A Causal Study Based On Mendelian Randomization Of Alzheimer’s Disease And Depression

Depression is often associated with Alzheimer’s disease in epidemiological studies,and although large epidemiological survey data show a strong relationship between Alzheimer’s disease and Depression,the causal relationship between the two is unclear due to confounding factors and the influence of reverse causation.In this study,the two-sample Mendelian randomization and colocalization analysis were used to explore the causal relationship between Alzheimer’s disease and Depression from different perspectives.In this study,pooled data on Alzheimer’s disease and Depression from genome-wide association studies were selected from both phenotypes from European populations.Among them,Alzheimer’s disease data came from the International Alzheimer’s Disease Genomics Project(sample size:63926);Depression data are from the MR-Base database and include three datasets:self-reported depression(sample size:462933),extensive depression(sample size:322580),and major depression(sample size:423217).In this study,the possible causal relationship between Alzheimer’s disease and depression was explored through two-way Mendelian randomization analysis of two samples,and the existence of shared causal variants between the two traits was tested by colocalization analysis.For the reliability of the results,Mendelian randomization analysis selected a total of eight methods,mainly the inverse variance weighting method.At the same time,heterogeneity tests,horizontal pleiotropy tests and sensitivity analyses are performed to ensure more robust results.The results of two-sample Mendelian randomization in both directions showed that Alzheimer’s disease was a risk factor for Depression,and the causal effect value of Alzheimer’s disease on self-reported depression was 0.00112(inverse-variance weighting:OR=1.00112;P=0.0351);The causal effect value of Alzheimer’s disease on extensive depression was 0.00346(inverse-variance weighting:OR=1.00347;P=0.0278);The causal effect value of Alzheimer’s disease on major depression was 0.00188(inverse-variance weighting:OR=1.00188;P=0.0025),and the conclusions of the other seven methods were basically consistent with the inverse variance weighting method.The above results suggest that Alzheimer’s has a positive causal effect on Depression,i.e.,people with Alzheimer’s disease have an increased risk of developing Depression than people without Alzheimer’s disease.Results from eight Mendelian randomization methods found no causal effect of Depression on Alzheimer’s disease.In addition,colocalization analysis did not find a genetically shared causal variant site between Alzheimer’s disease and Depression,suggesting that the causal effects found by Mendelian randomization analysis were not caused by the same site important for both Alzheimer’s disease and Depression,complementing the results of Mendelian randomization from another perspective.By innovatively combining Mendelian randomization analysis and colocalization analysis,it is hoped that this study can provide statistical support for further understanding of the pathological mechanism and disease prevention of Alzheimer’s disease and Depression,and provide new ideas and strategies for the study of the etiology of complex traits.