A Mendelian Randomization Study On The Causal Association Between Major Depressive Disorder And Common Metabolic Diseases And Digestive System Diseases

Objective:Major depressive disorder（MDD）is a complex and common mental illness that seriously affects the quality of life of patients.In recent years,the prevalence of MDD has gradually increased,and it is often associated with other diseases,including common metabolic diseases and digestive system diseases.Whether MDD is a risk factor for metabolic diseases and digestive system diseases has positive significance for the prevention and treatment of these diseases.Methods:We searched and downloaded the currently publicly available MDD Genome-Wide Association Studies（GWAS）data on the GWAS Catalog and Psychiatric Genomics Consortium platforms with the keyword“major depressive disorder”.In the Linux operating system,we used metal software to conduct meta-analysis on MDD GWAS.The SNPs obtained by the meta-analysis were screened with a P value<5×10^-8 and linkage disequilibrium removed,and the screened SNPs were used as instrumental variables（IVs）in this Mendelian randomization（MR）study.The GWAS data of metabolic diseases and digestive system diseases come from the MR-base platform.In this study,MDD was used to conduct the first exploratory MR analysis and the second confirmatory MR analysis on metabolic diseases and digestive system diseases from different database sources.At the same time,the sensitivity analysis of the effectiveness of IVs and the statistical power of SNPs and MR studies were evaluated.In order to check whether there is a reverse causal relationship between exposure and outcome,we used metabolic diseases and digestive system diseases as exposures and MDD as the outcome to conduct MR analysis to determine whether metabolic diseases and digestive system diseases are MDD risk factors.Result:1.MDD causality assessment for common metabolic diseasesA total of 107 SNPs were screened out as IVs of MDD after meta-analysis.In exploratory analysis,there was a positive causal association between MDD and obesity（P=0.001）,type 2 diabetes（T2D）（P=0.003）,hypertension（HTN）（P=0.038）,hyperlipidemia（P=0.002）,and between MDD and gout（P=0.081）there is no correlation.Among them,the statistical power of MDD and HTN,T2D,hyperlipidemia is 100%,while the statistical power of MDD and gout is only 5%,lack of authenticity.Sensitivity analysis revealed heterogeneity in the analysis of MDD and obesity as well as T2D,but after removal of outlier SNPs,there was still a positive causal association between MDD and T2D.In the confirmatory analysis,this study confirmed the results obtained in the exploratory analysis,MDD and obesity（P<0.001）,T2D（P=0.001）,HTN（P=0.017）,hyperlipidemia（P=0.031）in a positive causal relationship.There was no association between MDD and gout（P=0.892）,but with 47%power,lack of authenticity.2.MDD causal assessment of common digestive system diseasesAt this stage,107 SNPs screened after meta-analysis were used as IVs of MDD.In exploratory analysis,MDD was associated with chronic gastritis（P<0.001）,Helicobacter pylori infection（P<0.001）,hiatal hernia（P<0.001）,irritable bowel syndrome（IBS）（P<0.001）,gastroesophageal reflux disease（GERD）（P<0.001）and esophagitis（P<0.001）showed a positive causal association,and the MR statistical power of MDD and chronic gastritis,GERD and esophagitis reached 100%.Confirmatory analysis results confirmed positive causal associations between MDD and IBS（P=0.004）,GERD（P<0.001）,esophagitis（P=0.027）,with 100%MR statistical power.There was no heterogeneity and horizontal pleiotropy among the IVs used.There was no causal association between MDD and chronic gastritis（P=0.860）,but its MR statistical power was 5%,which was lack of authenticity.During to lack of GWAS data on hiatal hernia and Helicobacter pylori,we were unable to perform a confirmatory analysis.3.Causality assessment of common metabolic diseases on MDDWe took common metabolic diseases as exposure and MDD as outcome to conduct MR analysis of the causal relationship between common metabolic diseases and MDD.The results showed that there was a positive causal association between HTN and MDD（P=0.005）,and the sensitivity analysis showed that there was heterogeneity,but after removing the outlier SNP,the causal association was still significant（P=0.004）,the MR statistical power of the analysis is 100%,indicating the authenticity of the MR analysis results.No causal association was found between other metabolic diseases such as obesity,T2D,hyperlipidemia,gout and MDD.4.Causality assessment of common digestive system diseases on MDDWe took common digestive system diseases as exposure and MDD as outcome to conduct MR analysis of the causal relationship between common digestive system diseases and MDD.Due to the lack of valid digestive system disease IVs,causal inference analysis with digestive system disease as the exposure and MDD as the outcome could not be performed.Conclusion:（1）MDD can increase the risk of HTN,obesity,and hyperlipidemia,and there is a bidirectional causal relationship between MDD and HTN.（2）MDD increases the risk of chronic gastritis,IBS,and hiatal hernia.