ObjectiveTo investigate whether there is a causal relationship between reproductive history (number of children, age at first birth) and the risk of hormone-related cancers (breast, endometrial, and ovarian) in women. MethodsUnivariate and multivariate Mendelian randomization (MR) methods were used to investigate the causal effects of the number of children (childlessness in infertile women and number of children ever born in fertile women) and age at first birth on three hormone-related cancers. The inverse variance weighting method was used for the primary analysis, and sensitivity analyses and reliability tests were used to ensure the reliability of the results. ResultsUnivariate MR showed that infertile women had a higher risk of breast cancer compared with fertile women (OR=1.07, 95%CI 1.05 to 1.09, P<0.001). Multivariate MR showed that among fertile women, after accounting for the effect of age at first birth, higher number of children ever born may be associated with lower risk of breast cancer (OR=0.61, 95%CI 0.43 to 0.85, P<0.01). Neither univariate nor multivariate MR found a causal relationship between age at first birth and hormone-related cancers, and no causal relationship was found between the number of children ever born and endometrial and ovarian cancers; sensitivity analyses and reliability tests demonstrated that the results were unlikely to be affected by heterogeneity and horizontal pleiotropy. ConclusionThe more children a normal woman has, the lower her risk of breast cancer. Infertile women face a higher risk of breast cancer.
ObjectiveTo investigate the causal relationship between 731 kinds of immune cell phenotypes and positive-human epidermal growth factor receptor (HER+), negative-human epidermal growth factor receptor (HER–), negative-human epidermal growth factor receptor 2 (HER2–) breast cancer. MethodsGenome-wide association data using immune cell phenotype and breast cancer were used with inverse variance weighting as the primary analytical method; horizontal pleiotropy was tested using MR-PRESSO and outliers were corrected; in addition, the reliability of the obtained data was verified using Cochran’s Q test, Mendelian randomization (MR)- Egger regression and leave-one-out method were used to verify the reliability of the obtained data. ResultsFor HER+ breast cancer, CD3 on CD39+CD4+T cell [ OR=0.940, 95%CI (0.913, 0.968), P=0.019] was protective factor. For HER– breast cancer, no immune cell phenotype was found to be correlated with it. For HER2– breast cancer, CD3 on CD39+CD4+ T cell [OR=0.951, 95%CI (0.930, 0.973), P=0.014], CD3 on secreting CD4 regulatory T cell [OR=0.949, 95%CI (0.925, 0.974), P=0.023] were protective factors. ConclusionThere is a causal association between certain immune cell phenotypes and breast cancer, which may be predictive markers for early diagnosis of breast cancer and development of new immunotherapies.
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.
Objective To explore the causal association between obstructive sleep apnea (OSA) and venous thromboembolism (VTE). Methods Using the summary statistical data from the FinnGen biological sample library and IEU OpenGWAS database, the relationship between OSA and VTE, including deep vein thrombosis (DVT) and pulmonary embolism, was explored through Mendelian randomization (MR) method, with inverse variance weighted (IVW) as the main analysis method. Results The results of univariate MR analysis using IVW method showed that OSA was associated with VTE and pulmonary embolism (P<0.05), with odds ratios and 95% confidence intervals of 1.204 (1.067, 1.351) and 1.352 (1.179, 1.544), respectively. There was no correlation with DVT (P>0.05). Multivariate MR analysis showed that after adjustment for confounding factors (smoking, diabetes, obesity and cancer), OSA was associated with VTE, DVT and pulmonary embolism (P<0.05), with odds ratios and 95% confidence intervals of 1.168 (1.053, 1.322), 1.247 (1.064, 1.491) and 1.158 (1.021, 1.326), respectively. Conclusion OSA increases the risk of VTE, DVT, and pulmonary embolism.
Objective To analyze the potential causal relationship between sunscreen/ultraviolet protection and the risk of non-Hodgkin lymphoma using a two sample Mendelian randomization (MR) study method. Methods The summary data of genome-wide association study was used to select three types of non-Hodgkin lymphoma, namely diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, T/NK cell lymphoma, and sunscreen/ultraviolet protection highly correlated genetic loci, namely single nucleotide polymorphism (SNP), as instrumental variables. The reverse variance weighting method was used as the main method for MR analysis, MR Egger and MR-PRESO were used to detect level pleiotropy, and leave-one-out method was used for sensitivity analysis to ensure the robustness of the results. Results A total of 132 SNPs were included in the analysis. The results of the inverse variance weighted analysis showed that sunscreen/ultraviolet protection increased the incidence of DLBCL [odds ratio=2.439, 95% confidence interval (1.109, 5.362), P=0.027]. The heterogeneity test results showed that there was no heterogeneity in the causal relationship between sunscreen/ultraviolet protection and DLBCL (P>0.05). The results of the horizontal pleiotropy test showed that SNP did not exhibit horizontal pleiotropy (P>0.05). The leave-one-out method showed that no SNP with a significant impact on the results was found. There was no causal relationship between sunscreen/ultraviolet protection and follicular lymphoma and T/NK cell lymphoma. Conclusion There is a positive causal relationship between sunscreen/ultraviolet protection and the incidence of DLBCL.
Objective To investigate the causal relationship between 91 circulating inflammatory proteins and respiratory tract infection by bidirectional Mendelian randomization. Methods single nucleotide polymorphisms (SNPs) for 91 inflammatory circulating proteins were derived from GWAS data from a genome-wide association study of 14 824 subjects of European ancestry on the Olink Target platform, and SNPs for acute bronchitis, acute bronchiolitis, and acute laryngitis and tracheitis were derived from GWAS pooled data in the FinnGen database. Inverse variance weighting method was used as the main research method to conduct bidirectional Mendelian randomization analysis, and Cochran’ IVW Q test, MR-Egger regression method and one by one elimination method were used to conduct sensitivity tests to evaluate heterogeneity and horizontal pleiotropy. In order to reduce the incidence of Class I errors and improve the feasibility of the study, Bonferroni correction was performed.ResultsLevels of C hemokine C-X-C motif ligand 6 (CXCL6), matrix metalloproteinase-1 (MMP-1), hepatocyte growth factor (HGF), interleukin-10 (IL-10), chemokine C-X3-C motif ligand 1 (CX3CL1), and TNF-related activation-induced cytokine (TRANCE) were causally associated with acute bronchitis. MMP-1 level [OR: 1.239 0, 95%CI: 1.111 6-1.382 2, P<0.000 5] had a significant causal relationship with acute bronchitiss and played a promoting role. Levels of macrophage inflammatory protein-1α (MIP-1α), signaling lymphocyte activating molecules, and FMS-associated tyrosine kinase 3 ligand (FIt3L) were potentially causally associated with acute bronchiolitis. There was a potential causal relationship between C-X-C motif chemokine 5 (CXCL5), T cell surface glycoprotein CD6 subtype (CD6), fibroblast growth factor 19 (FGF-19), C-C motif chemokine 23 (CCL23), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor ligand superfamily member 12 (TNFSF12) levels and acute laryngitis and tracheitis. In reverse Mendelian randomization analysis, there were no positive results between acute bronchitis, acute bronchiolitis and 91 inflammatory factors. Acute laryngitis and tracheitis [OR: 1.076 3,95%CI: 1.012 9-1.143 7, P=0.017 6] were potentially causally associated with FGF-19 levels. Conclusions MMP-1 level have a significant causal relationship with acute bronchitis. The levels of other inflammatory factors such as CXCL6, HGF, MIP-1 alpha, FIt3L, CXCL5, FGF-19 are potentially causally associated with respiratory tract infections. MMP-1 may be an important target for the prediction or treatment of acute bronchitis.
ObjectiveTo investigate the bidirectional causal relationship between metabolic syndrome (MS) and inflammatory bowel disease (IBD) using Mendelian randomization (MR). MethodsWe extracted genetic variants with strong correlations from genome-wide association study data on MS as instrumental variables. Inverse variance weighting, MR-Egger regression methods, and weighted median methods were used to estimate the causal effect of MS and risk of developing IBD. ResultsInverse variance weighting found that genetically predicted MS was associated with an increased risk of developing IBD overall (OR=1.113, 95%CI 1.020 to 1.216, P=0.017) and Crohn's disease (OR=1.195, 95%CI 1.072 to 1.333, P=0.001). And inverse MR analysis found ulcerative colitis was associated with a reduced risk of developing MS (OR=0.969, 95%CI 0.948 to 0.991, P=0.005). ConclusionThe results based on MR analysis suggest that genetically predicted MS is associated with the risk of IBD as a whole and Crohn's disease and ulcerative colitis are associated with a reduced risk of developing MS.
ObjectiveTo analyze the causal relationship between SARS-CoV-2 infection and retinal vascular obstruction by mendelian randomization (MR). MethodsA two-sample MR analysis utilizing summary statistics from genome-wide association studies (GWAS) in European populations was conducted. The GWAS data for SARS-CoV-2 infection comprised cases of common infection (2 597 856), hospitalized infection (2 095 324), and severe infection (1 086 211). Data on retinal vascular obstruction were obtained from the FinnGen database, which included 203 269 cases of retinal artery obstruction and 182 945 cases of retinal vein obstruction (RVO). Inverse variance weighting (IVW), random effects models, weighted median (WM), MR-Egger regression, simple models, and weighted models were used to analyze the bidirectional causal relationship between different SARS-CoV-2 infection phenotypes and retinal obstruction. The Q statistic was used to assess heterogeneity among single nucleotide polymorphisms (SNP), while MR-Presso was utilized to detect SNP outliers, and MR-Egger intercept tests were performed to evaluate horizontal pleiotropy. ResultsThe MR analysis, using IVW, random effects models, MR-Egger, WM, and weighted models, indicated no significant association between common SARS-CoV-2 infection, hospitalized infection, severe infection, and retinal vascular obstruction (P＞0.05). Additionally, retinal vascular obstruction did not show a significant association with the various SARS-CoV-2 infection phenotypes (P＞0.05). In the simple model, a significant association was found between severe SARS-CoV-2 infection and RVO (P＜0.05), as well as between RVO and common SARS-CoV-2 infection (P＜0.05). No heterogeneity was observed in the IVW and MR-Egger analyses (P＞0.05). The MR-Egger test provided no evidence of horizontal pleiotropy (P＞0.05), and MR-Presso detected no outlier SNP. ConclusionThe findings of this study do not support a causal relationship between SARS-CoV-2 infection and the occurrence of retinal vascular obstruction.
Objective To analyze the causal relationship between gut microbiota and tic disorder based on Mendelian randomization (MR). Methods A total of 196 known microbiota (9 phyla, 16 classes, 20 orders, 32 families, and 119 genera) in the human intestinal microbiota dataset downloaded from the MiBioGen database were selected as the exposure factors, and the dataset of tic disorder (finn-b-KRA_PSY_TIC) containing 172 patients and 218620 controls was downloaded from the genome-wide association study database as the outcome variable. Inverse variance weighted was used as the main analysis method, and the causal relationship between gut microbiota and tic disorder was evaluated using odds ratio (OR) and its 95% confidence interval (CI). Horizontal pleiotropy was tested by MR-Egger intercept and MR-PRESSO global test, heterogeneity was assessed by Cochran’s Q test, and sensitivity analysis was performed by leave-one-out method. Results Inverse variance weighted results showed that the Family Rhodospirillaceae [OR=0.398, 95%CI (0.191, 0.831), P=0.014], Order Rhodospirillales [OR=0.349, 95%CI (0.164, 0.743), P=0.006], and Parasutterella [OR=0.392, 95%CI (0.171, 0.898), P=0.027] had negative causal relationships with tic disorder. The Genus Lachnospira [OR=8.784, 95%CI (1.160, 66.496), P=0.035] and Candidatus Soleaferrea [OR=2.572, 95%CI (1.161, 5.695), P=0.020] had positive causal relationships with tic disorder. In addition, MR-Egger intercept and MR-PRESSO global test showed no horizontal pleiotropy, Cochran’s Q test showed no heterogeneity, and leave-one-out sensitivity analysis showed the results were stable. Conclusions A causal relationship exists between gut microbiota and tic disorder. The Family Rhodospirillaceae, Order Rhodospirillales, and Parasutterella are associated with a decreased risk of tic disorder, while the Genus Lachnospira and Candidatus Soleaverea can increase the risk of tic disorder.
Objective To assess any potential associations between lung cancer and gut microbiota. Methods Mendelian randomization (MR) analysis was carried out by utilizing summary data from genome-wide association studies (GWAS) of the gut microbiota and lung cancer. The gut microbiota served as an exposure. Instrumental ariables (IVs) were identified from the GWAS of 18340 participants. The GWAS study of lung cancer from Europe served as an outcome, including 29 266 lung cancer patients and 56450 controls. We used the inverse-variance weighted (IVW) method as the primary analysis. Sensitivity analysis was used to test the reliability of MR analysis results. Results IVW results showed that Genus Parabacteroides (OR=1.258, 95%CI 1.034 to 1.531, P=0.022) and Phylum Bacteroidetes (OR=1.192, 95%CI 1.001 to 1.419, P=0.048) had a positive causal association with lung cancer, and there was a negative causal association between family Bifidobacteriaceae (OR=0.845, 95%CI 0.721 to 0.989, P=0.037) and order Bifidobacteriales (OR=0.865, 95%CI 0.721 to 0.989, P=0.037) with lung cancer. Sensitivity analysis showed no evidence of reverse causality, pleiotropy, and heterogeneity. Conclusion This study demonstrates that Genus Parabacteroides and Phylum Bacteroidetes are related to an increased risk of lung cancer, family Bifidobacteriaceae and order Bifidobacteriales can reduce the risk of lung cancer. Our thorough investigations provide evidence in favor of a potential causal relationship between a number of gut microbiota-taxa and lung cancer. To demonstrate how gut microbiota influences the development of lung cancer, further research is necessary.
