Objective To explore the causal relationship between DNA copy number and the risk of Alzheimer disease (AD) using Mendelian randomization (MR) methods, as well as to investigate the potential mediating effects of immune cells. Methods The data related to 731 immune cell types, DNA copy number and AD from the Genome-Wide Association Study database were collected. A bidirectional MR analysis was conducted to explore the causal relationship between DNA copy number and AD, primarily using the inverse-variance weighted method and MR-Egger method. Additionally, a two-step mediation analysis was performed to identify potential mediating immune cells. Results A total of 134 single-nucleotide polymorphisms were included for bidirectional MR analysis. The MR methods results showed a negative causal relationship between DNA copy number and the risk of AD (P<0.05), while the reverse analysis showed no statistical significance. Sensitivity analysis confirmed the robustness of these results. The mediation analysis indicated that the immune cell phenotype (HVEM on CD45RA-CD4+) partially mediated the causal relationship between DNA copy numbers and the risk of AD, with a mediation effect proportion of 4.6%. Conclusion An increase in DNA copy numbers may reduce the risk of AD, and immune cells partially mediate this causal relationship.
Objective To evaluate the potential causal relationship between asthma and the risk of gastroesophageal reflux disease (GERD) using a two-sample Mendelian randomization study. Methods A large sample of genome-wide association study was used to summarize the data, and the genetic loci [single nucleotide polymorphisms (SNPs)] closely related to asthma were selected as instrumental variables, and Mendelian randomization analysis was conducted by inverse variance weighting, weighted median and MR-Egger method, respectively. At the same time, the multi-effect of MR-Egger was detected and the sensitivity analysis was carried out by Leave-one-out method to ensure the robustness of the results. Results A total of 77 SNPs closely related to asthma were selected as instrumental variables. The results of inverse variance weighted analysis showed a significant positive correlation between asthma and the occurrence of gastroesophageal reflux disease [odds ratio (OR)=1.044, 95% confidence interval (CI) (1.006, 1.083), P=0.024]. Weighted median results showed similar causality [OR=1.075, 95%CI (1.021, 1.133), P=0.006]. The MR-Egger regression results showed that there was a positive correlation between asthma and GERD, but there was no statistical significance [OR=1.080, 95%CI (0.983, 1.187), P=0.115]. The heterogeneity test results showed that there was no heterogeneity in the causal relationship between asthma and GERD (P>0.05). The results of the horizontal pleiotropy test showed that there was no horizontal pleiotropy in SNPs (P>0.05). The results of the retention test showed that no SNPs with significant impact on the results were detected. Conclusion There is a positive causal relationship between asthma and GERD.
Mendelian randomization is a special type of instrumental variable analysis. Its application in the medical field increases in popularity because of its obvious advantages and the rapid development of genomics. This article aimed to introduce the basic concepts, principles, common methods, and limitations of Mendelian randomization. It is expected to provide guidance for researchers to conduct Mendelian randomization studies.
ObjectiveTo identify causal effects and potential mechanisms of oxidative stress (OS) genes in lung cancer. MethodsOS-related genes were extracted from the GeneCards database. Integration analysis of genome-wide association study (GWAS) data for lung cancer with gene expression and DNA methylation quantitative trait loci (eQTL and mQTL) in blood was performed using the summary data-based Mendelian randomization (SMR) approach to determine the causal relationship between OS genes and lung cancer risk. Colocalization analysis of OS gene QTLs and lung cancer risk loci was performed to gain insight into the potential regulatory mechanisms of lung cancer risk. ResultsA potential causal relationship between OS-related genes and lung cancer was identified by SMR analysis. AGER expression level was found to be associated with lung cancer risk [OR=1.944, 95%CI (1.431, 2.640), P<0.001], and ATF6B expression level was associated with lung cancer risk [OR=1.508, 95%CI (1.287, 1.767), P<0.001]. Meanwhile, ATF6B methylation level was associated with lung cancer risk. ConclusionOS-related genes are associated with lung cancer, which may be a potential site of action for anti-cancer drugs.
Objective To analyze the causal relationship between educational attainment and the risk of systemic lupus erythematosus (SLE). Methods Based on the data from publicly available genome-wide association studies, we employed single nucleotide polymorphisms (SNPs) strongly associated with educational attainment as instrumental variables. Two-sample Mendelian randomization analysis was used to investigate the causal relationship between educational attainment and SLE. The primary analysis method used was the inverse variance weighted with multiplicative random effects. Validation methods included inverse variance weighted with fixed effects and MR-Egger methods. Additionally, sensitivity analysis was conducted using the leave-one-out approach. Results Finally, 433 SNPs were included. The inverse variance weighted with multiplicative random effects analysis indicated no causal effect of educational attainment on the risk of SLE [odds ratio =1.111, 95% confidence interval (0.813, 1.518), P=0.509]. Similarly, the other two methods did not find any evidence of a causal relationship (P>0.05); however, significant heterogeneity was observed. The MR-Egger regression analysis provided no evidence of horizontal pleiotropy among the included instrumental variables (P>0.05). The leave-one-out approach did not identify any individual SNP that had a significant impact on the overall effect estimate. ConclusionIn conclusion, this study does not support a causal effect of educational attainment on the risk of SLE.
ObjectiveTo investigate the causal association between metabolic syndrome (MetS) components and osteoarthritis of the knee (KOA) by using Mendelian randomization analysis. MethodsThe genome-wide association study database (GWAS) was mined, in which the exposure factors were MetS components, namely waist circumference (WC) level, triglyceride (TG) level, high-density lipoprotein cholesterol (HDL-C) level, hypertension (HBP), and type 2 diabetes (T2DM), and the outcome factor was KOA. Mendelian randomization analysis was performed using regression models of inverse-variance weighted (IVW), MR-Egger, Simple Mode, Weighted Median, and Weighted Mode methods. ResultsIVW showed a causal relationship between WC level and KOA with a positive correlation (OR=3.088, 95%CI 2.574 to 3.704, P<0.01), and HDL-C level had a causal relationship with KOA with a negative correlation (OR=0.877, 95%CI 0.779 to 0.989, P<0.05). IVW did not show a causal relationship between TG levels, HBP, and T2DM with KOA (P>0.05). The results of the ME-Egger intercept test were not multiplicative (P>0.05), indicating that Mendelian randomization was a valid method for causal inference in this study. ConclusionCentral obesity and low HDL-C disorder are independent risk factors for KOA. The causal relationship between TG level, HBP, and T2DM with KOA is still uncertain.
Randomized controlled trial has been the "gold standard" for clinical trials, in which randomization serves as a fundamental principle of clinical trials and plays an important role in balancing covariates. The allocation probability in traditional design is fixed, while that in adaptive randomization can alter during the experiment according to the specified plan to achieve the purposes of balancing the sample size, maximizing the benefit of patient, or balancing covariates etc. In this study, the adaptive randomization methods applied in clinical trials are discussed to explore their advantages and disadvantages for providing reference for the randomization of clinical trials.
ObjectiveA two-sample Mendelian randomization analysis was used to explore the causal associations between four basic body indices (basal metabolic rate, body fat percentage, BMI and hip circumference) and myasthenia gravis (MG). MethodsPooled gene-wide association study (GWAS) data were obtained from large publicly searchable databases, and four basic body indices were selected as the exposure factors and myasthenia gravis as the outcome factors, and single nucleotide polymorphisms (SNPs), which were strongly correlated with the phenotype of the exposure factors, were screened as the instrumental variables, and two-sample Mendelian randomization analyses were performed in order to assess the potential causal relationship between the exposure and the disease. ResultsInverse variance weighting (IVW) analysis showed that increased basal metabolic rate (OR=1.39, 95%CI 1.00 to 1.93, P=0.047), body fat percentage (OR=1.61, 95%CI 1.06 to 2.44, P=0.024), and hip circumference (OR=1.67, 95%CI 1.29 to 2.17, P<0.001) increased the risk of MG. But there was no significant causal relationship between BMI and MG. ConclusionBasal metabolic rate, body fat percentage and hip circumference have a positive causal relationship with MG, while BMI does not have a significant causal relationship with MG.
ObjectiveTo investigate whether there is a causal relationship between the intake of milk or coffee and the risk of non-alcoholic fatty liver disease (NAFLD). MethodsUsing a two-sample Mendelian randomization approach, single nucleotide polymorphisms (SNPs) associated with milk or coffee intake were used as instrumental variables, and genome-wide association study data on NAFLD were used as the outcome event. Inverse-variance weighted (IVW) and MR-Egger methods were employed to investigate the causal effect of milk or coffee intake on the risk of NAFLD. ResultsBoth analyses indicated no causal association between milk or coffee intake and the risk of NAFLD (P>0.05). Sensitivity analysis indicated the robustness of the main findings, with no outliers, heterogeneity, horizontal pleiotropy, or significant influence of individual SNPs. ConclusionThis study does not support a causal relationship between the intake of milk or coffee and the risk of NAFLD.
Objective To analyze the causal relationship between cerebrospinal fluid (CSF) metabolites and tic disorder (TD) based on two-sample Mendelian randomization (MR). Methods CSF metabolites data from humans were downloaded from genome-wide association study databases, and CSF metabolites were selected as exposure factors. single nucleotide polymorphisms (SNPs) strongly associated with the exposure factors and independent of each other were selected as instrumental variables. The TD dataset from the Finngen database was downloaded, including 365 cases of TD and 411 816 controls. Analysis was conducted using inverse variance weighting, MR-Egger, weighted median, weighted mode, and simple mode. Sensitivity analysis was conducted using leave-one-out, and multiple-effects testing was conducted using MR-Egger and MR-PRESSO. Heterogeneity was detected using Cochran’s Q. Results A total of 9 CSF metabolites were found to have a causal relationship with the occurrence and development of TD (P<0.05), with a total of 394 SNPs included in the analysis. Inverse variance weighting results showed that N-acetylneuraminic acid [odds ratio (OR)=2.715, 95% confidence interval (CI) (1.102, 6.961), P=0.030], γ-glutamylglutamine [OR=1.402, 95%CI (1.053, 1.868), P=0.021], lysine [OR=2.816, 95%CI (1.084, 7.319), P=0.034] could increase the risk of TD. Cysteinylglycine disulfide [OR=0.437, 95%CI (0.216, 0.885), P=0.021], propionylcarnitine [OR=0.762, 95%CI (0.616, 0.941), P=0.012], pantothenate [OR=0.706, 95%CI (0.523, 0.952), P=0.023], gulareic acid [OR=0.758, 95%CI (0.579, 0.992), P=0.044], and cysteine-glycine [OR=0.799, 95%CI (0.684, 0.934), P=0.005] could reduce the risk of TD. The results of leave-one-out sensitivity analysis were stable, and no horizontal pleiotropy or heterogeneity was observed. Conclusions N-acetylneuraminic acid, γ-glutamylglutamine, and lysine can increase the risk of TD, but cysteinylglycine disulfide, propionylcarnitine, pantothenate, gulagic acid and cysteine-glycine can reduce the risk of TD. However, the mechanism of their effects on TD still needs to be further explored.