Socioeconomic traits and the risk of Barrett’s esophagus and gastroesophageal reflux disease: A Mendelian randomization study

BACKGROUND Previous observational studies have shown that the prevalence of gastroesophageal reflux disease(GERD)and Barrett’s esophagus(BE)is associated with socioeconomic status.However,due to the methodological limitations of traditional observational studies,it is challenging to definitively establish causality.AIM To explore the causal relationship between the prevalence of these conditions and socioeconomic status using Mendelian randomization(MR).METHODS We initially screened single nucleotide polymorphisms(SNPs)to serve as proxies for eight socioeconomic status phenotypes for univariate MR analysis.The inverse variance weighted(IVW)method was used as the primary analytical method to estimate the causal relationship between the eight socioeconomic status phenotypes and the risk of GERD and BE.We then collected combinations of SNPs as composite proxies for the eight socioeconomic phenotypes to perform multivariate MR(MVMR)analyses based on the IVW MVMR model.Furthermore,a two-step MR mediation analysis was used to examine the potential mediation of the associations by body mass index,major depressive disorder(MDD),smoking,alcohol consumption,and sleep duration.RESULTS The study identified three socioeconomic statuses that had a significant impact on GERD.These included household income[odds ratio(OR):0.46;95% confidence interval(95%CI):0.31-0.70],education attainment(OR:0.23;95%CI:0.18-0.29),and the Townsend Deprivation Index at recruitment(OR:1.57;95%CI:1.04-2.37).These factors were found to independently and predominantly influence the genetic causal effect of GERD.Furthermore,the mediating effect of educational attainment on GERD was found to be mediated by MDD(proportion mediated:10.83%).Similarly,the effect of educational attainment on BE was mediated by MDD(proportion mediated:10.58%)and the number of cigarettes smoked per day(proportion mediated:3.50%).Additionally,the mediating effect of household income on GERD was observed to be mediated by sleep duration(proportion mediated:9.75%)CONCLUSION This MR study shed light on the link between socioeconomic status and GERD or BE,providing insights for the prevention of esophageal cancer and precancerous lesions.

Immune cell signatures and causal association with irritable bowel syndrome:A mendelian randomization study

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.

Causal associations between gastroesophageal reflux disease and essential hypertension: A bidirectional Mendelian randomization study

BACKGROUND Clinical studies have reported that patients with gastroesophageal reflux disease(GERD)have a higher prevalence of hypertension.AIM To performed a bidirectional Mendelian randomization(MR)analysis to investi-gate the causal link between GERD and essential hypertension.METHODS Eligible single nucleotide polymorphisms(SNPs)were selected,and weighted median,inverse variance weighted(IVW)as well as MR egger(MR-Egger)re-gression were used to examine the potential causal association between GERD and hypertension.The MR-Pleiotropy RESidual Sum and Outlier analysis was used to detect and attempt to reduce horizontal pleiotropy by removing outliers SNPs.The MR-Egger intercept test,Cochran’s Q test and“leave-one-out”sen-sitivity analysis were performed to evaluate the horizontal pleiotropy,heterogen-eities,and stability of single instrumental variable.RESULTS IVW analysis exhibited an increased risk of hypertension(OR=1.46,95%CI:1.33-1.59,P=2.14E-16)in GERD patients.And the same result was obtained in replication practice(OR=1.002,95%CI:1.0008-1.003,P=0.000498).Meanwhile,the IVW analysis showed an increased risk of systolic blood pressure(β=0.78,95%CI:0.11-1.44,P=0.021)and hypertensive heart disease(OR=1.68,95%CI:1.36-2.08,P=0.0000016)in GERD patients.Moreover,we found an decreased risk of Barrett's esophagus(OR=0.91,95%CI:0.83-0.99,P=0.043)in essential hypertension patients.CONCLUSION We found that GERD would increase the risk of essential hypertension,which provided a novel prevent and therapeutic perspectives of essential hypertension.

Genetically predicted fatty liver disease and risk of psychiatric disorders: A mendelian randomization study

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)and alcohol-related liver disease(Ar-LD)constitute the primary forms of chronic liver disease,and their incidence is progressively increasing with changes in lifestyle habits.Earlier studies have do-cumented a correlation between the occurrence and development of prevalent mental disorders and fatty liver.AIM To investigate the correlation between fatty liver and mental disorders,thus ne-cessitating the implementation of a mendelian randomization(MR)study to elu-cidate this association.METHODS Data on NAFLD and ArLD were retrieved from the genome-wide association studies catalog,while information on mental disorders,including Alzheimer's disease,schizophrenia,anxiety disorder,attention deficit hyperactivity disorder(ADHD),bipolar disorder,major depressive disorder,multiple personality dis-order,obsessive-compulsive disorder(OCD),post-traumatic stress disorder(PTSD),and schizophrenia was acquired from the psychiatric genomics consor-tium.A two-sample MR method was applied to investigate mediators in signifi-cant associations.RESULTS After excluding weak instrumental variables,a causal relationship was identified between fatty liver disease and the occurrence and development of some psychia-tric disorders.Specifically,the findings indicated that ArLD was associated with a significantly elevated risk of developing ADHD(OR:5.81,95%CI:5.59-6.03,P<0.01),bipolar disorder(OR:5.73,95%CI:5.42-6.05,P=0.03),OCD(OR:6.42,95%CI:5.60-7.36,P<0.01),and PTSD(OR:5.66,95%CI:5.33-6.01,P<0.01).Meanwhile,NAFLD significantly increased the risk of developing bipolar disorder(OR:55.08,95%CI:3.59-845.51,P<0.01),OCD(OR:61.50,95%CI:6.69-565.45,P<0.01),and PTSD(OR:52.09,95%CI:4.24-639.32,P<0.01).CONCLUSION Associations were found between genetic predisposition to fatty liver disease and an increased risk of a broad range of psychiatric disorders,namely bipolar disorder,OCD,and PTSD,highlighting the significance of preven-tive measures against psychiatric disorders in patients with fatty liver disease.

Risk Factors of Depression Screened by Two-Sample Mendelian Randomization Analysis:A Systematic Review

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.

Two-sample Mendelian randomization analysis of causal relationship between eczema and autoimmune diseases

Objective:The causal relationship between eczema and autoimmune diseases has not been previously reported.This study aims to evaluate the causal relationship between eczema and autoimmune diseases.Methods:The two‐sample Mendelian randomization(MR)method was used to assess the causal effect of eczema on autoimmune diseases.Summary data from the Genome-Wide Association Study Catalog(GWAS)were obtained from the Integrative Epidemiology Unit(IEU)database.For eczema and autoimmune diseases,genetic instrument variants(GIVs)were identified according to the significant difference(P<5×10−8).Causal effect estimates were generated using the inverse‐variance weighted(IVW)method.MR Egger,maximum likelihood,MR-PRESSO,and MR-RAPS methods were used for alternative analyses.Sensitivity tests,including heterogeneity,horizontal pleiotropy,and leave-one-out analyses,were performed.Finally,reverse causality was assessed.Results:Genetic susceptibility to eczema was associated with an increased risk of Crohn’s disease(OR=1.444,95%CI 1.199 to 1.738,P<0.001)and ulcerative colitis(OR=1.002,95%CI 1.001 to 1.003,P=0.002).However,no causal relationship was found for the other 6 autoimmune diseases,including systemic lupus erythematosus(SLE)(OR=0.932,P=0.401),bullous pemphigoid(BP)(OR=1.191,P=0.642),vitiligo(OR=1.000,P=0.327),multiple sclerosis(MS)(OR=1.000,P=0.965),ankylosing spondylitis(AS)(OR=1.001,P=0.121),rheumatoid arthritis(RA)(OR=1.000,P=0.460).Additionally,no reverse causal relationship was found between autoimmune diseases and eczema.Conclusion:Eczema is associated with an increased risk of Crohn’s disease and ulcerative colitis.No causal relationship is found between eczema and SLE,MS,AS,RA,BP,or vitiligo.

Genetic Evidence for Causal Association Between Hypertension and Chronic Pain:A Bidirectional Two-Sample Mendelian Randomization Study

Objective The extent to which the association between hypertension and chronic pain in observational studies is either causally linked or influenced by other shared risk factors has not been substantially addressed.In the present study,Mendelian randomization(MR)was employed to examine the potential causal relationship between hypertension and risk of chronic pain.Methods The study data were derived from the pooled dataset of the genome-wide association study(GWAS),enabling the evaluation of the causal effects of hypertension on various types of chronic pain including chronic headache as well as chest,abdominal,joint,back,limb,and multisite chronic pain.We performed a bidirectional two-sample MR analysis using random effect inverse variance weighting(IVW),MR-Egger,weighted median,and weighted mode,quantified by odds ratio(OR).Results Genetically predicted essential hypertension was associated with an increased risk of chronic headache(OR=1.007,95%CI:1.003-1.011,P=0.002)and limb pain(OR=1.219,95%CI:1.033-1.439,P=0.019).No potential causal associations were identified between chronic pain and essential hypertension in the reverse direction MR(P>0.05).In addition,there was no potential causal association between secondary hypertension and chronic pain(P>0.05).Conclusion This study provided genetic evidence that a unidirectional causal relationship exists between essential hypertension and the increased risks of chronic headache and limb pain,and no causal relationship was found between secondary hypertension and chronic pain.These findings offer theoretical underpinnings for future research on managing hypertension and chronic pain.

Causal association of obesity-related anthropometric traits with myopia and the mediating role of educational attainment:a Mendelian randomization study

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.

Causal relationship between circulating vitamin C and 25-hydroxyvitamin D concentrations and common mental disorders-a Mendelian randomization study

Mental disorders seriously affect people’s health and social stability.This Mendelian randomization(MR)study was designed to investigate the causal relationship between circulating vitamin C(VC)or 25-hydroxyvitamin D(25(OH)D)levels and mental disorders.The data used for the MR analysis were derived from the summary genome-wide association studies(GWAS)database for VC and 25(OH)D and from the Finn Gen consortium for fourteen mental disorders.Based on the inverse variance weighted(IVW)method,we found a potential causal association between circulating VC and anxiety disorders(IVW:OR=1.139,95%CI:1.023-1.269,P=0.018).However,no causal association was found between VC or 25(OH)D and other mental disorders(P>0.05).In the reverse MR analysis,individuals with Alzheimer’s disease was causally associated with higher concentrations of circulating VC(P=0.012),while individuals with anxiety disorders had a negative association between the concentrations of 25(OH)D(P=0.012).However,the current evidence does not support a causal relationship between VC or 25(OH)D and other mental disorders.In addition,there was no causal association between circulating VC and 25(OH)D(P>0.05).Future studies are needed to confirm these findings and to elucidate the mechanisms of potential causality.

Investigating the causal link between gut microbiota and dry age-related macular degeneration:a bidirectional Mendelian randomization study

AIM:To assess the causal link between 211 gut microbiota(GM)taxa and dry age-related macular degeneration(dAMD)risk.METHODS:Mendelian randomization using instrumental factors taken from a genome-wide association study(GWAS)were used.Inverse variance weighted(IVW)analysis and sensitivity analysis were performed on the FinnGen project,which included 5095 cases and 222590 controls.RESULTS:The IVW analysis showed substantial genusand family-level relationships between GM taxa and dAMD risk.Specifically,the family Peptococcaceae(P=0.03),genus Bilophila(P=3.91×10^(-3)),genus Faecalibacterium(P=6.55×10^(-3)),and genus Roseburia(P=0.04)were linked to a higher risk of developing dAMD,while the genus Candidatus Soleaferrea(P=7.75×10^(-4)),genus Desulfovibrio(P=0.04)and genus Eubacterium ventriosum group(P=0.04)exhibited a protective effect against dAMD.No significant causal relationships were observed at higher taxonomic levels.Additionally,in the reverse IVW analysis,no meaningful causal effects of the 7 GM taxa.CONCLUSION:These findings give support for the gutretina axis participation in dAMD and shed light on putative underlying processes.Investigations on the connection between GM and dAMD have not yet revealed the underlying mechanism.

Inflammatory bowel disease and risk of ophthalmic inflammation-related diseases:a two-sample Mendelian randomization study

AIM:To investigate the causal effect of inflammatory bowel disease(IBD)on ocular inflammation using Mendelian randomization(MR)analysis.METHODS:Genetic instruments associated with inflammatory bowel disease(IBD),ulcerative colitis(UC),and Crohn’s disease(CD)were derived from the largest genome-wide association studies(GWAS)published to date.The FinnGen research project was utilized to identify genetic risk variants associated with conjunctivitis,keratitis,iridocyclitis,chorioretinitis,episcleritis,and optic neuritis.All participants were of European ancestry.Three methods which included inverse variance weighting(IVW),weighted median(WM),and MR-Egger regression were performed to estimate the causal association in this study.IVW took the inverse variance of each study as the weight to calculate the weighted average of effect sizes,to summarize the effect sizes of multiple independent studies,which could provide the most precise estimated results.IVW was used as the primary outcome,while WM and MR-Egger were used to improve the estimation of IVW.RESULTS:A nominal causal effect of genetically predicted IBD on risk of non-infectious conjunctivitis,keratitis,iridocyclitis,and optic neuritis,but not on chorioretinitis or episcleritis.After Bonferroni correction,the results showed that genetically predicted UC was significantly associated with an increased risk of iridocyclitis(IVW:OR,1.17;95%CI,1.10-1.24,P=2.54×10^(-7)).CD was significantly associated with conjunctivitis(IVW:OR,1.05;95%CI,1.03-1.08,P=3.20×10^(-5)),keratitis(IVW:OR,1.06;95%CI,1.02-1.09;P=1.13×10^(-3)),and iridocyclitis(IVW:OR,1.09;95%CI,1.04-1.14;P=1.43×10^(-4)).CONCLUSION:IBD causally poses a risk of inflammation of conjunctiva,cornea,Iris-ciliary body complex,and optic neuritis.CD is more closely associated with the eye inflammation than UC.These impliy that the relationship of IBD and different parts of the eye structure are different,and provide novel evidence linking based on the association of the gut-eye axis.

Dissecting Causal Relationships Between Plasma Metabolites and Osteoporosis:A Bidirectional Mendelian Randomization Study

Objective To investigate the causal relationships between plasma metabolites and osteoporosis via Mendelian randomization(MR) analysis.Methods Bidirectional MR was used to analyze pooled data from different genome-wide association studies(GWAS). The causal effect of plasma metabolites on osteoporosis was estimated using the inverse variance weighted method, intersections of statistically significant metabolites obtained from different sources of osteoporosis-related GWAS aggregated data was determined, and then sensitivity analysis was performed on these metabolites. Heterogeneity between single nucleotide polymorphisms was evaluated by Cochran's Q test. Horizontal pleiotropy was assessed through the application of the MR-Egger intercept method and the MRPRESSO method. The causal effect of osteoporosis on plasma metabolites was also evaluated using the inverse variance weighted method. Additionally, pathway analysis was conducted to identify potential metabolic pathways involved in the regulation of osteoporosis.Results Primary analysis and sensitivity analysis showed that 77 and 61 plasma metabolites had a causal relationship with osteoporosis from the GWAS data in the GCST90038656 and GCST90044600 datasets, respectively. Five common metabolites were identified via intersection. X-13684 levels and the glucose-to-maltose ratio were negatively associated with osteoporosis, whereas glycoursodeoxycholate levels and arachidoylcarnitine(C20) levels were positively associated with osteoporosis(all P < 0.05). The relationship between X-11299 levels and osteoporosis showed contradictory results(all P < 0.05). Pathway analysis indicated that glycine, serine, and threonine metabolism, valine, leucine, and isoleucine biosynthesis, galactose metabolism, arginine biosynthesis, and starch and sucrose metabolism pathways were participated in the development of osteoporosis.Conclusion We found a causal relationship between plasma metabolites and osteoporosis. These results offer novel perspectives with important implications for targeted metabolite-focused interventions in the management of osteoporosis.

Serum urate is associated with an increased risk of inflammatory bowel disease: A bidirectional Mendelian randomization study

BACKGROUND Previous studies have indicated bidirectional associations between urate levels and inflammatory bowel disease(IBD),including ulcerative colitis(UC)and Crohn’s disease(CD).However,it remains unclear whether the observations are causal because of confounding factors.AIM To investigate the causal associations between urate levels and IBD using bidirec-tional Mendelian randomization(MR).METHODS Independent genetic variants for urate levels and IBD were selected as instru-mental variables from published genome-wide association studies(GWASs).Summary statistics for instrument-outcome associations were retrieved from three separate databases for IBD(the UK Biobank,the FinnGen database and a large GWAS meta-analysis)and one for urate levels(a large GWAS meta-analysis).MR analyses included the inverse-variance-weighted method,weighted-median estimator,MR-Egger and sensitivity analyses(MR-PRESSO).A meta-analysis was also conducted to merge the data from separate outcome databases using a fixed-effects model.RESULTS Genetically higher serum urate levels were strongly associated with an increased risk of UC[odds ratio(OR):1.95,95%confidence interval(CI):1.86-2.05]after outlier correction,and the ORs(95%CIs)for IBD and CD were 0.94(95%CI:0.86-1.03)and 0.91(95%CI:0.80-1.04),respectively.Animal studies have confirmed the positive association between urate levels and UC.Moreover,genetically predicted IBD was inversely related to urate levels(OR:0.97,95%CI:0.94-0.99).However,no association was observed between genetically influenced UC or CD and urate levels.CONCLUSION Urate levels might be risk factors for UC,whereas genetically predicted IBD was inversely associated with urate levels.These findings provide essential new insight for treating and preventing IBD.

Association of education with cholelithiasis and mediating effects of cardiometabolic factors:A Mendelian randomization study

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.

Causal relationships between gut microbiota and dementia:A twosample,bidirectional,Mendelian randomization study

BACKGROUND Existing evidence suggests that gut microbiota represent a significant environmental risk factor for various forms of dementia,including Alzheimer's dementia,vascular dementia,and dementia in other diseases classified elsewhere.However,the exact causal relationships between gut microbiota and the different forms of dementia or their subtypes remain unclear.AIM To investigate putative causal relationships between gut microbiota and dementia or its subtypes using Mendelian randomization(MR)analysis.METHODS A bidirectional,two-sample,MR analysis was conducted utilizing publicly available gut microbiota-related genome-wide association study(GWAS)summary data from the MiBioGen consortium alongside GWAS summary statistics for dementia and its subtypes from the FinnGen consortium.Instrumental variables were selected according to the fundamental tenets of MR and their strengths were evaluated using the F-statistic.Five MR methods were employed,and the robustness of our findings was validated.To account for multiple comparisons,we applied the Bonferroni method for P-value adjustment.RESULTS We identified several gut microbiota taxa exhibiting putative causal relationships with dementia or its subtypes,potentially serving as risk or protective factors for the disease.In addition,reverse MR analysis indicated that the relative abundance of several gut microbiota taxa might be influenced by dementia or its subtypes.An exhaustive sensitivity analysis confirmed the absence of heterogeneity and horizontal pleiotropy.After applying correction for multiple testing,we observed that the order Bacillales(odds ratio:0.830,95%confidence interval:0.740-0.932,P=0.00155,Padjust=0.0311)exhibited a strong association with Alzheimer’s disease-related dementia.CONCLUSION The results suggest that gut microbiota is causally associated with dementia.Our findings provide novel insights into the pathophysiology of dementia and have important implications for its treatment and prevention.

Mendelian randomization analysis of causal relationship between cheese intake and diabetic retinopathy

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.

Modifiable factors mediating the effects of educational attainment on gestational diabetes mellitus: A two-step Mendelian randomization study

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.

Different effects of 24 dietary intakes on gastroesophageal reflux disease: A mendelian randomization

BACKGROUND In observational studies,dietary intakes are associated with gastroesophageal re-flux disease(GERD).AIM To conduct a two-sample mendelian randomization(MR)analysis to determine whether those associations are causal.METHODS To explore the relationship between dietary intake and the risk of GERD,we extracted appropriate single nucleotide polymorphisms from genome-wide asso-ciation study data on 24 dietary intakes.Three methods were adopted for data analysis:Inverse variance weighting,weighted median methods,and MR-Egger's method.The odds ratio(OR)and 95%confidence interval(CI)were used to eva-luate the causal association between dietary intake and GERD.RESULTS Our univariate Mendelian randomization(UVMR)results showed significant evidence that pork intake(OR,2.83;95%CI:1.76-4.55;P=1.84×10–5),beer intake(OR,2.70,95%CI:2.00-3.64;P=6.54×10–11),non-oily fish intake(OR,2.41;95%CI:1.49-3.91;P=3.59×10–4)have a protective effect on GERD.In addition,dried fruit intake(OR,0.37;95%CI:0.27-0.50;6.27×10–11),red wine intake(OR,0.34;95%CI:0.25-0.47;P=1.90×10-11),cheese intake(OR,0.46;95%CI:0.39-0.55;P=3.73×10-19),bread intake(OR,0.72;95%CI:0.56-0.92;P=0.0009)and cereal intake(OR,0.45;95%CI:0.36-0.57;P=2.07×10-11)were negatively associated with the risk of GERD.There was a suggestive asso-ciation for genetically predicted coffee intake(OR per one SD increase,1.22,95%CI:1.03-1.44;P=0.019).Multi-variate Mendelian randomization further confirmed that dried fruit intake,red wine intake,cheese intake,and cereal intake directly affected GERD.In contrast,the impact of pork intake,beer intake,non-oily fish intake,and bread intake on GERD was partly driven by the common risk factors for GERD.However,after adjusting for all four elements,there was no longer a suggestive association between coffee intake and GERD.CONCLUSION This study provides MR evidence to support the causal relationship between a broad range of dietary intake and GERD,providing new insights for the treatment and prevention of GERD.

Causal association between 25-hydroxyvitamin D status and cataract development:A two-sample Mendelian randomization study

BACKGROUND Vitamin deficiencies are linked to various eye diseases,and the influence of vitamin D on cataract formation has been noted in prior research.However,detailed investigations into the causal relationship between 25-(OH)D status and cataract development remain scarce.AIM To explore a possible causal link between cataracts and vitamin D.METHODS In this study,we explored the causal link between 25-(OH)D levels and cataract development using Mendelian randomization.Our analytical approach included inverse-variance weighting(IVW),MR-Egger,weighted median,simple mode,and weighted mode methods.The primary analyses utilized IVW with random effects,supplemented by sensitivity and heterogeneity tests using both IVW and MR-Egger.MR-Egger was also applied for pleiotropy testing.Additionally,a leave-one-out analysis helped identify potentially impactful single-nucleotide polymorphisms.RESULTS The analysis revealed a positive association between 25-(OH)D levels and the risk of developing cataracts(OR=1.11,95%CI:1.00-1.22;P=0.032).The heterogeneity test revealed that our IVW analysis exhibited minimal heterogeneity(P>0.05),and the pleiotropy test findings confirmed the absence of pleiotropy within our IVW analysis(P>0.05).Furthermore,a search of the human genotype-phenotype association database failed to identify any potentially relevant risk-factor single nucleotide polymorphisms.CONCLUSION There is a potential causal link between 25-(OH)D levels and the development of cataracts,suggesting that greater 25-(OH)D levels may be a contributing risk factor for cataract formation.Further experimental research is required to confirm these findings.

Association between gut microbiota and hepatocellular carcinoma and biliary tract cancer:A mendelian randomization study

BACKGROUND An increasing number of studies have begun to discuss the relationship between gut microbiota and diseases,yet there is currently a lack of corresponding articles describing the association between gut microbiota and hepatocellular carcinoma(HCC)and biliary tract cancer(BTC).This study aims to explore the relationship between them using Mendelian randomization(MR)analysis method.AIM To assess the relationship between gut microbiota and HCC and BTC.METHODS We obtained Genome-wide association study(GWAS)data for the gut microbiome from the intestinal microbiota genomic library(MiBioGen,https://mibiogen.gcc.rug.nl/).Additionally,we accessed data pertaining to HCC and BTC from the IEU open GWAS platform(https://gwas.mrcieu.ac.uk/).Our analysis employed fundamental instrumental variable analysis methods,including inverse-variance weighted,MR and Egger.To ensure the dependability of the results,we subjected the results to tests for multiple biases and heterogeneity.RESULTS During our investigation,we discovered 11 gut microbiota linked to an increased risk to BTC and HCC.The former included the genus Eubacterium hallii group(P=0.017),Candidatus Soleaferrea(P=0.034),Flavonifractor(P=0.021),Lachnospiraceae FCS020(P=0.034),the order Victivallales(P=0.018),and the class Lentisphaeria(P=0.0.18).The latter included the genus Desulfovibrio(P=0.042),Oscillibacter(P=0.023),the family Coriobacteriaceae(P=0.048),the order Coriobacteriales(P=0.048),and the class Coriobacteriia(P=0.048).Furthermore,in BTC,we observed 2 protective gut microbiota namely the genus Dorea(P=0.041)and Lachnospiraceae ND3007 group(P=0.045).All results showed no evidence of multiplicity or heterogeneity.CONCLUSION This study explores a causal link between gut microbiota and HCC and BTC.These insights may enhance the mechanistic knowledge of microbiota-related HCC and BTC pathways,potentially informing therapeutic strategies.