Background Numerous studies have consistently demonstrated that a considerable proportion of patients with major depressive disorder (MDD) frequently exhibit pronounced dyslipidaemia. However, the causal dynamics betw...Background Numerous studies have consistently demonstrated that a considerable proportion of patients with major depressive disorder (MDD) frequently exhibit pronounced dyslipidaemia. However, the causal dynamics between MDD and dyslipidaemia remain elusive.Aims To comprehensively disentangle the genetic causality between MDD and various phenotypes of blood lipids, thereby facilitating the advancement of management strategies for these conditions.Methods We conducted a two-sample univariable Mendelian randomisation (MR) analysis using different models, including the inverse variance weighted (IVW) method and causal analysis using the summary effect (CAUSE) estimates, as well as a multivariable MR analysis. This analysis used summary statistics from genome-wide association studies (GWAS) of MDD and five lipid traits: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, total cholesterol and triglycerides (TG), encompassing 5 237 893 individuals of European and East Asian ancestries. For MDD, a total of 598 701 individuals were included, with 500 199 individuals of European ancestry (Ncase=170 756, Ncontrol=329 443) and 98 502 of East Asian ancestry (Ncase=12 588, Ncontrol=85 914). Lipid data were collected from 4 639 192 individuals through the Global Lipids Genetics Consortium (European, N=4 096 085;East Asian, N=543 107). Next, we used the two-step MR to explore the mediating factors between MDD and TG, and the risk factors affecting TG through MDD. Finally, we conducted a GWAS meta-analysis and enrichment analysis.Results In univariable MR, we observed a negative causal effect of low-density lipoprotein on MDD in both European populations (IVW: odds ratio (OR): 0.972, 95% confidence interval (CI) 0.947 to 0.998, p=0.037) and East Asian populations (IVW: OR: 0.928, 95% CI 0.864 to 0.997, p=0.042). Additionally, we identified a bidirectional causal relationship between TG and MDD, with TG having a causal effect on MDD (IVW: OR: 1.052, 95% CI 1.020 to 1.085, p=0.001) and MDD having a causal effect on TG (IVW: OR: 1.075, 95% CI 1.047 to 1.104, p<0.001). Multivariable MR analysis further supported the role of TG in MDD (OR: 1.205, 95% CI 1.034 to 1.405, p=0.017). CAUSE estimates indicated that the causal model of MDD on TG provided a better fit than the sharing model (p=0.003), while the association of TG on MDD was more likely due to horizontal correlated pleiotropy than causality. Mediation analyses revealed that waist-hip ratio (WHR) mediated 69% of the total causal effect of MDD on TG, while other identified risk factors exhibited lower mediating proportions either mediated through MDD (≤17%) or originating from MDD (≤29%). The GWAS meta-analysis highlighted potential pathways related to lipid processes and nucleosome assembling, with significant cell types identified in brain regions and liver tissues.Conclusions The findings indicate that genetic proxies of MDD are associated with elevated levels of TG, with WHR serving as a clinical indicator of the association. This suggests that interventions targeting WHR may be effective in reducing TG levels in patients with MDD.展开更多
Purpose Systemic inflammation has been increasingly implicated in the pathogenesis of polycystic ovary syndrome(PCOS),but the causal nature and direction of this relationship remain uncertain.This study aimed to evalu...Purpose Systemic inflammation has been increasingly implicated in the pathogenesis of polycystic ovary syndrome(PCOS),but the causal nature and direction of this relationship remain uncertain.This study aimed to evaluate the potential causal associations between circulating inflammatory cytokines and the risk of PCOS using a Mendelian randomisation(MR)approach.Methods We conducted a two-sample MR analysis using summary-level data from large-scale genome-wide association studies involving 91 systemic inflammatory markers(n=14824)and PCOS(10074 cases and 103164 controls)among individuals of European ancestry.Genetic variants associated with cytokines at genome-wide significance(p<5×10^(-8))were selected as instrumental variables.The inverse-variance weighted method was used as the primary analytical strategy,supplemented by sensitivity analyses and correction for multiple testing.Results Genetically predicted higher circulating levels of C-X-C motif chemokine ligand 11(CXCL11)were significantly associated with a reduced risk of PCOS(OR=0.740,95%CI 0.625 to 0.871,p<0.001),and this association remained statistically significant after multiple testing correction(adjusted p=0.030).Nominal associations with decreased PCOS risk were also observed for interleukin-13(IL-13),IL-10 and adenosine deaminase(ADA),but these did not withstand correction for multiple comparisons.No evidence of horizontal pleiotropy was detected,and leave-one-out sensitivity analyses supported the robustness of the findings.Conclusion These results support a potential causal role of systemic inflammation in the development of PCOS,with CXCL11 emerging as a promising inflammatory marker and potential therapeutic target.Further studies are needed to validate these findings and explore their clinical relevance in PCOS management.展开更多
Mendelian randomisation(MR)is a widely used method that employs genetic variants as instrumental variables(IVs,also referred to as genetic instruments below and they represent eligible genetic variants in MR)from geno...Mendelian randomisation(MR)is a widely used method that employs genetic variants as instrumental variables(IVs,also referred to as genetic instruments below and they represent eligible genetic variants in MR)from genome-wide association studies(GWAS)to explore the causative relationship between putative risk factors(ie,exposures)and outcomes.1 According to a Web of Science literature search conducted at the end of 2024,the number of related publications has grown exponentially,reaching 3545 in 2023 and 6607 in 2024(figure 1).Almost simultaneously,we observed a peak of citations from 2019 to 2021,which reflected the popularity and acknowledgement of papers published in these 3 years.However,a decline in citations has been witnessed from 2022 and here are two possible explanations for it:(1)papers published in 2022 or later only have two or fewer years to be cited,and it can lead to fewer citations absolutely;(2)some papers published from 2022 are of low quality and may even be redundant analyses,thus,they are less likely to be cited.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)has emerged as the most prevalent cause of chronic liver disease worldwide affecting over one-third of the adult population.Despite the recent evolution o...Metabolic dysfunction-associated steatotic liver disease(MASLD)has emerged as the most prevalent cause of chronic liver disease worldwide affecting over one-third of the adult population.Despite the recent evolution of new nomenclature and diagnostic criteria for MASLD,progress in drug development for this condition remains limited.This review highlights the potential of drug-target Mendelian randomisation(MR),a study design that leverages human genetics and genomics,for the discovery,repositioning and safety assessment of drug targets in MASLD.We summarised key aspects of designing and appraising a drug-target MR study,discussing its inherent assumptions and considerations for instrument selection.Furthermore,we presented real-world examples from studies in MASLD which focused on opportunities and challenges in identifying novel drug targets,repositing existing drug targets,informing adjunctive treatments and addressing issues in paediatric MASLD.展开更多
Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without...Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without critical thought,we may simply have replaced one set of implausible assumptions(no unmeasured confounding or reverse causation)with another set of implausible assumptions(no pleiotropy or other instrument invalidity).The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables.Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy;in general,a biologically motivated strategy is preferred.In this review,we discuss various ways of implementing a biologically motivated selection strategy:using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels,using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy.In some cases,a genome-wide analysis can provide important complementary evidence,even when its reliability is questionable.In other cases,a biologically-motivated analysis may not be possible.The choice of genetic variants must be informed by biological and functional considerations where possible,requiring collaboration to combine biological and clinical insights with appropriate statistical methodology.展开更多
Background Despite studies confirming that patients with inflammatory bowel disease(IBD)present with dyslipidaemia,the associations between IBD and the serum lipid profile have not been determined.The present study ai...Background Despite studies confirming that patients with inflammatory bowel disease(IBD)present with dyslipidaemia,the associations between IBD and the serum lipid profile have not been determined.The present study aimed to investigate the causal relationship between the serum lipid profile and IBD risk and elucidate the nature of the interactions between them.Methods Two-sample Mendelian randomisation(MR)analysis was performed to investigate the causal links between total cholesterol(TC),total triglyceride(TG),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),apolipoprotein A(Apo A),apolipoprotein B(Apo B)and lipoprotein(a)(Lp(a))and IBD.The study was carried out using the R TwoSampleMR and Mendelian randomisation packages.Results All MR methods,including the weighted median,weighted mode,inverse-variance weighted model,MR-PRESSO,contamination mixture and MR Egger,supported a null causal relationship between TG,TC,HDL-C,LDL-C,Apo A,Apo B and Lp(a)and between IBD,Crohn’s disease and ulcerative colitis.Null causal effects of lipid indices on IBD were validated through independent genome-wide association studies(GWAS),indicating that the findings are robust.Conclusion Our findings suggest that none of the seven lipid indices may be a potential risk factor for the onset of IBD.However,additional research is needed since our MR analyses cannot assess the potential non-linear causal relationship between serum lipids and IBD.展开更多
Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease of the nasal mucosa mediated mainly by immunoglobulin E (IgE) in atopic individuals after exposure to allergens, with the typical symptoms of par...Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease of the nasal mucosa mediated mainly by immunoglobulin E (IgE) in atopic individuals after exposure to allergens, with the typical symptoms of paroxysmal sneezing, watery runny nose, itchy nose and nasal congestion. Mendelian randomization (MR), an innovative epidemiological approach that uses common genetic variants as instrumental variables for exposure, thus enabling prediction of their causal relationship with outcomes, has been widely used in recent years in studies related to AR. This paper provides a review of the method and its progress in the field of allergic rhinitis research.展开更多
Background Although studies in recent years have explored the impact of gut microbiota on various sleep characteristics,the interaction between gut microbiota and insomnia remains unclear.Aims We aimed to evaluate the...Background Although studies in recent years have explored the impact of gut microbiota on various sleep characteristics,the interaction between gut microbiota and insomnia remains unclear.Aims We aimed to evaluate the mutual influences between gut microbiota and insomnia.Methods We conducted Mendelian randomisation(MR)analysis using genome-wide association studies datasets on insomnia(N=386533),gut microbiota data from the MiBioGen alliance(N=18340)and the Dutch Microbiome Project(N=8208).The inverse variance weighted(IVW)technique was selected as the primary approach.Then,Cochrane’s Q,Mendelian randomization-Egger(MR-Egger)and MR Pleiotropy RESidual Sum and Outlier test(MRPRESSO)tests were used to detect heterogeneity and pleiotropy.The leave-one-out method was used to test the stability of the MR results.In addition,we performed the Steiger test to thoroughly verify the causation.Results According to IVW,our results showed that 14 gut bacterial taxa may contribute to the risks of insomnia(odds ratio(OR):1.01 to 1.04),while 8 gut bacterial taxa displayed a protective effect on this condition(OR:0.97 to 0.99).Conversely,reverse MR analysis showed that insomnia may causally decrease the abundance of 7 taxa(OR:0.21 to 0.57)and increase the abundance of 12 taxa(OR:1.65 to 4.43).Notably,the genus Odoribacter showed a significant positive causal relationship after conducting the Steiger test.Cochrane’s Q test indicated no significant heterogeneity between most singlenucleotide polymorphisms.In addition,no significant level of pleiotropy was found according to MR-Egger and MRPRESSO.Conclusions Our study highlighted the reciprocal relationships between gut microbiota and insomnia,which may provide new insights into the treatment and prevention of insomnia.展开更多
Background Metabolic dysregulation has been implicated in major depressive disorder(MDD).Aims We aimed to explore the potential role of plasma metabolites in MDD.Methods We conducted Mendelian randomisation(MR)analysi...Background Metabolic dysregulation has been implicated in major depressive disorder(MDD).Aims We aimed to explore the potential role of plasma metabolites in MDD.Methods We conducted Mendelian randomisation(MR)analysis to evaluate the causal effects of 871 circulating metabolites on MDD,using the Genome-Wide Association Studies datasets of MDD(N=1035760)and metabolites(N=8299).Bayesian colocalisation and druggability analyses were employed to identify genetic variants contributing to both MDD and levels of metabolites in plasma and to pinpoint metabolites with therapeutic potential,respectively.Results MR analysis identified 11 metabolites associated with MDD(false discovery rate<0.05).Eight metabolites,including arachidonate(20:4n6)(odds ratio(OR):0.97),1-arachidonoyl-GPC(20:4n6)(OR:0.98),1-(1-enylpalmitoyl)-2-palmitoleoyl-GPC(P-16:0/16:1)(OR:0.97),succinoyltaurine(OR:0.98),3-methoxycatechol sulphate(1)(OR:0.98)and 11β-hydroxyandrosterone glucuronide(OR:0.97),showed protective effects against MDD.Three metabolites were associated with increased risk,namely,butyrylglycine(OR:1.03),3-carboxy-4-methyl-5-propyl-2-furanpropanoate(OR:1.02)and 1-(1-enyl-stearoyl)-2-oleoyl-GPE(P-18:0/18:1)(OR:1.02).Colocalisation analysis supported shared genetic signals between five lipid metabolites and MDD,particularly at loci harbouring FADS and ATP9A.Notably,a majority of metabolites associated with MDD are being explored as therapeutic targets for various psychiatric disorders.Conclusions Genetically predicted levels of certain circulating metabolites make a causal contribution to MDD.Further investigation of their roles may provide novel pathophysiological insights and give clues for targeted therapies.展开更多
Background:Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterised by a rapid loss of lower and upper motor neurons.As a complex disease,the ageing process and complicated gene-environment...Background:Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterised by a rapid loss of lower and upper motor neurons.As a complex disease,the ageing process and complicated gene-environment interactions are involved in the majority of cases.Main body:Significant advances have been made in unravelling the genetic susceptibility to ALS with massively parallel sequencing technologies,while environmental insults remain a suspected but largely unexplored source of risk.Several studies applying the strategy of Mendelian randomisation have strengthened the link between environmental insults and ALS,but none so far has proved conclusive.We propose a new ALS model which links the current knowledge of genetic factors,ageing and environmental insults.This model provides a mechanism as to how ALS is initiated,with environmental insults playing a critical role.Conclusion:The available evidence has suggested that inherited defect(s)could cause mitochondrial dysfunction,which would establish the primary susceptibility to ALS.Further study of the underlying mechanism may shed light on ALS pathogenesis.Environmental insults are a critical trigger for ALS,particularly in the aged individuals with other toxicant susceptible genes.The identification of ALS triggers could lead to preventive strategies for those individuals at risk.展开更多
基金supported by the National Natural Science Foundation of China(82071500,82271540,32370724,82401759,81871055,32070679)Shanghai Clinical Research Center for Mental Health(19MC1911100)+11 种基金Shanghai Key Laboratory of Psychotic Disorders(13dz2260500)Shanghai Municipal Administrator of Traditional Chinese Medicine(ZY-(2021-2023)-0207-01)Shanghai Municipal Health Commission Collaborative Innovation Group(2024CXJQ03)Shanghai Science and Technology Innovation Action Program(24JS2840400,24ZR1439900,21Y11921100)Shanghai Municipal Science and Technology Major Project,the National Key R&D Program of China(2023YFA0913804,2024YFA0916603,2022FYC2503300)the Program of Shanghai Academic/Technology Research Leader(21XD1423300)Shanghai Pujiang Program(21PJD063)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)Shanghai Municipal Commission of Education(2024AIZD016)the National Key R&D Program of China(2019YFA0905400,2017YFC0908105,2021YFC2702100)National Program for Support of Top-Notch Young Professionals,Taishan Scholar Program of Shandong Province(tstp20240526)the Natural Science Foundation of Shandong Province(ZR2019YQ14,YDZX2021009,2021ZDSYS06).
文摘Background Numerous studies have consistently demonstrated that a considerable proportion of patients with major depressive disorder (MDD) frequently exhibit pronounced dyslipidaemia. However, the causal dynamics between MDD and dyslipidaemia remain elusive.Aims To comprehensively disentangle the genetic causality between MDD and various phenotypes of blood lipids, thereby facilitating the advancement of management strategies for these conditions.Methods We conducted a two-sample univariable Mendelian randomisation (MR) analysis using different models, including the inverse variance weighted (IVW) method and causal analysis using the summary effect (CAUSE) estimates, as well as a multivariable MR analysis. This analysis used summary statistics from genome-wide association studies (GWAS) of MDD and five lipid traits: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, total cholesterol and triglycerides (TG), encompassing 5 237 893 individuals of European and East Asian ancestries. For MDD, a total of 598 701 individuals were included, with 500 199 individuals of European ancestry (Ncase=170 756, Ncontrol=329 443) and 98 502 of East Asian ancestry (Ncase=12 588, Ncontrol=85 914). Lipid data were collected from 4 639 192 individuals through the Global Lipids Genetics Consortium (European, N=4 096 085;East Asian, N=543 107). Next, we used the two-step MR to explore the mediating factors between MDD and TG, and the risk factors affecting TG through MDD. Finally, we conducted a GWAS meta-analysis and enrichment analysis.Results In univariable MR, we observed a negative causal effect of low-density lipoprotein on MDD in both European populations (IVW: odds ratio (OR): 0.972, 95% confidence interval (CI) 0.947 to 0.998, p=0.037) and East Asian populations (IVW: OR: 0.928, 95% CI 0.864 to 0.997, p=0.042). Additionally, we identified a bidirectional causal relationship between TG and MDD, with TG having a causal effect on MDD (IVW: OR: 1.052, 95% CI 1.020 to 1.085, p=0.001) and MDD having a causal effect on TG (IVW: OR: 1.075, 95% CI 1.047 to 1.104, p<0.001). Multivariable MR analysis further supported the role of TG in MDD (OR: 1.205, 95% CI 1.034 to 1.405, p=0.017). CAUSE estimates indicated that the causal model of MDD on TG provided a better fit than the sharing model (p=0.003), while the association of TG on MDD was more likely due to horizontal correlated pleiotropy than causality. Mediation analyses revealed that waist-hip ratio (WHR) mediated 69% of the total causal effect of MDD on TG, while other identified risk factors exhibited lower mediating proportions either mediated through MDD (≤17%) or originating from MDD (≤29%). The GWAS meta-analysis highlighted potential pathways related to lipid processes and nucleosome assembling, with significant cell types identified in brain regions and liver tissues.Conclusions The findings indicate that genetic proxies of MDD are associated with elevated levels of TG, with WHR serving as a clinical indicator of the association. This suggests that interventions targeting WHR may be effective in reducing TG levels in patients with MDD.
基金supported by the Multidisciplinary Clinical Research Innovation Team Project of Beijing Chao-Yang Hospital(grant no.CYDXK202203)。
文摘Purpose Systemic inflammation has been increasingly implicated in the pathogenesis of polycystic ovary syndrome(PCOS),but the causal nature and direction of this relationship remain uncertain.This study aimed to evaluate the potential causal associations between circulating inflammatory cytokines and the risk of PCOS using a Mendelian randomisation(MR)approach.Methods We conducted a two-sample MR analysis using summary-level data from large-scale genome-wide association studies involving 91 systemic inflammatory markers(n=14824)and PCOS(10074 cases and 103164 controls)among individuals of European ancestry.Genetic variants associated with cytokines at genome-wide significance(p<5×10^(-8))were selected as instrumental variables.The inverse-variance weighted method was used as the primary analytical strategy,supplemented by sensitivity analyses and correction for multiple testing.Results Genetically predicted higher circulating levels of C-X-C motif chemokine ligand 11(CXCL11)were significantly associated with a reduced risk of PCOS(OR=0.740,95%CI 0.625 to 0.871,p<0.001),and this association remained statistically significant after multiple testing correction(adjusted p=0.030).Nominal associations with decreased PCOS risk were also observed for interleukin-13(IL-13),IL-10 and adenosine deaminase(ADA),but these did not withstand correction for multiple comparisons.No evidence of horizontal pleiotropy was detected,and leave-one-out sensitivity analyses supported the robustness of the findings.Conclusion These results support a potential causal role of systemic inflammation in the development of PCOS,with CXCL11 emerging as a promising inflammatory marker and potential therapeutic target.Further studies are needed to validate these findings and explore their clinical relevance in PCOS management.
文摘Mendelian randomisation(MR)is a widely used method that employs genetic variants as instrumental variables(IVs,also referred to as genetic instruments below and they represent eligible genetic variants in MR)from genome-wide association studies(GWAS)to explore the causative relationship between putative risk factors(ie,exposures)and outcomes.1 According to a Web of Science literature search conducted at the end of 2024,the number of related publications has grown exponentially,reaching 3545 in 2023 and 6607 in 2024(figure 1).Almost simultaneously,we observed a peak of citations from 2019 to 2021,which reflected the popularity and acknowledgement of papers published in these 3 years.However,a decline in citations has been witnessed from 2022 and here are two possible explanations for it:(1)papers published in 2022 or later only have two or fewer years to be cited,and it can lead to fewer citations absolutely;(2)some papers published from 2022 are of low quality and may even be redundant analyses,thus,they are less likely to be cited.
基金supported by Seed Fund for Basic Science(2302101604),the University of Hong Kong.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)has emerged as the most prevalent cause of chronic liver disease worldwide affecting over one-third of the adult population.Despite the recent evolution of new nomenclature and diagnostic criteria for MASLD,progress in drug development for this condition remains limited.This review highlights the potential of drug-target Mendelian randomisation(MR),a study design that leverages human genetics and genomics,for the discovery,repositioning and safety assessment of drug targets in MASLD.We summarised key aspects of designing and appraising a drug-target MR study,discussing its inherent assumptions and considerations for instrument selection.Furthermore,we presented real-world examples from studies in MASLD which focused on opportunities and challenges in identifying novel drug targets,repositing existing drug targets,informing adjunctive treatments and addressing issues in paediatric MASLD.
基金SB is supported by the Wellcome Trust(225790/Z/22/Z)the United Kingdom Research and Innovation Medical Research Council(MC_UU_00002/7)This research was supported by the National Institute for Health Research Cambridge Biomedical Research Centre(NIHR203312).
文摘Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without critical thought,we may simply have replaced one set of implausible assumptions(no unmeasured confounding or reverse causation)with another set of implausible assumptions(no pleiotropy or other instrument invalidity).The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables.Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy;in general,a biologically motivated strategy is preferred.In this review,we discuss various ways of implementing a biologically motivated selection strategy:using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels,using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy.In some cases,a genome-wide analysis can provide important complementary evidence,even when its reliability is questionable.In other cases,a biologically-motivated analysis may not be possible.The choice of genetic variants must be informed by biological and functional considerations where possible,requiring collaboration to combine biological and clinical insights with appropriate statistical methodology.
基金funded by Department of Science and Technology of Jilin Province(Grant numbers:20200201316JC and YDZJ202201ZYTS121).
文摘Background Despite studies confirming that patients with inflammatory bowel disease(IBD)present with dyslipidaemia,the associations between IBD and the serum lipid profile have not been determined.The present study aimed to investigate the causal relationship between the serum lipid profile and IBD risk and elucidate the nature of the interactions between them.Methods Two-sample Mendelian randomisation(MR)analysis was performed to investigate the causal links between total cholesterol(TC),total triglyceride(TG),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),apolipoprotein A(Apo A),apolipoprotein B(Apo B)and lipoprotein(a)(Lp(a))and IBD.The study was carried out using the R TwoSampleMR and Mendelian randomisation packages.Results All MR methods,including the weighted median,weighted mode,inverse-variance weighted model,MR-PRESSO,contamination mixture and MR Egger,supported a null causal relationship between TG,TC,HDL-C,LDL-C,Apo A,Apo B and Lp(a)and between IBD,Crohn’s disease and ulcerative colitis.Null causal effects of lipid indices on IBD were validated through independent genome-wide association studies(GWAS),indicating that the findings are robust.Conclusion Our findings suggest that none of the seven lipid indices may be a potential risk factor for the onset of IBD.However,additional research is needed since our MR analyses cannot assess the potential non-linear causal relationship between serum lipids and IBD.
文摘Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease of the nasal mucosa mediated mainly by immunoglobulin E (IgE) in atopic individuals after exposure to allergens, with the typical symptoms of paroxysmal sneezing, watery runny nose, itchy nose and nasal congestion. Mendelian randomization (MR), an innovative epidemiological approach that uses common genetic variants as instrumental variables for exposure, thus enabling prediction of their causal relationship with outcomes, has been widely used in recent years in studies related to AR. This paper provides a review of the method and its progress in the field of allergic rhinitis research.
文摘Background Although studies in recent years have explored the impact of gut microbiota on various sleep characteristics,the interaction between gut microbiota and insomnia remains unclear.Aims We aimed to evaluate the mutual influences between gut microbiota and insomnia.Methods We conducted Mendelian randomisation(MR)analysis using genome-wide association studies datasets on insomnia(N=386533),gut microbiota data from the MiBioGen alliance(N=18340)and the Dutch Microbiome Project(N=8208).The inverse variance weighted(IVW)technique was selected as the primary approach.Then,Cochrane’s Q,Mendelian randomization-Egger(MR-Egger)and MR Pleiotropy RESidual Sum and Outlier test(MRPRESSO)tests were used to detect heterogeneity and pleiotropy.The leave-one-out method was used to test the stability of the MR results.In addition,we performed the Steiger test to thoroughly verify the causation.Results According to IVW,our results showed that 14 gut bacterial taxa may contribute to the risks of insomnia(odds ratio(OR):1.01 to 1.04),while 8 gut bacterial taxa displayed a protective effect on this condition(OR:0.97 to 0.99).Conversely,reverse MR analysis showed that insomnia may causally decrease the abundance of 7 taxa(OR:0.21 to 0.57)and increase the abundance of 12 taxa(OR:1.65 to 4.43).Notably,the genus Odoribacter showed a significant positive causal relationship after conducting the Steiger test.Cochrane’s Q test indicated no significant heterogeneity between most singlenucleotide polymorphisms.In addition,no significant level of pleiotropy was found according to MR-Egger and MRPRESSO.Conclusions Our study highlighted the reciprocal relationships between gut microbiota and insomnia,which may provide new insights into the treatment and prevention of insomnia.
文摘Background Metabolic dysregulation has been implicated in major depressive disorder(MDD).Aims We aimed to explore the potential role of plasma metabolites in MDD.Methods We conducted Mendelian randomisation(MR)analysis to evaluate the causal effects of 871 circulating metabolites on MDD,using the Genome-Wide Association Studies datasets of MDD(N=1035760)and metabolites(N=8299).Bayesian colocalisation and druggability analyses were employed to identify genetic variants contributing to both MDD and levels of metabolites in plasma and to pinpoint metabolites with therapeutic potential,respectively.Results MR analysis identified 11 metabolites associated with MDD(false discovery rate<0.05).Eight metabolites,including arachidonate(20:4n6)(odds ratio(OR):0.97),1-arachidonoyl-GPC(20:4n6)(OR:0.98),1-(1-enylpalmitoyl)-2-palmitoleoyl-GPC(P-16:0/16:1)(OR:0.97),succinoyltaurine(OR:0.98),3-methoxycatechol sulphate(1)(OR:0.98)and 11β-hydroxyandrosterone glucuronide(OR:0.97),showed protective effects against MDD.Three metabolites were associated with increased risk,namely,butyrylglycine(OR:1.03),3-carboxy-4-methyl-5-propyl-2-furanpropanoate(OR:1.02)and 1-(1-enyl-stearoyl)-2-oleoyl-GPE(P-18:0/18:1)(OR:1.02).Colocalisation analysis supported shared genetic signals between five lipid metabolites and MDD,particularly at loci harbouring FADS and ATP9A.Notably,a majority of metabolites associated with MDD are being explored as therapeutic targets for various psychiatric disorders.Conclusions Genetically predicted levels of certain circulating metabolites make a causal contribution to MDD.Further investigation of their roles may provide novel pathophysiological insights and give clues for targeted therapies.
文摘Background:Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterised by a rapid loss of lower and upper motor neurons.As a complex disease,the ageing process and complicated gene-environment interactions are involved in the majority of cases.Main body:Significant advances have been made in unravelling the genetic susceptibility to ALS with massively parallel sequencing technologies,while environmental insults remain a suspected but largely unexplored source of risk.Several studies applying the strategy of Mendelian randomisation have strengthened the link between environmental insults and ALS,but none so far has proved conclusive.We propose a new ALS model which links the current knowledge of genetic factors,ageing and environmental insults.This model provides a mechanism as to how ALS is initiated,with environmental insults playing a critical role.Conclusion:The available evidence has suggested that inherited defect(s)could cause mitochondrial dysfunction,which would establish the primary susceptibility to ALS.Further study of the underlying mechanism may shed light on ALS pathogenesis.Environmental insults are a critical trigger for ALS,particularly in the aged individuals with other toxicant susceptible genes.The identification of ALS triggers could lead to preventive strategies for those individuals at risk.
