC were analyzed in relationship with CA,and the MR results showed no significant effects of sex-specific factors.CONCLUSION:Body weight,BMI,and WC are causally associated with an increased risk of CA,with WC identified as the most important risk factor.展开更多
Objective Pneumoconiosis,a lung disease caused by irreversible fibrosis,represents a significant public health burden.This study investigates the causal relationships between gut microbiota,gene methylation,gene expre...Objective Pneumoconiosis,a lung disease caused by irreversible fibrosis,represents a significant public health burden.This study investigates the causal relationships between gut microbiota,gene methylation,gene expression,protein levels,and pneumoconiosis using a multi-omics approach and Mendelian randomization(MR).Methods We analyzed gut microbiota data from MiBioGen and Esteban et al.to assess their potential causal effects on pneumoconiosis subtypes(asbestosis,silicosis,and inorganic pneumoconiosis)using conventional and summary-data-based MR(SMR).Gene methylation and expression data from Genotype-Tissue Expression and eQTLGen,along with protein level data from deCODE and UK Biobank Pharma Proteomics Project,were examined in relation to pneumoconiosis data from FinnGen.To validate our findings,we assessed self-measured gut flora from a pneumoconiosis cohort and performed fine mapping,drug prediction,molecular docking,and Phenome-Wide Association Studies to explore relevant phenotypes of key genes.Results Three core gut microorganisms were identified:Romboutsia(OR=0.249)as a protective factor against silicosis,Pasteurellaceae(OR=3.207)and Haemophilus parainfluenzae(OR=2.343)as risk factors for inorganic pneumoconiosis.Additionally,mapping and quantitative trait loci analyses revealed that the genes VIM,STX8,and MIF were significantly associated with pneumoconiosis risk.Conclusions This multi-omics study highlights the associations between gut microbiota and key genes(VIM,STX8,MIF)with pneumoconiosis,offering insights into potential therapeutic targets and personalized treatment strategies.展开更多
Objective To explore the causality between reproductive traits and risk of psoriasis by using a large Mendelian randomization(MR)study.Methods A two-sample MR study was performed using summarized statistics from the g...Objective To explore the causality between reproductive traits and risk of psoriasis by using a large Mendelian randomization(MR)study.Methods A two-sample MR study was performed using summarized statistics from the genome-wide association studies(GWAS)conducted in reproductive traits,as well as GWAS data on overall psoriasis,psoriatic arthritis(PsA),and psoriasis vulgaris(PV).Besides univariable MR(UVMR),multivariable MR and two-step MR was used to calculate the independent effects and quantify the proportion mediated by education or body mass index(BMI).Results Genetically predicted early age at first sexual intercourse(AFS)led to an increased risk of overall psoriasis[odds ratio(OR)UVMR:0.54];36.13%of this effect was mediated through BMI and 47.79%through educational attainment.The direct negative casual association between age at first birth(AFB)-PsA was dominant(ORUVMR:0.76),with 49.61%proportion of the mediation due to BMI.The mediating effect was found for BMI on the AFS-PV relationship,which accounted for 26.27%of the proportion.AFS was inversely associated with the risk of overall psoriasis and PV,with considerable mediation by BMI and educational attainment.Conclusion Early AFB may cause a higher risk of PsA,while the AFS-PsA association was fully mediated by BMI.展开更多
Objective To clarify the causal relationship between the level of cytoplasmic unactivated mineralocorticoid receptor(MR)and the development of tubulointerstitial nephritis(TIN),and to evaluate the impact of MR on dysl...Objective To clarify the causal relationship between the level of cytoplasmic unactivated mineralocorticoid receptor(MR)and the development of tubulointerstitial nephritis(TIN),and to evaluate the impact of MR on dyslipidemia,particularly secondary hyperlipemia,in patients with diabetic kidney disease.Methods We conducted a two-sample Mendelian randomization study using genome-wide association study(GWAS)summary data.Genetic variants associated with MR levels were selected as exposures,with TIN and lipid profiles[including low-density lipoprotein cholesterol(LDL-C),triglyceride,and high-density lipoprotein cholesterol]as outcomes.A two-step Mendelian randomization approach was used to assess TIN as a mediator,employing inverse variance weighted regression as the primary analysis,supplemented by Mendelian randomization-Egger,weighted median,and sensitivity analyses.Results Cytoplasmic unactivated MR level exhibited a significant causal association with a decreased risk of TIN(OR=0.8598,95%CI[0.7775-0.9508],P<0.001).Although no significant causal relationship was identified between MR level and secondary hyperlipemia,a potential association of cytoplasmic unactivated MR level with lower LDL-C levels was observed(OR=0.9901,95%CI[0.9821-0.9983],P=0.018).Additionally,TIN exhibited causal links with secondary hyperlipemia(OR=1.0016,95%CI[1.0002-1.0029],P=0.020)and elevated LDL-C(OR=1.0111,95%CI[1.0024-1.0199],P=0.012),particularly LDL-C in European males(OR=1.0230,95%CI[1.0103-1.0358],P<0.001).Inverse Mendelian randomization analysis revealed causal relationships between TIN and genetically predicted triglyceride(OR=0.7027,95%CI[0.6189-0.7978],P<0.001),high-density lipoprotein cholesterol(OR=1.1247,95%CI[1.0019-1.2626],P=0.046),and LDL-C(OR=0.8423,95%CI[0.7220-0.9827],P=0.029).Notably,TIN mediated 16.7%of the causal association between MR and LDL-C levels.Conclusions MR plays a critical role in the development of TIN and lipid metabolism,highlighting the potential of MR-antagonists in reducing renal damage and lipid metabolism-associated complications.展开更多
Background:Whether chronic hepatitis B or C virus infection is a risk factor for autoimmune liver diseases(AILDs)remains unclear.This study aimed to investigate the causal relationship between the two disease entities...Background:Whether chronic hepatitis B or C virus infection is a risk factor for autoimmune liver diseases(AILDs)remains unclear.This study aimed to investigate the causal relationship between the two disease entities and underlying mechanisms.Methods:Bidirectional Mendelian randomization analysis was performed using genome-wide association study summary statistics for hepatitis B or C virus infection and AILDs in individuals of European ancestry.Statistically significant findings underwent meta-analysis for validation and single-cell RNA-seq were conducted to explore the potential mechanisms.Results:A causal relationship was observed between chronic hepatitis B virus(HBV)infection and an elevated risk of primary biliary cholangitis(PBC).Meta-analysis of all PBC-outcome findings confirmed the association(Odds ratio:1.32,95%confidence interval:1.23–1.42)without a reverse causal effect.Chronic HBV infection was also potentially associated with an increased risk of autoimmune hepatitis,but not with primary sclerosing cholangitis.No causal relationship was found between hepatitis C virus infection and AILDs.Single-cell RNA-seq revealed HLA gene activated in liver and impaired innate immune suppressive function in chronic hepatitis B patients.Conclusion:This study demonstrates a one-way causal association between chronic HBV infection and certain AILDs(PBC and autoimmune hepatitis),but not chronic hepatitis C virus infection.Single-cell transcriptome analysis revealed immune dysfunction caused by chronic HBV infection persists and is difficult to resolve even after HBV clearance,potentially leading to autoimmune hepatic diseases.展开更多
Background Hypertension is associated with an increased risk of calcific aortic valve stenosis(CAVS).However,the directionality of causation between blood pressure traits and aortic stenosis is unclear,as is the benef...Background Hypertension is associated with an increased risk of calcific aortic valve stenosis(CAVS).However,the directionality of causation between blood pressure traits and aortic stenosis is unclear,as is the benefit of antihypertensive drugs for CAVS.Methods Using genome-wide association studies(GWAS)summary statistics,we performed bidirectional two-sample univariable mendelian randomization(UVMR)to assess the causal associations of systolic blood pressure(SBP),diastolic blood pressure(DBP),and pulse pressure(PP)with CAVS.Multivariable mendelian randomization(MVMR)was conducted to evaluate the direct effect of hypertension on CAVS,adjusting for confounders.Drug target mendelian randomization(MR)and summary-level MR(SMR)were used to estimate the effects of 12 classes of antihypertensive drugs and their target genes on CAVS risk.Inverse variance weighting was the primary MR method,with sensitivity analyses to validate results.Results UVMR showed SBP,DBP,and PP have causal effects on CAVS,with no significant reverse causality.MVMR confirmed the causality between hypertension and CAVS after adjusting for confounders.Drug-target MR analyses indicated that calcium channel blockers(CCBs),loop diuretics,and thiazide diuretics via SBP lowering exerted protective effects on CAVS risk.SMR analysis showed that the CCBs target gene CACNA2D2 and ARBs target gene AGTR1 were positively associated with CAVS risk,while diuretics target genes SLC12A5 and SLC12A1 were negatively associated with aortic stenosis risk.Conclusions Hypertension has a causal relationship with CAVS.Managing SBP in hypertensive patients with CCBs may prevent CAVS.ARBs might exert protective effects on CAVS independent of blood pressure reduction.The relationship between diuretics and CAVS is complex,with opposite effects through different mechanisms.展开更多
Objective Vitamin deficiencies,particularly in vitamins A,B12,and D,are prevalent across populations and contribute significantly to a range of health issues.While these deficiencies are well documented,the underlying...Objective Vitamin deficiencies,particularly in vitamins A,B12,and D,are prevalent across populations and contribute significantly to a range of health issues.While these deficiencies are well documented,the underlying etiology remains complex.Recent studies suggest a close link between the gut microbiota and the synthesis,absorption,and metabolism of these vitamins.However,the specific causal relationships between the gut microbiota composition and vitamin deficiencies remain poorly understood.Identifying key bacterial species and understanding their role in vitamin metabolism could provide critical insights for targeted interventions.Methods We conducted a two-sample Mendelian randomization(MR)study to assess the causal relationship between the gut microbiota and vitamin deficiencies(A,B12,D).The genome-wide association study data for vitamin deficiencies were sourced from the FinnGen biobank,and the gut microbiota data were from the MiBioGen consortium.MR analyses included inverse variance-weighted(IVW),MR‒Egger,weighted median,and weighted mode approaches.Sensitivity analyses and reverse causality assessments were performed to ensure robustness and validate the findings.Results After FDR adjustment,vitamin B12 deficiency was associated with the class Verrucomicrobiae,order Verrucomicrobiales,family Verrucomicrobiaceae,and genus Akkermansia.Vitamin A deficiency was associated with the phylum Firmicutes and the genera Fusicatenibacter and Ruminiclostridium 6.Additional associations for vitamin B12 deficiency included the Enterobacteriaceae and Rhodospirillaceae and the genera Coprococcus 2,Lactococcus,and Ruminococcaceae UCG002.Vitamin D deficiency was associated with the genera Allisonella,Eubacterium,and Tyzzerella 3.Lachnospiraceae and Lactococcus were common risk factors for both B12 and D deficiency.Sensitivity analyses confirmed the robustness of the findings against heterogeneity and horizontal pleiotropy,and reverse MR tests indicated no evidence of reverse causality.Conclusions Our findings reveal a possible causal relationship between specific gut microbiota characteristics and vitamin A,B12 and D deficiencies,providing a theoretical basis for addressing these nutritional deficiencies through the modulation of the gut microbiota in the future and laying the groundwork for related interventions.展开更多
BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outc...BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines,which may play critical roles in the pathogenesis of sepsis.This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.METHODS:First,a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and sepsis.A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetical y proxied lipid-modifying therapies on the risk of sepsis,sepsis-related critical care admission,and sepsis-related death.The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines.Finally,enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.RESULTS:Genetically proxied cholesteryl ester transfer protein(CETP) inhibitors were significantly associated with sepsis-related critical care admission(OR=0.84,95% CI [0.74,0.95],P=0.008,) and sepsisrelated death(OR=0.68,95% CI [0.52,0.88],P=0.004).The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines.Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.CONCLUSION:This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death.These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines,influencing the inflammatory response pathway.展开更多
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.
基金funded by the National Natural Science Foundation of China(No.82273704)Noncommunicable Chronic Diseases-National Science and Technology Major Project(No.2023ZD0501400-2023ZD0501402)+4 种基金Beijing Hospitals Authority’s Ascent Plan(DFL20241102)Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support(No.ZLRK202325)China Postdoctoral Science Foundation(2024M760152)Peking University Medicine Fund for World’s Leading Discipline or Discipline Cluster Development(No.BMU2022XKQ004)Science Foundation of Peking University Cancer Hospital(Nos.BJCH2024BJ02,XKFZ2410,BJCH2025CZ04,and 2022-27)。
文摘Objective:Based on multistage metabolomic profiling and Mendelian randomization analyses,the current study identified plasma metabolites that predicted the risk of developing gastric cancer(GC)and determined whether key metabolite levels modified the GC primary prevention effects.Methods:Plasma metabolites associated with GC risk were identified through a case-control study.Bi-directional two-sample Mendelian randomization analyses were performed to determine potential causal relationships utilizing the Shandong Intervention Trial(SIT),a nested case-control study of the Mass Intervention Trial in Linqu,Shandong province(MITS),China,the UK Biobank,and the Finn Gen project.Results:A higher genetic risk score for plasma L-aspartic acid was significantly associated with an increased GC risk in the northern Chinese population(SIT:HR=1.26 per 1 SD change,95%CI:1.07±1.49;MITS:HR=1.07,95%CI:1.00±1.14)and an increased gastric adenocarcinoma risk in Finn Gen(OR=1.68,95%CI:1.16±2.45).Genetically predicted plasma L-aspartic acid levels also modified the GC primary prevention effects with the beneficial effect of Helicobacter pylori eradication notably observed among individuals within the top quartile of L-aspartic acid level(P-interaction=0.098)and the beneficial effect of garlic supplementation only for those within the lowest quartile of L-aspartic acid level(P-interaction=0.02).Conclusions:Elevated plasma L-aspartic acid levels significantly increased the risk of developing GC and modified the effects of GC primary prevention.Further studies from other populations are warranted to validate the modification effect of plasma L-aspartic acid levels on GC prevention and to elucidate the underlying mechanisms.
基金supported by the Deputyship for Research&Innovation,Ministry of Education in Saudi Arabia(Project No.MoE-IF-UJ-R2-22-04220773-1).
文摘Domain randomization is a widely adopted technique in deep reinforcement learning(DRL)to improve agent generalization by exposing policies to diverse environmental conditions.This paper investigates the impact of different reset strategies,normal,non-randomized,and randomized,on agent performance using the Deep Deterministic Policy Gradient(DDPG)and Twin Delayed DDPG(TD3)algorithms within the CarRacing-v2 environment.Two experimental setups were conducted:an extended training regime with DDPG for 1000 steps per episode across 1000 episodes,and a fast execution setup comparing DDPG and TD3 for 30 episodes with 50 steps per episode under constrained computational resources.A step-based reward scaling mechanism was applied under the randomized reset condition to promote broader state exploration.Experimental results showthat randomized resets significantly enhance learning efficiency and generalization,with DDPG demonstrating superior performance across all reset strategies.In particular,DDPG combined with randomized resets achieves the highest smoothed rewards(reaching approximately 15),best stability,and fastest convergence.These differences are statistically significant,as confirmed by t-tests:DDPG outperforms TD3 under randomized(t=−101.91,p<0.0001),normal(t=−21.59,p<0.0001),and non-randomized(t=−62.46,p<0.0001)reset conditions.The findings underscore the critical role of reset strategy and reward shaping in enhancing the robustness and adaptability of DRL agents in continuous control tasks,particularly in environments where computational efficiency and training stability are crucial.
基金supported by the Key Support Project of Regional Innovation and Development Joint Fund of National Natural Science Foundation of China(U20A20398)the National Natural Science Foundation of China(82104454,82374399)+1 种基金the Clinical Medical Research Transformation Project of Anhui Province(202304295107020111)the Natural Science Research Key Project of Anhui Provincial Department of Education(KJ2021A0542).
文摘Background:Chronic obstructive pulmonary disease(COPD)is a prevalent respiratory ailment that has risen to become the foremost cause of mortality globally,and statins are a widely used class of lipid-modifying drugs.Data from some observational studies suggest an association between statins use and COPD.Objectives:The main objective of this study was to investigate whether lipids and apolipoproteins are bidirectionally causally associated with COPD at the genetic level using a Mendelian randomization(MR)design,and to determine the potential role of circulating inflammatory proteins as mediators in this association.Methods:The publicly available Genome-Wide Association Study(GWAS)database was utilised for the purposes of the analysis.The data on high-density lipoprotein(HDL-C),low-density lipoprotein(LDL-C),triglycerides(TG),apolipoprotein A-1(ApoA1),and apolipoprotein B(ApoB)were obtained from the UK BioBank,while the COPD dataset was obtained from the FinnGen BioBank R11(number of cases:21,617,number of controls:372,627).Furthermore,data were gathered on genetic variants linked to inflammatory processes,encompassing 91 circulating inflammatory proteins(n=14,823 individuals).A two-sample MR study was conducted using these data to assess the association between HDL-C,LDL-C,TG,ApoA1,and ApoB with the risk of COPD.Furthermore,in order to investigate the potential mediating influence of inflammatory factor alterations between lipids and COPD,a two-step Mendelian randomization(MR)mediation analysis was conducted.Results:The forward MR methods identified two lipids that were found to have a causal relationship with the development of COPD.An elevated level of LDL-C and ApoB was found to be associated with a diminished risk of COPD.Furthermore,the researchers identified circulating inflammatory factors that were determined to be the causal agents in the development of COPD.Mediation analysis indicated that the inflammatory protein S100-A12 may act as a mediator between the LDL-C and COPD pathways.Conclusion:The present MR study provides genetic evidence for a causal relationship between lipids and apolipoproteins and COPD,as well as identifying the inflammatory protein S100-A12 as a potential mediator of the COPD association.The findings offer valuable insights into the mechanistic studies of statins for COPD and potential targets for disease intervention and treatment.
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.
基金supported by the China Postdoctoral Science Foundation(Grant No.2021M703366)Shenzhen Science and Technology Program(Grant No.KQTD20190929172835662).
文摘Objective Observational studies have found associations between inflammatory bowel disease(IBD)and the risk of dementia,including Alzheimer’s dementia(AD)and vascular dementia(VD);however,these findings are inconsistent.It remains unclear whether these associations are causal.Methods We conducted a meta-analysis by systematically searching for observational studies on the association between IBD and dementia.Mendelian randomization(MR)analysis based on summary genome-wide association studies(GWASs)was performed.Genetic correlation and Bayesian colocalization analyses were used to provide robust genetic evidence.Results Ten observational studies involving 80,565,688 participants were included in this metaanalysis.IBD was significantly associated with dementia(risk ratio[RR]=1.36,95%CI=1.04-1.78;I2=84.8%)and VD(RR=2.60,95%CI=1.18-5.70;only one study),but not with AD(RR=2.00,95%CI=0.96-4.13;I^(2)=99.8%).MR analyses did not supported significant causal associations of IBD with dementia(dementia:odds ratio[OR]=1.01,95%CI=0.98-1.03;AD:OR=0.98,95%CI=0.95-1.01;VD:OR=1.02,95%CI=0.97-1.07).In addition,genetic correlation and co-localization analyses did not reveal any genetic associations between IBD and dementia.Conclusion Our study did not provide genetic evidence for a causal association between IBD and dementia risk.The increased risk of dementia observed in observational studies may be attributed to unobserved confounding factors or detection bias.
基金supported by the Director General,Indian Council of Agricultural Research(ICAR),New Delhithe Director,ICAR-National Rice Research Institute,Cuttack.
文摘Consecutive stresses,such as initial submergence during germination followed by water deficit during the seedling stage,pose significant challenges to direct-seeded rice cultivation.By Linkage disequilibrium analysis,Sub1 and Dro1(Δbp:10 Mb),as well as Sub1 and TPP7(Δbp:6 Mb)were identified to exhibit long-range linkage disequilibrium(LRLD).Meta-QTL analysis further revealed that Sub1 and TPP7 co-segregated for tolerance to submergence at the germination and seedling stages.Based on this,we hypothesized that LRLD might influence plant responses to consecutive stresses.To test this hypothesis,we developed a structured recombinant inbred line population from a cross between Bhalum 2 and Nagina 22,with alleles(Sub1 and TPP7)in linkage equilibrium.Mendelian randomization analysis validated that the parental alleles,rather than the recombinant alleles of Sub1 and TPP7,significantly influenced 13 out of 41 traits under consecutive stress conditions.Additionally,16 minor additive effect QTLs were detected between the genomic regions,spanning Sub1 and TPP7 for various traits.A single allele difference between these genomic regions enhanced crown root number,root dry weight,and specific root area by 11.45%,15.69%,and 33.15%,respectively,under flooded germination conditions.Candidate gene analysis identified WAK79 and MRLK59 as regulators of stress responses during flooded germination,recovery,and subsequent water deficit conditions.These findings highlight the critical role of parental allele combinations and genomic regions between Sub1 and TPP7 in regulating the stress responses under consecutive stresses.Favourable haplotypes derived from these alleles can be utilized to improve stress resilience in direct-seeded rice.
基金Supported by Shenzhen Science and Technology Program(No.JCYJ20220530152005013,No.JCYJ20230807114605011)Sanming Project of Medicine in Shenzhen(No.SZZYSM202411007).
文摘In recent years,Mendelian randomization(MR)has been increasingly utilized,leveraging genetic variants as instrumental variables.This approach significantly mitigates confounder effects and reverse causation,precisely clarifying the causal links between exposures and outcomes.MR’s unique advantages have made it instrumental in medicine,especially in elucidating glaucoma’s etiology.It facilitates the identification of potential risk factors,laying the groundwork for developing preventative and therapeutic strategies against glaucoma.Recent MR research has delved into diverse potential glaucoma risk factors,including behavioral habits,metabolic profiles,and their causative linkage to the disease.This review encapsulates MR’s analysis in glaucoma etiology,heralding new avenues for understanding underlying mechanisms and establishing causality.
基金by grants from the Jiangsu Province 333 High-level Talent Training Project(Grant No.LGY2016010)the Nanjing Science and Technology Development Plan(Grant No.201715003)the Jiangsu Province Six Talent Peaks(Grant No.WSN-030).
文摘Dear Editor,Observational studies in epidemiology have identified a correlation between hypothyroidism and cholelithiasis[1–2].However,the causal relationship between the two diseases remains unclear.To investigate the potential causal relationship,we employed a two-sample bidirectional Mendelian randomization(MR)analysis.
基金supported by Zhongda Hospital Affiliated to Southeast University,Jiangsu Province High-Level Hospital Construction Funds(Grant No.GSP-LCYJFH07)。
文摘Chronotype is determined by circadian rhythms,influenced by polygenic variations and environmental factors. Typically, chronotypes are categorized into morning-, intermediate-, and evening-types^([1]). Most cognitive functions follow daily and circadian rhythms, with the “synchronization effect” reflecting performance variations between optimal and non-optimal times based on an individual's chronotype.
基金supported by the National Natural Science Foundation of China(82322059)the Chinese Academy of Medical·Sciences Innovation Fund for Medical Sciences(2021-I2M-1-010)+1 种基金the National Key Research and Development Program of China(2021YFC2500500)the National High Level Hospital Clinical Research Funding(2023-GSPRC-19).
文摘Objective Observational studies have shown inconsistent associations of loneliness or social isolation(SI)with ischemic heart disease(IHD),with unknown mediators.Methods Using data from genome-wide association studies of predominantly European ancestry,we performed a bidirectional two-sample Mendelian Randomization(MR)study to estimate causal effects of loneliness(N=487,647)and SI traits on IHD(N=184,305).SI traits included whether individuals lived alone,participated in various types of social activities,and how often they had contact with friends or family(N=459,830 to 461,369).A network MR study was conducted to evaluate the mediating roles of 20 candidate mediators,including metabolic,behavioral and psychological factors.Results Loneliness increased IHD risk(OR=2.129;95%confidence interval[CI]:1.380 to 3.285),mediated by body fat percentage,waist-hip ratio,total cholesterol,and low-density lipoprotein cholesterol.For SI traits,only fewer social activities increased IHD risk(OR=1.815;95%CI:1.189 to 2.772),mediated by hypertension,high-density lipoprotein cholesterol,triglycerides,fasting insulin,and smoking cessation.No reverse causality of IHD with loneliness and SI was found.Conclusion These findings suggested more attention should be paid to individuals who feel lonely and have fewer social activities to prevent IHD,with several mediators as prioritized targets for intervention.
基金Supported by National Natural Science Foundation of China(No.82371033)Tianjin Health Bureau Fund(No.ZC20030)+4 种基金Tianjin Eye Hospital Fund Project(No.YKYB1911)Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-016A)Nankai University Institute of Optometry Science Research Open Fund(No.YKPY2208)Tianjin Eye Hospital Science and Technology Fund(No.NKSGY202405)Xianyang Science and Technology Plan Project(No.L2022ZDYFSF038).
文摘AIM:To elucidate causal pathways between oxidative biomarkers and age-related macular degeneration(AMD)phenotypes.METHODS:A bidirectional Mendelian randomization(MR)analytical protocol was implemented,which utilized genome-wide association study(GWAS)summary statistics derived from the IEU OpenGWAS repositories.The investigation focused on 11 oxidative stress markers and AMD phenotypes,encompassing both wet and dry subtypes.The MR methodology incorporated inverse-variance weighted(IVW)calculations,MR-Egger statistical regression,weighted median approximation,and weighted mode assessments to estimate causative relationships.Sensitivity evaluations were conducted to verify result robustness and identify potential pleiotropy.RESULTS:Genetically predicted elevated catalase(CAT)concentrations demonstrated significant associations with heightened risks of overall AMD(IVW OR=1.084,95%CI:1.021-1.151,P=0.008)and wet AMD phenotype(IVW OR=1.113,95%CI:1.047-1.247,P=0.007).Higher genetically predicted albumin concentrations corresponded with reduced AMD risk(IVW OR=0.827,95%CI:0.715-0.957,P=0.013)but increased wet AMD risk(IVW OR=1.229,95%CI:1.036-1.458,P=0.018).Reverse MR analysis revealed that genetically predicted dry AMD exhibited significant association with reduced albumin levels(IVW OR=0.987,95%CI:0.979-0.996,P=0.004),while wet AMD corresponded with decreased total bilirubin(TBIL)and paraoxonase(PON)activity.CONCLUSION:The results offer strong support for a causal link between markers of oxidative stress and the development of AMD,indicating that oxidative processes play a role in driving the disease progression.
基金This study is supported by the National Natural Science Foundation of China (No. 82072127)。
文摘BACKGROUND:This study aims to explore the causal relationship of body weight,body mass index(BMI),and waist circumference (WC) with the risk of cardiac arrest (CA) using two-sample Mendelian randomization (MR).METHODS:Data were summarized using genome-wide association studies (GWAS).Twosample MR analyses were performed using the inverse variance weighting (IVW) method,the weighted median method,and the MR-Egger analysis.Heterogeneity test and sensitivity analysis were performed using Cochran’s Q test and the leave-one-out method,respectively.The Steiger test was used to detect reverse causality.Bayesian model-averaged MR was used to identify the most influential risk factors.RESULTS:A total of 13 GWAS data were collected for BMI,body weight and WC.IVW analyses showed a positive correlation of body weight,BMI,and WC with CA (all OR>1 and P<0.05),with MR-Egger and weighted median methods confirming the IVW findings.No horizontal pleiotropy or heterogeneity was observed.Sensitivity analysis indicated that no single nucleotide polymorphism(SNP) caused significant changes in overall causality.Bayesian model-averaged MR was also used to rank causality based on marginal inclusion probability (MIP),and the corresponding modelaveraged causal estimate (MACE) were confirmed,which indicated that WC (GWAS ID:ukb-b-9405)was the highest-ranked risk factor (MIP=0.119,MACE=0.011);its posterior probability was 0.057.A total of 14 sex-specific GWAS data on weight,BMI,and WC were analyzed in relationship with CA,and the MR results showed no significant effects of sex-specific factors.CONCLUSION:Body weight,BMI,and WC are causally associated with an increased risk of CA,with WC identified as the most important risk factor.
基金the Central Guidance for Regional Science and Technology Development Projects(YDZJSX2024B010)Research project of Shanxi Provincial Health Commission(2024067)。
文摘Objective Pneumoconiosis,a lung disease caused by irreversible fibrosis,represents a significant public health burden.This study investigates the causal relationships between gut microbiota,gene methylation,gene expression,protein levels,and pneumoconiosis using a multi-omics approach and Mendelian randomization(MR).Methods We analyzed gut microbiota data from MiBioGen and Esteban et al.to assess their potential causal effects on pneumoconiosis subtypes(asbestosis,silicosis,and inorganic pneumoconiosis)using conventional and summary-data-based MR(SMR).Gene methylation and expression data from Genotype-Tissue Expression and eQTLGen,along with protein level data from deCODE and UK Biobank Pharma Proteomics Project,were examined in relation to pneumoconiosis data from FinnGen.To validate our findings,we assessed self-measured gut flora from a pneumoconiosis cohort and performed fine mapping,drug prediction,molecular docking,and Phenome-Wide Association Studies to explore relevant phenotypes of key genes.Results Three core gut microorganisms were identified:Romboutsia(OR=0.249)as a protective factor against silicosis,Pasteurellaceae(OR=3.207)and Haemophilus parainfluenzae(OR=2.343)as risk factors for inorganic pneumoconiosis.Additionally,mapping and quantitative trait loci analyses revealed that the genes VIM,STX8,and MIF were significantly associated with pneumoconiosis risk.Conclusions This multi-omics study highlights the associations between gut microbiota and key genes(VIM,STX8,MIF)with pneumoconiosis,offering insights into potential therapeutic targets and personalized treatment strategies.
基金supported by the National Key R&D Program of China(No,2019YFA0112100)the National Natural Science Foundation of China(No.81472073)the Fundamental Research Funds for the Central Universities of Central South University(Grant Number:2022ZZTS0824).
文摘Objective To explore the causality between reproductive traits and risk of psoriasis by using a large Mendelian randomization(MR)study.Methods A two-sample MR study was performed using summarized statistics from the genome-wide association studies(GWAS)conducted in reproductive traits,as well as GWAS data on overall psoriasis,psoriatic arthritis(PsA),and psoriasis vulgaris(PV).Besides univariable MR(UVMR),multivariable MR and two-step MR was used to calculate the independent effects and quantify the proportion mediated by education or body mass index(BMI).Results Genetically predicted early age at first sexual intercourse(AFS)led to an increased risk of overall psoriasis[odds ratio(OR)UVMR:0.54];36.13%of this effect was mediated through BMI and 47.79%through educational attainment.The direct negative casual association between age at first birth(AFB)-PsA was dominant(ORUVMR:0.76),with 49.61%proportion of the mediation due to BMI.The mediating effect was found for BMI on the AFS-PV relationship,which accounted for 26.27%of the proportion.AFS was inversely associated with the risk of overall psoriasis and PV,with considerable mediation by BMI and educational attainment.Conclusion Early AFB may cause a higher risk of PsA,while the AFS-PsA association was fully mediated by BMI.
文摘Objective To clarify the causal relationship between the level of cytoplasmic unactivated mineralocorticoid receptor(MR)and the development of tubulointerstitial nephritis(TIN),and to evaluate the impact of MR on dyslipidemia,particularly secondary hyperlipemia,in patients with diabetic kidney disease.Methods We conducted a two-sample Mendelian randomization study using genome-wide association study(GWAS)summary data.Genetic variants associated with MR levels were selected as exposures,with TIN and lipid profiles[including low-density lipoprotein cholesterol(LDL-C),triglyceride,and high-density lipoprotein cholesterol]as outcomes.A two-step Mendelian randomization approach was used to assess TIN as a mediator,employing inverse variance weighted regression as the primary analysis,supplemented by Mendelian randomization-Egger,weighted median,and sensitivity analyses.Results Cytoplasmic unactivated MR level exhibited a significant causal association with a decreased risk of TIN(OR=0.8598,95%CI[0.7775-0.9508],P<0.001).Although no significant causal relationship was identified between MR level and secondary hyperlipemia,a potential association of cytoplasmic unactivated MR level with lower LDL-C levels was observed(OR=0.9901,95%CI[0.9821-0.9983],P=0.018).Additionally,TIN exhibited causal links with secondary hyperlipemia(OR=1.0016,95%CI[1.0002-1.0029],P=0.020)and elevated LDL-C(OR=1.0111,95%CI[1.0024-1.0199],P=0.012),particularly LDL-C in European males(OR=1.0230,95%CI[1.0103-1.0358],P<0.001).Inverse Mendelian randomization analysis revealed causal relationships between TIN and genetically predicted triglyceride(OR=0.7027,95%CI[0.6189-0.7978],P<0.001),high-density lipoprotein cholesterol(OR=1.1247,95%CI[1.0019-1.2626],P=0.046),and LDL-C(OR=0.8423,95%CI[0.7220-0.9827],P=0.029).Notably,TIN mediated 16.7%of the causal association between MR and LDL-C levels.Conclusions MR plays a critical role in the development of TIN and lipid metabolism,highlighting the potential of MR-antagonists in reducing renal damage and lipid metabolism-associated complications.
基金supported by the National Natural Science Foundation of China(82270626)China Mega-Project for Infectious Diseases(2017ZX10203202,2013ZX10002005)the Project of Beijing Science and Technology Committee(Z191100007619037).
文摘Background:Whether chronic hepatitis B or C virus infection is a risk factor for autoimmune liver diseases(AILDs)remains unclear.This study aimed to investigate the causal relationship between the two disease entities and underlying mechanisms.Methods:Bidirectional Mendelian randomization analysis was performed using genome-wide association study summary statistics for hepatitis B or C virus infection and AILDs in individuals of European ancestry.Statistically significant findings underwent meta-analysis for validation and single-cell RNA-seq were conducted to explore the potential mechanisms.Results:A causal relationship was observed between chronic hepatitis B virus(HBV)infection and an elevated risk of primary biliary cholangitis(PBC).Meta-analysis of all PBC-outcome findings confirmed the association(Odds ratio:1.32,95%confidence interval:1.23–1.42)without a reverse causal effect.Chronic HBV infection was also potentially associated with an increased risk of autoimmune hepatitis,but not with primary sclerosing cholangitis.No causal relationship was found between hepatitis C virus infection and AILDs.Single-cell RNA-seq revealed HLA gene activated in liver and impaired innate immune suppressive function in chronic hepatitis B patients.Conclusion:This study demonstrates a one-way causal association between chronic HBV infection and certain AILDs(PBC and autoimmune hepatitis),but not chronic hepatitis C virus infection.Single-cell transcriptome analysis revealed immune dysfunction caused by chronic HBV infection persists and is difficult to resolve even after HBV clearance,potentially leading to autoimmune hepatic diseases.
基金supported by the National Natural Science Foundation of China(82170375,U23A20395)1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University(ZYGD23021,23HXF-H009)Sichuan Science and Technology Program 2023NSFSC1645。
文摘Background Hypertension is associated with an increased risk of calcific aortic valve stenosis(CAVS).However,the directionality of causation between blood pressure traits and aortic stenosis is unclear,as is the benefit of antihypertensive drugs for CAVS.Methods Using genome-wide association studies(GWAS)summary statistics,we performed bidirectional two-sample univariable mendelian randomization(UVMR)to assess the causal associations of systolic blood pressure(SBP),diastolic blood pressure(DBP),and pulse pressure(PP)with CAVS.Multivariable mendelian randomization(MVMR)was conducted to evaluate the direct effect of hypertension on CAVS,adjusting for confounders.Drug target mendelian randomization(MR)and summary-level MR(SMR)were used to estimate the effects of 12 classes of antihypertensive drugs and their target genes on CAVS risk.Inverse variance weighting was the primary MR method,with sensitivity analyses to validate results.Results UVMR showed SBP,DBP,and PP have causal effects on CAVS,with no significant reverse causality.MVMR confirmed the causality between hypertension and CAVS after adjusting for confounders.Drug-target MR analyses indicated that calcium channel blockers(CCBs),loop diuretics,and thiazide diuretics via SBP lowering exerted protective effects on CAVS risk.SMR analysis showed that the CCBs target gene CACNA2D2 and ARBs target gene AGTR1 were positively associated with CAVS risk,while diuretics target genes SLC12A5 and SLC12A1 were negatively associated with aortic stenosis risk.Conclusions Hypertension has a causal relationship with CAVS.Managing SBP in hypertensive patients with CCBs may prevent CAVS.ARBs might exert protective effects on CAVS independent of blood pressure reduction.The relationship between diuretics and CAVS is complex,with opposite effects through different mechanisms.
文摘Objective Vitamin deficiencies,particularly in vitamins A,B12,and D,are prevalent across populations and contribute significantly to a range of health issues.While these deficiencies are well documented,the underlying etiology remains complex.Recent studies suggest a close link between the gut microbiota and the synthesis,absorption,and metabolism of these vitamins.However,the specific causal relationships between the gut microbiota composition and vitamin deficiencies remain poorly understood.Identifying key bacterial species and understanding their role in vitamin metabolism could provide critical insights for targeted interventions.Methods We conducted a two-sample Mendelian randomization(MR)study to assess the causal relationship between the gut microbiota and vitamin deficiencies(A,B12,D).The genome-wide association study data for vitamin deficiencies were sourced from the FinnGen biobank,and the gut microbiota data were from the MiBioGen consortium.MR analyses included inverse variance-weighted(IVW),MR‒Egger,weighted median,and weighted mode approaches.Sensitivity analyses and reverse causality assessments were performed to ensure robustness and validate the findings.Results After FDR adjustment,vitamin B12 deficiency was associated with the class Verrucomicrobiae,order Verrucomicrobiales,family Verrucomicrobiaceae,and genus Akkermansia.Vitamin A deficiency was associated with the phylum Firmicutes and the genera Fusicatenibacter and Ruminiclostridium 6.Additional associations for vitamin B12 deficiency included the Enterobacteriaceae and Rhodospirillaceae and the genera Coprococcus 2,Lactococcus,and Ruminococcaceae UCG002.Vitamin D deficiency was associated with the genera Allisonella,Eubacterium,and Tyzzerella 3.Lachnospiraceae and Lactococcus were common risk factors for both B12 and D deficiency.Sensitivity analyses confirmed the robustness of the findings against heterogeneity and horizontal pleiotropy,and reverse MR tests indicated no evidence of reverse causality.Conclusions Our findings reveal a possible causal relationship between specific gut microbiota characteristics and vitamin A,B12 and D deficiencies,providing a theoretical basis for addressing these nutritional deficiencies through the modulation of the gut microbiota in the future and laying the groundwork for related interventions.
文摘BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines,which may play critical roles in the pathogenesis of sepsis.This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.METHODS:First,a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and sepsis.A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetical y proxied lipid-modifying therapies on the risk of sepsis,sepsis-related critical care admission,and sepsis-related death.The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines.Finally,enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.RESULTS:Genetically proxied cholesteryl ester transfer protein(CETP) inhibitors were significantly associated with sepsis-related critical care admission(OR=0.84,95% CI [0.74,0.95],P=0.008,) and sepsisrelated death(OR=0.68,95% CI [0.52,0.88],P=0.004).The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines.Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.CONCLUSION:This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death.These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines,influencing the inflammatory response pathway.
