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 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.
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 analyze the causal relationship between the intake of cheese or tea and the risk of gastroesophageal reflux disease (GERD). MethodsUsing a two-sample Mendelian randomization approach, single nucleotide polymorphisms (SNPs) associated with milk or tea intake were used as instrumental variables. The causal effect of milk or tea intake on the risk of GERD was investigated using the MR Egger method, the weighted median method, the inverse-variance weighted (IVW) random-effects model, and the IVW fixed-effects model. Multivariable analysis was conducted using the MR Egger method, and leave-one-out sensitivity analysis was performed to validate the reliability of the data. ResultsCheese intake could reduce the occurrence of GERD [IVW random-effects model β=–1.010, 95%CI (0.265, 0.502), P<0.05], while tea intake could lead to the occurrence of GERD [IVW random-effects model β=0.288, 95%CI (1.062, 1.673), P<0.05]. ConclusionCheese intake may have a positive causal relationship with reducing the risk of GERD occurrence, while tea intake may have a positive causal relationship with increasing the risk of GERD occurrence.
ObjectiveTo investigate the causal relationship between gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA) with its typical symptoms (snoring and daytime sleepiness) by using Mendelian randomization (MR). MethodsThe inverse-variance weighted method was used as the main analysis method to assess the causal effect. Sensitivity and pleiotropy analyses were carried out using leave-one-out and MR-Egger analysis, and then heterogeneity tests were conducted. ResultsIn the MR analysis, genetically predicted GERD was associated with a greater risk of OSA (IVW: OR=1.528, 95%CI 1.374 to 1.699, P=5.315E‒15). Additional MR results were consistent with the IVW results, and no pleiotropy or heterogeneity was found. We also discovered a significant causal relationship between GRED and snoring (IVW: OR=0.959, 95%CI 0.949 to 0.969, P=1.507E‒15), and daytime sleepiness (IVW: OR=1.024, 95%CI 1.021 to 1.036, P=4.580E‒5), with no evidence of pleiotropy. ConclusionThe MR study supports a causal effect between GERD and OSA with its typical symptoms (daytime sleepiness and snoring).
Objective To explore the causal association between radiation exposure and risk of head and neck cancer using Mendelian randomization (MR) method. Methods Genome-wide association studies of radiation exposure and head and neck cancer in the public database IEU OpenGWAS were identified, and single nucleotide polymorphisms (SNPs) were screened as instrumental variables. Two-sample MR analyses were performed using random-effect inverse variance weighted (IVW), fixed-effect IVW, weighted median, and MR-Egger methods to assess the causal association between radiation exposure and risk of head and neck cancer. Outliers were tested using the MR-PRESSO method, and heterogeneity was assessed using the Cochran Q test. MR-Egger regression intercept was utilized to detect gene-level pleiotropy, and a leave-one-out sensitivity analysis was conducted to evaluate the robustness of the study results. Results96 valid SNPs were included as instrumental variables. The analysis results of random-effect IVW method, fixed-effect IVW method, and weighted median method all showed that radiation exposure was associated with an increased risk of head and neck cancer [odds ratio and 95% confidence interval: 1.139 (1.065, 1.218), 1.139 (1.068, 1.215), and 1.141 (1.039, 1.253); P<0.05]. Heterogeneity testing did not reveal significant heterogeneity, MR-Egger regression analysis did not find gene level pleiotropy, and the leave-one-out method did not find a single SNP significantly affecting the overall estimation results. Conclusion Radiation exposure increases the risk of head and neck cancer, but this conclusion still needs further validation in more high-quality, large sample studies.
Objective To evaluate the association between vitamin D levels and polycystic ovarian syndrome (PCOS) by Mendelian randomization (MR) analysis, and assess the role of obesity in this association. Methods Public genome-wide association studies were used to obtain single nucleotide polymorphism (SNP) data of exposure and outcome. Inverse variance weighting (IVW) was used as the main analysis method to analyze the causal relationship between vitamin D level (including total vitamin D level, serum 25-hydroxyvitamin D level) and vitamin D-binding protein level and polycystic ovary syndrome. In addition, multivariate MR method was used to explore the influence of obesity. Results IVW method showed that 25-hydroxyvitamin D was a protective factor for PCOS (OR=0.185, 95%CI 0.058 to 0.585, P=0.004). There was no interference of heterogeneity or horizontal pleiotropy among the data, and the data tended to be stable in general. The remaining total vitamin D levels and vitamin D-binding protein levels did not show an association with PCOS at the genetic level. MVMR analysis adjusted for obesity and BMI in adolescents showed that 25-hydroxyvitamin D was still negatively associated with the risk of PCOS. Conclusion By bidirectional Mendelian randomization analysis, serum 25-hydroxyvitamin D is identified as a protective factor for PCOS, and the increase of serum 25-hydroxyvitamin D level can reduce the risk of PCOS. Obesity does not affect the causal relationship between serum 25-hydroxyvitamin D and PCOS at the genetic level.
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.
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.