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.
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 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.
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 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.
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.
Objective To explore the potential causal relationship between thyroid dysfunction and osteoporosis (OP) through bidirectional two-sample Mendelian randomization (MR) analysis to provide genetic evidence for the risk association between thyroid dysfunction and OP, and provide reference for early prevention and treatment of OP. Methods Causal relationships were estimated based on data from genome-wide association studies for hypothyroidism (n=410141), hyperthyroidism (n=460499), Hashimoto thyroiditis (n=395640), and OP (n=212778). The inverse variance weighted method was used as the main analysis method, and the other four methods were used as the supplementary analysis methods to evaluate the causal effect of thyroid dysfunction and OP. Results The results of inverse variance weighted method showed that hypothyroidism [odds ratio (OR)=1.097, 95% confidence interval (CI) (1.017, 1.183), P=0.017], hyperthyroidism [OR=1.089, 95%CI (1.000, 1.186), P=0.049] and Hashimoto thyroiditis [OR=1.190, 95%CI (1.054, 1.343), P=0.005] were positively correlated with the causal effect of OP. The results of reverse MR analysis did not support that OP would increase the risk of hypothyroidism, hyperthyroidism or Hashimoto thyroiditis (P>0.05). In the bidirectional MR analyses, there was no heterogeneity in Cochran Q detection, MR-Egger intercept test results showed that there was no horizontal pleotropy, and the leave-one-out method analysis results showed that the MR analysis results were reliable. Conclusion Hypothyroidism, hyperthyroidism, and Hashimoto thyroiditis increase the risk of OP, while OP is not found to increase the risk of thyroid dysfunction in reverse studies.
Objective Mendelian randomization (MR) was used to analyze the potential relationship between blood pressure and proliferative diabetic retinopathy (PDR). MethodsTwo-sample MR analysis was performed using summary statistics from genome-wide association studies. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were selected as the exposure, PDR as the outcome. The instrumental variable of SBP and DBP came from the publicly available data of the the UK Medical Research Council Comprehensive Epidemiology Unit and Neale Laboratory; the outcome data (8 681 cases in the case group, 204 208 cases in the control group, European population) are from the FinnGen database. Inverse variance weighting (IVW) and weighted median (WM) were used to analyze the potential relationships between SBP, DBP and PDR. ResultsMR analysis showed that IVW [SBP: odds ratio (OR)=1.36, 95% confidence interval (CI) 1.17-1.57, P=4.22E-05; DBP: OR=1.29, 95%CI 1.11-1.51, P=8.6E-04], WM (SBP: OR=1.33, 95%CI 1.07-1.66, P=0.009; DBP: OR=1.28, 95%CI=1.03-1.59, P=0.002). The results showed that elevated SBP and DBP increased the risk of PDR. ConclusionBlood pressure (SBP, DBP) change is positively correlated with the risk of PDR.
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.
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.