Objective To explore the relationship between the gut microbiome (GM) and psoriasis using a two-sample two-way Mendelian randomization (MR) approach. Methods The forward analysis uses the gut microbiota as the exposure factor, and its genetic data are derived from the genome-wide association study dataset published by the MiBioGen consortium. Psoriasis was used as the outcome variable, and its genetic data were obtained from the UK Biobank. The reverse MR analysis, on the other hand, took psoriasis as the exposure and the specific gut microbiota taxonomic units identified in the forward analysis as the outcome variable. MR analysis was conducted using maximum likelihood, MR Egger regression, weighted median, inverse variance weighting (IVW), and weighted models to study the causal relationship between the gut microbiota and psoriasis. Then, sensitivity analyses including horizontal pleiotropy test, Cochran’s Q test, and leave-one-out analysis were used to evaluate the reliability of the results. Results A total of 51 single nucleotide polymorphisms from 5 fungi were included in the forward study. The forward IVW analysis results showed that, the class Mollicutes [odds ratio (OR)=1.003, 95% confidence interval (CI) (1.001, 1.006), P=0.004], genus Lachnospiraceae FCS020 group [OR=1.003, 95%CI (1.000, 1.006), P=0.041], and phylum Tenericutes [OR=1.003, 95%CI (1.001, 1.006), P=0.004] were causally associated with an increased risk of psoriasis. The family Victivallaceae [OR=0.998, 95%CI (0.997, 1.000), P=0.005] and order Pasteurellales [OR=0.998, 95%CI (0.996, 1.000), P=0.047] were also linked to a decreased risk of psoriasis. The results of the sensitivity analysis were robust. There was no evidence of a reverse causal relationship from psoriasis to the identified bacterial taxa found in the results of reverse MR analysis results. Conclusions The abundance of three species, class Mollicutes, genus Lachnospiraceae and phylum Tenericutes, may increase the risk of psoriasis. The abundance of two species, family Victivallaceae and order Pasteurellales may reduce the risk of psoriasis. These results provide new directions for the prevention and treatment of psoriasis in the future, but further research is needed to explore how the aforementioned microbiome affects the progression of psoriasis.
Objective To analyze whether there is a causal association between psoriasis and Alzheimer disease (AD) by a two-sample two-way Mendelian randomization (MR) method. Methods In the forward study, the single nucleotide polymorphisms (SNPs) associated with psoriasis were obtained from the comprehensive statistical data of the genome-wide association study database as the instrumental variables, and AD as the outcome; in the reverse study, the SNPs associated with AD were taken as instrumental variables, and psoriasis as the outcome. Using two-sample two-way MR analysis, the odds ratio (OR) value and 95% confidence interval (CI) of regression models, namely inverse variance weighted (IVW) method, MR-Egger regression method, weighted median method, simple pattern method, and weighted pattern method, were used to evaluate the causal relationship between psoriasis and AD. Cochran’s Q test was used to assess the heterogeneity of genetic instrumental variables, MR-Egger intercept method was used to test the horizontal pleiotropy of the assessment, “leave-one-out” method was used to assess the sensitivity of a SNP to the effect of causality, and the symmetry of funnel plot was observed to assess bias. Results A total of 19 SNPs associated with psoriasis were included as instrumental variables in the forward study. The IVW analysis of the forward study showed that there was a causal correlation between psoriasis and AD [OR=1.032, 95%CI (1.014, 1.051), P<0.001], and MR-Egger regression method [OR=1.042, 95%CI (1.012, 1.073), P=0.013], weighted median [OR=1.048, 95%CI (1.023, 1.074), P<0.001], and weighted model [OR=1.046, 95%CI (1.020, 1.073), P=0.002] all supported this result. Heterogeneity test (IVW result: Q=13.752, P=0.745; MR-Egger regression result: Q=13.134, P=0.727), MR-Egger intercept method (Egger intercept=–0.004, P=0.442), the results of “leave-one-out” method and funnel plot showed that the results of MR analysis were reliable. A total of 127 AD-related SNPs were included as instrumental variables in the reverse study. In reverse research, there was no evidence to support the AD could increase the risk of psoriasis (P>0.05). Heterogeneity test (IVW result: Q=232.496, P<0.001; MR-Egger regression result: Q=232.119, P<0.001) suggested heterogeneity, but MR-Egger intercept method (Egger intercept=0.003, P=0.652), the results of “leave-one-out” method and funnel plot showed that the results of MR analysis were reliable. Conclusion There is a causal association between psoriasis and AD, and psoriasis may increase the risk of AD.
Objective To investigate the potential causal relationship between specific oral microbiota and peptic ulcer disease (PUD) using a Mendelian randomization (MR) approach. Methods The genome-wide association study (GWAS) data from East Asian populations was utilized to perform a two-sample MR analysis to determine the causal relationship between oral microbiota and PUD. The MR analysis was primarily conducted using the inverse-variance weighted (IVW) method, supplemented by MR-Egger and weighted median methods. Heterogeneity and pleiotropy were assessed, and the leave-one-out method was employed to evaluate the stability of the MR results. Results There was a complex association between specific bacterial genera of the oral microbiota and PUD. Prevotella was found to potentially promote duodenal ulcers while exerting a protective effect against gastric ulcers. Campylobacter and Streptococcus demonstrated differing effects on gastric and duodenal ulcers. Furthermore, Fusobacterium and Haemophilus_A were positively associated with peptic ulcers, suggesting an increased risk of gastroduodenal ulcer development. Conclusion This study explores the causal relationship between oral microbiota and PUD, providing new insights into the prevention and treatment of PUD mediated by oral microbiota.
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.
ObjectiveTo assess the causal relationship between cervical vertebra related disorders and essential hypertension using a bidirectional two-sample Mendelian randomization study approach. MethodsThe research data comes from the genome-wide association study dataset. Four types of cervical vertebra related disorders: cervicalgia, cervical disc disorders, cervical root disorders, injury of nerves and spinal cord at neck level, as well as data on essential hypertension, were selected for the study. Relevant single nucleotide polymorphisms were selected as instrumental variables to assess the causal relationship between cervical vertebra related disorders and essential hypertension mainly by inverse variance weighted model ratio. Cochran's Q test was used to detect heterogeneity, MR-Egger intercept term and MR-PRESSO was used to detect multiplicity, and leave-one-out method was used for sensitivity analysis. ResultsCervicalgia had a positive causal relationship with the essential hypertension (OR=1.01, 95%CI 1.00 to1.02, P=0.019). Essential hypertension had a positive causal relationship with the cervical disc disorders (OR=4.08, 95%CI 1.57 to10.61, P=0.004). There was no significant causal relationship between cervical root disorders, injury of nerves and spinal cord at neck level and essential hypertension. Reliability assessment indicates that the study results were reliable. ConclusionCervicalgia is a risk factor for essential hypertension; Essential hypertension is a risk factor for cervical disc lesions; There is no correlation between cervical root disorders, injury of nerves and spinal cord at neck level and essential hypertension.
Objective To analyze the relationship between neuroticism and gastroesophageal reflux disease (GERD) using the Mendelian randomization (MR) method. Methods Exposure and outcome data were downloaded from the Integrative Epidemiology Unit (IEU) database in August 2023, including summary statistics from genome-wide association studies (GWAS) for neuroticism (n=374 323) and GERD (n=602 604). MR was conducted using the weighted median method, MR-Egger method, inverse variance weighted method, weighted mode method, and simple mode method. The causal relationship between the two was assessed using odds ratio (OR), and sensitivity analyses were performed to ensure the accuracy of the results. ResultsNeuroticism was associated with an increased risk of GERD [OR=1.229, 95%CI (1.186, 1.274), P<0.001]. Similarly, GERD was associated with an increased risk of neuroticism [OR=1.786, 95%CI (1.623, 1.965), P<0.001]. Conclusion There is a bidirectional causal relationship between neuroticism and gastroesophageal reflux disease.
How to accurately identify factors of cancer occurrence and to provide intervention early are the key issues that urgently need to be addressed in cancer prevention and treatment. Mendelian randomization (MR) analysis uses genetic variants as instrument variables for exposures of interest, which compensates the shortcomings of traditional observational studies and clinical trials. This review introduced the current application status of MR analysis in cancer etiology and treatment researches in details, including assessment of cancer risk factors, exploration of cancer treatment targets, and evaluation of drug efficiency and adverse reactions. The scopes and dimensions of cancer etiology and treatment researches are greatly expanded because of various MR designs and abundant high-level omics data. As well, it provides a practical and feasible method for constructing cancer etiology networks and drug targeted databases, which are promising for supporting the development of precision cancer prevention and treatment.
ObjectiveThyroid nodules are an exceptionally common thyroid disorder. Past studies suggested a possible link between thyroid diseases and breast neoplasms. However, few studies have delved into the causal relationship between thyroid nodules and breast neoplasms. This study conducted a Mendelian randomization (MR) analysis to further investigate the causal relationship between them. MethodsThis study was conducted using data sourced from genome-wide association study (GWAS) summary datasets. The study focused on thyroid nodules, benign breast tumors, and malignant breast cancers as the research objects, and relevant single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs). The inverse-variance weighted (IVW) was primarily used to assess the causal relationship between thyroid nodules and breast neoplasms. Cochran’s Q test was employed to detect heterogeneity, while MR-Egger intercept and MR-PRESSO were used to test for pleiotropy. Sensitivity analysis was conducted using the leave-one-out method. ResultsThere was a significant causal relationship between thyroid nodules and malignant neoplasm of breast (OR=0.88, 95%CI 0.83 to 0.95, P<0.01), with no evidence of reverse causality between them (OR=1.01, 95%CI 0.99 to 1.03, P=0.16). No causal relationship was found between thyroid nodules and benign neoplasm of breast, as indicated by both forward MR analysis (OR=0.97, 95%CI 0.89 to 1.06, P=0.51) and reverse MR analysis (OR=0.97, 95%CI 0.92 to 1.04, P=0.40). Sensitivity analyses suggested that the study findings were accurate and reliable. ConclusionThe present study identifies thyroid nodules as a potential protective factor for malignant neoplasm of breast.
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.
ObjectiveTo investigate the potential causal relationship between four types of reproductive behaviors and rheumatoid arthritis (RA), with the goal of establishing a theoretical foundation for clinical prevention and treatment strategies. MethodsPooled gene-wide association study (GWAS) data were obtained from large publicly searchable databases. Four characteristics like menarche, menopause, the age of first pregnancy and the age of last pregnancy, which related to reproductive behavior were selected as the exposure factors and RA as the outcome factors. 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 used to assess the potential causal relationship between the exposure and the disease. Results① The Mendelian randomization analysis utilizing the inverse variance weighted method on two distinct samples revealed a significant negative correlation between the age of first pregnancy and last pregnancy with the risk of RA (OR=0.91, 95%CI 0.85 to 0.98, P=0.011; OR=0.54, 95%CI 0.31 to 0.93, P=0.026). Conversely, no causal relationship was observed between menarche and menopause with RA. Sensitivity analysis confirmed the robustness of the causal relationship, while MR Egger intercept analysis did not identify any potential horizontal pleiotropy (Page of first gestation -RA=0.169, Page of last gestation -RA=0.283). ② Reverse Mendelian randomization analysis revealed a significant positive causal association between RA and the age of first pregnancy, while no causal relationship was observed with the age of last pregnancy (OR=1.07, 95%CI 1.02 to 1.11, P=0.001). ③ Multivariate Mendelian randomization analysis demonstrated that both the age of first pregnancy and last pregnancy in women were inversely associated with the risk of RA (OR=0.88, 95%CI 0.80 to 0.97, P=0.010; OR=0.68, 95%CI 0.48 to 0.97, P=0.033). ④ There existed a negative correlation between the age of pregnancy in women and the risk of developing RA, suggesting a potential protective effect. ConclusionPregnancy age may have a negative causal relationship with the risk of RA, while menarche and menopause have no causal relationship with RA.