Two-sample Mendelian Randomization Study Research Articles

Causal effect of gut microbiota on juvenile idiopathic arthritis: A two-sample Mendelian a randomization study.

There is increasing evidence of a significant association between the gut microbiome and juvenile idiopathic arthritis (JIA). However, whether this association is causal remains to be determined. This study was a two-sample Mendelian randomization (MR) study using publicly available genome-wide association study (GWAS) summary data to investigate the causal relationship between the gut microbiome and JIA. We used summary data on gut flora and JIA obtained from genome-wide association studies (GWAS) from MiBioGen and NHGRI-EBI, using inverse variance weighting as the main method to analyse causality in the TSMR causality analysis. To check the stability of the TSMR results, we performed several sensitivity analyses and assessed the presence of reverse causality through a reverse TSMR analysis. We calculated the degree of sample overlap where applicable. The current TSMR analyses identified four bacterial taxa associated with JIA. Specifically, two bacteria, Catenibacterium (p = 2 × 10-2) and Holdemania (p = 4 × 10-2), were negatively associated with the risk of developing JIA, suggesting a protective effect, while Olsenella (p = 1 × 10-2) and Rikenellaceae (RC9gutgroup) (p = 1 × 10-2) were positively associated with the risk of JIA, suggesting that these two bacteria may be risk factors for JIA. However, the results for Catenibacterium and Holdemania should be interpreted with caution due to instability observed in 'leave-one-out' sensitivity analyses. Reverse TSMR analyses found no evidence of reverse causality between JIA and gut flora. Our confirmation of a causal relationship between gut flora and JIA provides an innovative perspective for the study of JIA: targeting and modulating dysregulation of specific bacterial taxa to prevent and treat JIA.

Association Between Serum Galectin-3 and Parkinson's Disease: A Two-Sample Mendelian Randomization Study.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder with poor prognosis. Observational studies have demonstrated a significant correlation between serum galectin-3 and PD, suggesting a potential role of galectin-3 as a biomarker for PD. However, it is still unclear whether galectin-3 contributes to the risk of the disease. A two-sample Mendelian randomization (MR) approach was used in this study. Genetic instruments for serum galectin-3 level were selected from a genome-wide association study (GWAS), including 30,931 European individuals. Summary-level statistics for PD were derived from another published GWAS, including 33,674 cases and 449,056 controls. Primary analysis was conducted using the inverse-variance weighting (IVW) method. Weighted median, MR-Egger, simple mode, weighted mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods were used as complementary analyses. To detect heterogeneity, Cochran's Q statistic and leave-one-out analysis were used. For testing potential horizontal pleiotropy, the MR-Egger intercept test and MR-PRESSO global test were conducted. MR analysis using IVW model (OR 1.112, 95% CI 1.025-1.206, p = 0.010), weighted median (OR 1.135, 95% CI 1.037-1.242, p = 0.006), weighted mode (OR 1.142, 95% CI 1.038-1.257, p = 0.030), and MR-PRESSO (OR 1.112, 95% CI 1.046-1.182, p = 0.012) presented a consistent result, indicating that increased serum galectin-3 was associated with a higher risk of PD. No heterogeneity or horizontal pleiotropy was detected in the analyses. The study shows a suggestive association between galectin-3 and PD. Increasing serum galectin-3 was associated with an increase in PD risk. Galectin-3 may play an important role in the causal pathway to PD.

Association between myopia and diabetic retinopathy: A two-sample mendelian randomization study

ObjectiveThe association between myopia and diabetic retinopathy (DR) is unclear, with inconsistent results reported, and whether the association represents causality remains unknown. This study aimed to investigate the causal associations of genetically determined myopia with DR, and further explore specific mechanisms. MethodsWe conducted two-sample mendelian randomization (MR) analyses of any myopia and high myopia on six DR phenotypes, including any DR, background DR, severe background DR, proliferative DR (PDR), diabetic maculopathy and unspecific DR in the primary study. Mechanism exploration of spherical equivalent refraction (SER), corneal curvature (CC) and axial length (AL) on any DR was carried out subsequently. Single-nucleotide polymorphisms (SNPs), used as genetic instruments, were derived from UK Biobank, Genetic Epidemiology Research on Adult Health and Aging cohort and FinnGen. The inverse variance weighted (IVW) method was mainly used to assess the causality, and was complemented with sensitivity analyses and causality direction analyses. ResultsUsing SNPs that have excluded possible confounders, we discovered suggestive and positive causal associations of any myopia with any DR (IVW: odds ratio [OR] = 1.133, 95% confidence interval [95%CI]: 1.070–1.201, P = 1.91×10−5) and PDR (IVW: OR = 1.182, 95%CI: 1.088–1.285, P = 8.31×10−5). Similar but more significant associations were found of high myopia with any DR and PDR (IVW: OR = 1.107, 95%CI: 1.051–1.166, P = 1.39×10−4; OR = 1.163, 95%CI: 1.088–1.244, P = 8.76×10−6, respectively). Further mechanism analyses found only AL, rather than SER or CC, was strongly and significantly associated with any DR. These associations were robust in sensitivity analyses and causality direction analyses. ConclusionsWe found significant and positive causal associations of any myopia and high myopia with the risk of DR and PDR, which might be related with AL, indicating the significance of myopia control for preventing DR development and progression.

Effects of Body Mass Index on Rapid Kidney Function Decline: A Two-Sample Mendelian Randomization Study

Effects of Body Mass Index on Rapid Kidney Function Decline: A Two-Sample Mendelian Randomization Study

Assessing the causal relationship between gut microbiota and prostate cancer: A two-sample Mendelian randomization study

BackgroundNumerous studies indicate that the gut microbiome is closely associated with prostate cancer (PCa), however, owing to various confounding factors, the causal relationship between gut microbiota and PCa remains unclear. MethodsA 2-sample Mendelian randomization (MR) analysis utilized genome-wide association study (GWAS) data on the gut microbiota of 18,340 participants and GWAS summary statistics on PCa involving 46,3010 participants. Inverse variance weighted (IVW) served as the primary method, complemented by the MR-Egger method, weighted median method (WME), simple mode method (SM), and weighted mode method (WM). Finally, to confirm the robustness of the results, heterogeneity test, pleiotropy test, and leave-one-out sensitivity test were conducted. ResultsIVW analysis revealed that 12 specific gut microbial taxa were potentially causally associated with PCa; the genera Victivallis, Akkermansia, Odoribacter, Butyrivibrio, and the families Enterobacteriaceae, Verrucomicrobiaceae, as well as the orders Verrucomicrobiales, Enterobacteriales and the class Verrucomicrobiae, were found to be positively associated with PCa risk. Conversely, the genera Eubacterium ruminantium group, Candidatus Soleaferrea, and RuminococcaceaeUCG003 were negatively associated with PCa risk. ConclusionsOur MR study's results support a genetically predicted causal relationship between the gut microbiota and PCa, and we identified 12 specific gut microbial taxa. These findings could offer new targets for PCa screening and treatment.

Periodontitis and Hepatocellular Carcinoma: A Two-Sample Mendelian Randomisation Study

Introduction and AimsObservational studies have reported conflicting associations between periodontitis (PD) and hepatocellular carcinoma (HCC). To overcome these limitations, we performed a two-sample Mendelian randomization (MR) analysis to investigate the potential association between PD and HCC. MethodsWe used summary data from genome-wide association studies (GWASs) of European ancestry, integrating data from chronic/acute periodontitis (CP/AP) samples (n1 = 34,615; n2 = 277,036; n3 = 410,811) and HCC samples (n1 = 456,348; n2 = 475,638). The inverse variance-weighted (IVW) approach represents our primary analysis method, supplemented by MR-Egger regression, weighted median, weighted-mode, and simple-mode methods. Pleiotropy and heterogeneity tests were also performed. ResultsIVW analysis suggested that PD had no effect on HCC (Group 1: odds ratio [OR] = 0.912, 95% confidence interval [CI] = 0.690-1.204, P = .514; Group 2: OR = 1.038, 95% CI = 0.895-1.203, P = .623; Group 3: OR = 0.966, 95% CI = 0.851-1.096, P = .591; Group 4: OR = 1.103, 95% CI = 0.576-2.113, P = .768; Group 5: OR = 1.257, 95% CI = 0.511-1.037, P = .540; Group 6: OR = 0.728, 95% CI = 0.511-1.037, P = .079). Four complementary analyses further support this conclusion. Both the IVW and MR-Egger results indicate that the instrumental variables in each group did not exhibit significant pleiotropy. MR-Egger regression analysis showed no evidence of pleiotropic effects. ConclusionOur MR analysis suggests that PD does not significantly impact the risk of developing HCC. These results provide a new perspective on the relationship between these 2 conditions. Clinical RelevanceThis MR study suggests no significant genetic causal relationship between PD and HCC, providing a new perspective. It indicates that clinicians may not need to over-intervene in periodontal disease to prevent liver cancer, thereby avoiding unnecessary psychological burden on patients.

Causal relationship between cancer and immune cell traits: A two-sample mendelian randomization study

BackgroundObservational studies provide evidence of correlations between cancer and the immune system. Previous research has established associations between immune traits and the propensity for developing certain cancers. However, a systematic exploration of these connections remains largely uncharted. Therefore, further investigation is needed to examine the causal association between cancer and immune cell traits using Mendelian randomization (MR) approach. MethodsWe identified genetic instruments for breast cancer (BC), lung cancer (LC), endometrial cancer (EC), ovarian cancer (OC), prostate cancer (PC), and their subtype cancers to investigate their potential causal impact on immune traits. Data on cancer and immune cell traits were obtained from the IEU Open GWAS project. To assess whether these five cancer types and subtype cancers have a causal association with immune cell traits, we conducted two-sample MR analyses. Additionally, we conducted bidirectional MR analyses to examine the direction of causal relationships and adjusted for potentially related pleiotropy through multivariable MR analysis. ResultsWe have identified several causal relationships between different types of cancer and immune traits. We found that breast cancer may influence 49 immune cell traits, endometrial cancer may influence 38, lung cancer may influence 25, ovarian cancer may influence 19, and prostate cancer may influence 28. Among these, breast cancer and lung cancer were associated with four common immune traits: CD25 on IgD− CD38dim, CD25 on sw mem, CD24 on IgD− CD38−, and CD25 on IgD− CD38−. Lung cancer and prostate cancer shared four immune traits: CD25 on IgD+ CD24+, CD25 on IgD+ CD38−, CD66b on CD66b++ myeloid cell, DN (CD4−CD8−) AC. Endometrial cancer and ovarian cancer shared two immune traits: TD DN (CD4−CD8−) %DN, EM DN (CD4−CD8−) %DN. Breast cancer and endometrial cancer shared one immune trait: CD20 on IgD− CD38dim. Endometrial cancer and prostate cancer shared one immune trait: CCR2 on myeloid DC. Lastly, breast cancer, lung cancer, and prostate cancer shared one immune trait: CD25 on CD24+ CD27+. Additionally, we identified specific immune traits that may serve as protective or risk factors for cancers. We found 14 immune traits may influence breast cancer, 9 immune traits may influence endometrial cancer, 22 immune traits may influence lung cancer, 9 immune traits may influence ovarian cancer, and 14 immune traits may influence prostate cancer. Among these, breast cancer and prostate cancer shared three immune traits: HLA DR++ monocyte %monocyte, HLA DR on plasmacytoid DC, and HLA DR on DC. Lung cancer and ovarian cancer shared one immune trait: CD62L− monocyte %monocyte. Prostate cancer and endometrial cancer shared one immune trait: HLA DR on CD33dim HLA DR + CD11b+. Lastly, ovarian cancer and prostate cancer shared one immune trait: CD3 on resting Treg. ConclusionsOur MR study suggests a potential relationship between immune traits and cancers, particularly highlighting 14 immune traits that are simultaneously influenced by two or three of five cancer types, while also indicating that 6 immune traits may simultaneously contribute to the development of two of the cancers. This elucidation enables us to reveal a significant involvement of immune traits in cancer progression, providing critical insights into how immune traits affect cancer susceptibility.

The causal association between epilepsy and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study.

Epilepsy and amyotrophic lateral sclerosis (ALS) are common neurological disorders. The association between the two disorders has been raised in observational studies. However, it is uncertain to what extent they have mutual causal effects. In this study, we aimed to investigate their causal association using a two-sample Mendelian randomization (MR) method. We performed a two-sample bidirectional MR analysis to evaluate the causal association of epilepsy with the risk of ALS. Publicly published genome-wide association study statistics for epilepsy and ALS were used in the study. The primary analysis included genetic variants with a p value of less than 1 × 10-5 as instrumental variables. We applied several alternative methods, including inverse variance weighting, weighted median, simple mode, weighted mode, MR-Egger regression and MR pleiotropy residual sum and outlier, and statistical graphs to assess the associations of epilepsy and its subtype with the risk of ALS. Reverse MR analyses were also performed to examine the association of ALS with the risk of epilepsy. The primary MR analysis found no causal effect of epilepsy on risk of ALS (odds ration [OR]: 1.133, 95% confidence interval [CI]: 0.964-1.332, p=.130). Among subtypes of epilepsy, it also failed to observe any causal association between general epilepsy and ALS (OR: 1.036, 95% CI: 0.969-1.108, P=.300). However, focal epilepsy contributed to an increase in the risk of ALS (OR: 1.177, 95% CI: 1.027-1.348, p=.019). Moreover, the investigation of reverse causalities did not reveal significant results. The current study supports a causal influence of focal epilepsy on ALS risk. Future studies are needed to explore its potential role in ALS.

Causal association between common rheumatic diseases and arrhythmia: a Mendelian randomization study.

Observational studies have suggested a link between rheumatic diseases and arrhythmias. However, these studies have been limited by confounding factors and reverse causality, leaving the causal relationship between rheumatic diseases and arrhythmias uncertain. This study addresses this inquiry using genetic evidence. Selected single nucleotide polymorphisms (SNPs) from genome-wide association study (GWAS) data were employed as instrumental variables. Inverse variance weighting (IVW), MR-Egger regression, and the weighted median method were utilized in the two-sample Mendelian randomization analysis. Horizontal pleiotropy was identified and rectified through the MR-PRESSO test and MR-Egger regression. The stability and reliability of the Mendelian randomization results were appraised using the remain-one method, Cochran Q-test, and funnel plot. Odds ratios (OR) were utilized to assess the causal relationship between six rheumatic diseases and five types of arrhythmias. The Inverse Variance Weighted (IVW) method indicated a significant association between rheumatoid arthritis (RA) and an elevated risk of right bundle branch block (RBBB) (OR: 1.10, 95% CI: 1.02-1.18, p = 0.009). Additionally, gout was significantly correlated with an augmented risk of RBBB (OR: 1.28, 95% CI: 1.09-1.51, p = 0.003). Conversely, dermatomyositis (DM) exhibited a negative association with the risk of atrioventricular block (AVB) (OR: 0.94, 95% CI: 0.90-0.99, p = 0.020). No significant associations were observed between other rheumatic diseases and arrhythmias. A two-sample Mendelian Randomization (MR) study provides data indicating that in European populations, a genetically predicted gout or rheumatoid arthritis (RA) may increase the incidence of right bundle branch block (RBBB). To clarify and investigate the processes behind these causal links, more research is necessary. Because racial genetic variability exists, care should be used when interpreting our findings.

Thyroid Dysfunction and Alopecia Areata: A Genetic Prediction Causality Analysis Study.

Observational studies have suggested a correlation between alopecia areata (AA) and thyroid dysfunction (TD). However, the causal relationship between AA and TD remains uncertain. The purpose of this study is to investigate the causal relationship between these two conditions. Understanding the potential causal relationship between AA and TD is valuable for elucidating the pathogenesis of AA and for designing innovative methods to prevent and treat AA and its related complications. All data for this two-sample Mendelian randomization (MR) study were sourced from public databases. This study selected hypothyroidism, Hashimoto's thyroiditis, hyperthyroidism, subacute thyroiditis, and Graves' disease as exposure factors, with AA as the outcome variable. Data for hypothyroidism, Hashimoto's thyroiditis, hyperthyroidism, subacute thyroiditis, Graves' disease, and AA were obtained from related genome-wide association studies (GWAS). Various MR analysis methods such as inverse variance weighted (IVW), MR-Egger, and weighted median were utilized. Additionally, Cochrane's Q test was used to detect heterogeneity in MR results, and the MR-Egger intercept test and MR pleiotropy residual sum and outlier (MR-PRESSO) test were used to detect horizontal pleiotropy. A leave-one-out analysis was conducted to investigate the sensitivity of this association. We found statistically significant genetic predictions of AA with hypothyroidism, Hashimoto's thyroiditis, and subacute thyroiditis (IVW OR=1.4009815, 95% confidence interval [CI]: 1.1210399-1.750829; p=0.003030698, OR=1.396101, 95% CI: 1.030134-1.89208; p=0.03144273, OR=0.732702, 95% CI: 0.604812-0.887634; p=0.001483368). Furthermore, tests for pleiotropy showed no evidence of pleiotropy, enhancing the credibility of the study results. Finally, the leave-one-out test demonstrated the stability and robustness of this association. This study provides new evidence of a potential genetic link between thyroid issues and AA. By employing the two-sample MR method to eliminate confounding factors and reverse causation, unbiased results were obtained, confirming a causal relationship between hypothyroidism, Hashimoto's thyroiditis, subacute thyroiditis, and AA. This lays the foundation for further mechanistic studies and potential clinical applications. Future research should further explore the specific biological mechanisms between TD and the onset of AA.

Association of Walking Pace and Risk of Stroke: A Two- Sample Mendelian Randomization Study in a European Ancestry Cohort.

Walking pace (WP), a simple physiological indicator, has been found to be strongly associated with a variety of health outcomes in recent years. Among them, the relationship between walking pace and stroke is of particular interest. Given the high morbidity, disability and mortality associated with stroke, identifying modifiable indicators of health, such as walking pace, could help in stroke prevention strategies. However, the causal relationship between WP and stroke risk remains unclear. This study aims to determine the causal relationship between walking pace and risk of stroke using a two-sample Mendelian randomization approach in a European-ancestry population. In order to evaluate the potential for a causal relationship between WP and stroke in people of European heritage, a two-sample Mendelian randomization (MR) study was carried out. Statistics about the association of single nucleotide polymorphisms (SNPs) with stroke were taken from FinnGen (R8) (n = 284,040), while the UK Biobank genome-wide association studies (GWAS) provided the summary data on the association of SNPs with WP (n = 459,915). The inverse-variance weighted (IVW) method was utilised as the primary strategy to examine the causal connection between WP and stroke. Additionally, complementary analyses were conducted using the MR-Egger and weighted median. In order to identify the potential directional pleiotropy and heterogeneity, the MR-Egger intercept test, the MR-PRESSO test, and Cochran's Q statistic were all carried out. This connection was evaluated using OR with 95% confidence intervals (CIs). A total of 48 SNPs were identified as valid instrumental variables in our two-sample MR analysis. The result showed that a slower walking pace is associated with a higher risk of stroke (OR = 0.573; 95% CI, 0.383-0.858, P = 0.007). The "leave-one-out" analysis demonstrated that the absence of a single SNP did not affect the robustness of our results. The MR-Egger intercept test indicated that genetic pleiotropy did not introduce bias into the results [intercept = -2.9E-03, SE = 0.008, P = 0.719] and Cochran's Q test revealed no heterogeneity. Therefore, the sensitivity analyses yielded comparable results. Consequently, the results of the sensitivity analyses were consistent. Our MR study revealed that WP is inversely associated with risk of stroke. These results provided evidence that slower WP causally increased the risk of stroke, recommending that patients with lower WP should have a prompt physical examination and targeted interventions to reduce their risk of stroke and enhance their quality of life.

Causal relationship between metabolic syndrome and hidradenitis suppurativa: A two-sample bidirectional Mendelian randomization study.

Observational studies have suggested an association between metabolic syndrome (MetS) and hidradenitis suppurativa (HS), but whether this relationship is causal remains unclear. Elucidating the causal direction could provide insights into disease mechanisms and potential interventions. We performed bidirectional two-sample Mendelian randomization (MR) using summary statistics from genome-wide association studies (GWAS) of MetS and HS. For validation, we replicated the MetS analysis using data from an independent GWAS. We applied multiple MR methods, primarily inverse variance-weighted (IVW) regression, and conducted sensitivity analyses to assess heterogeneity and pleiotropy. The MR analysis demonstrated MetS causally increased HS risk (IVW odds ratio [OR], 1.428 [95% CI, 1.193-1.710]; p < 0.001), with consistent evidence from sensitivity analyses. However, HS did not appear to causally influence MetS risk (IVW OR, 1.008 [95% CI, 0.988-1.028]; p = 0.438). This study provides evidence that MetS causally increases the risk of developing HS. However, we found no evidence for a causal relationship in the reverse direction from HS to MetS. Further research is warranted to elucidate the mechanisms underlying the identified causal association between MetS and subsequent HS development.

Genetically Proxied Antidiabetic Drug Target and Primary Open-Angle Glaucoma: A Mendelian Randomization Study.

Observational studies suggest that antidiabetic drugs may lower POAG risk; while the causal relationship remains unclear. Naturally occurring variation in genes encoding antidiabetics drug targets can be used as proxies to investigate long-term therapeutic effect of these drugs on POAG risk. We performed a two-sample Mendelian randomization study to evaluate the potential effect of antidiabetic drug targets on POAG in Europeans and East Asians. To proxy antidiabetic drugs (ABCC8, PPARG, GLP1R, SLC5A2), we leveraged genetic variants located near or within drug target genes that were associated with HbA1c. The validity of our ancestry-specific genetic instrument was checked with multipul positive control outcomes. Genetic summary statistics of POAG from the International Glaucoma Genetics Consortium, Global Biobank Meta-analysis Initiative, and FinnGen consortia were analyzed for Europeans (38,164 cases and 1,576,179 controls) and East Asians (16,650 cases and 288,833 controls) separately. Inverse-variance weighted random-effects models were used as primary method. MR results provided consistent evidence of a protective effect of ABCC8 inhibition on POAG using data sets from IGG, GBMI, and FinnGen. Genetically predicted one-standard deviation reduction in HbA1c from ABCC8 inhibition were significant associated with lower risk of POAG in Europeans (OR = 0.211, 95% CI: 0.133-0.333; p < 0.001) and East Asians (OR = 0.070, 95% CI: 0.011-0.459; p = 0.0056). The association between genetically predicted ABCC8 inhibition and risk of POAG was mainly mediated through intraocular pressure. No association was found for PPARG, SLC5A2, or GLP1R. Sensitivity analyses supported this observation. We found a protective effect of genetically proxied ABCC8 inhibition on POAG risk in both Europeans and East Asians, highlighting ABCC8 as a promising candidate drug target for POAG, and mechanisms underlying the protective effect should also be investigated.

Ferritin and Iron Levels Inversely Associated With Lymphoma Risk: A Mendelian Randomization Study.

Current knowledge on iron's role in lymphoma development is very limited, with studies yielding inconsistent findings. To address this gap, we conducted a rigorous two-sample mendelian randomization study, aiming to elucidate the potential associations between iron storage and the risk of developing lymphoma. This study leveraged extensive genetic data derived from a comprehensive genome-wide association study (GWAS) comprising 257,953 individuals. The primary objective was to pinpoint single-nucleotide polymorphisms (SNPs) that are significantly associated with iron storage. Subsequently, this genetic information was analyzed in conjunction with summary-level data pertaining to lymphoma cases and controls, sourced from the IEU open GWAS project, which included a sample size of 3,546 lymphoma cases and 487,257 controls. To evaluate the relationship between iron storage and lymphoma risk, an inverse variance-weighted method with random effects was employed, complemented by rigorous sensitivity analyses. Genetic predisposition to high ferritin and serum iron status was causally associated with lower odds of lymphoma. Ferritin exhibited an odds ratio (OR) of 0.777 (95% confidence interval (CI): 0.628 - 0.961, P = 0.020), indicating 22.3% reduced odds of lymphoma associated with a one standard deviation increase in ferritin levels. Similarly, serum iron demonstrated an OR of 0.776 (95% CI: 0.609 - 0.989, P = 0.040), corresponding to 22.4% decreased odds of lymphoma for a one standard deviation increase in serum iron. This study suggests that individuals with genes linked to higher iron storage levels have a lower risk of developing lymphoma, but further research is necessary before making any clinical recommendations.

Evidence for a Causal Relationship between Heart Failure and Cerebral Infarction: A Bidirectional Two-Sample Mendelian Randomization Study

Evidence for a Causal Relationship between Heart Failure and Cerebral Infarction: A Bidirectional Two-Sample Mendelian Randomization Study

Common mental disorders and risk of female infertility: a two-sample Mendelian randomization study.

Female infertility is a global issue that impacts on public health seriously and many mental disorders are observed in infertility groups. To investigate the casual relationship between those, genome-wide association studies summary data of anxiety disorder (n=9,897), broad depression (n=322,580), major depressive disorder (n=480,359 and n=500,199), bipolar disorder (n=51,710), insomnia (n= 462,341), and female infertility (n=126,342) were extracted from the existing datasets and was analyzed through the two-sample mendelian randomization study. The following heterogeneity and sensitivity test were applied to ensure the robustness of results. Based on inverse variance weighted results, major depressive disorder was associated with female infertility (P = 0.0001, odds ratio 1.396, 95 % confidence interval 1.175-1.658). No causal relationship was identified between the other four mental disorders and infertility. was found. Additionally, reverse mendelian randomization did not indicate a causal relationship among these disorders. The early identification and management of anxiety symptoms in women of reproductive age, in conjunction with the effective treatment of major depressive disorder, may be crucial for preserving female fertility.

Causal effect of psoriasis on aortic valve stenosis: a two-sample Mendelian randomization study.

Epidemiological studies have suggested a potential connection between psoriasis and an increased risk of aortic valve stenosis (AS), though the impact of psoriasis on AS progression remains uncertain. The study aims to investigate the causal relationship between psoriasis and AS using Mendelian randomization (MR) analysis, as well as to uncover potential mechanisms underlying this association. A two-sample MR analysis was conducted using publicly available summary statistics from genome-wide association studies (GWAS) of psoriasis and AS. Cis-eQTL and significant genes were identified for each causal single-nucleotide polymorphisms (SNPs), followed by pathway enrichment and protein-protein interaction (PPI) analysis for functional evaluation. Hub genes were pinpointed by Cytospace. The transcriptional profile of AS population was acquired, and interconnected genes networks were clustered using Molecular Complex Detection (MCODE). Our results demonstrate a significant causal relationship between psoriasis and AS, with a genetic predisposition to psoriasis associated with a higher AS risk (odds ratio: 1.46). Pathway and PPI analyses unveiled 15 hub genes, including HLA-C, HLA-B, ISG15, IFIT3, and MX2, along with immune-related pathways linking psoriasis and AS. Moreover, the transcriptional profiling of the AS database highlighted the significant involvement of adaptive immune cells in AS development. Notably, among the 15 hub genes, ISG15, MX2, OAS3, OASL, IFI6, and EPSTI1 exhibited higher expression in the AS population. Our study provides compelling evidence supporting a causal relationship between psoriasis and AS. Furthermore, the identified hub genes and immune-related pathways may play an important role in the development of both diseases.

The relationship between diverticular disease of intestine and cirrhosis: a two-sample mendelian randomization study.

The correlation between diverticular disease of the intestine and cirrhosis is well-established, however, the presence of a genetic causal link between the two conditions remains uncertain. The study employed a two-sample Mendelian randomization approach utilizing the most recent genome-wide association study (GWAS) data to investigate the correlation between diverticulosis and liver cirrhosis. The primary analysis was conducted using the Inverse Variance Weighted (IVW) method, and was further corroborated by an array of statistical techniques including MR-Egger, Weighted Median, Weighted Mode, cML-MA, ConMix, MR-RAPS, and DIVW to ensure robustness and reliability of the findings.Heterogeneity was evaluated using Cochran's Q test, horizontal pleiotropy was assessed through MR-Egger regression, and leave-one-out analyses were performed to validate the causal relationships. The IVW method found that diverticular disease significantly reduces the risk of cirrhosis (OR = 0.849, 95% CI: 0.743-0.971, P = 0.016). All models had P-values < 0.05 and negative β values. MR-Egger regression showed no horizontal pleiotropy (P = 0.215), confirming SNP reliability. Cochran's Q values for IVW and MR-Egger were 57.23 (P = 0.39) and 55.62 (P = 0.41), indicating no heterogeneity. Sensitivity analysis with the leave-one-out method validated the robustness of the results. This research utilizes Mendelian randomization to illustrate the potential protective role of diverticulosis against liver cirrhosis. The results are analyzed through the lenses of gut microbiota and cytokine levels, providing new perspectives that may inform clinical approaches to diagnosis and treatment.

The causal relationship between hydatidiform mole and nutrients: A two-sample Mendelian randomization study

BackgroundHydatidiform mole (HM), a subset of gestational trophoblastic disease, is considered precancerous and exhibits geographical variation. The incidence of HM is linked to nutritional factors. This study aimed to investigate the causal relationship between nutrients and HM using a bidirectional two-sample Mendelian randomization (MR) approach. MethodsWe utilized publicly available genome-wide association study data to assess the causal associations between levels of specific vitamins (retinol, vitamins B12, B6, C, D, E, folate, and carotene) and minerals (iron, calcium, and magnesium) with HM. The MR analysis was conducted and reported following the STROBE-MR guidelines, employing MR Egger and inverse variance weighted (IVW) methods to estimate associations, with MR-PRESSO for pleiotropy testing. ResultsThe study revealed vitamin B6 as a significant protective factor against HM (MR-Egger OR: 0.094, 95% CI: 0.011-0.0778, P < 0.05; IVW OR: 0.365, 95% CI: 0.142-0.936, P < 0.05). Folate and magnesium showed suggestive associations with HM, whereas most other nutrients did not exhibit a causal relationship. MR-PRESSO analysis supported the absence of horizontal pleiotropy of vitamin B6. Besides, reverse MR analysis did not reveal a significant causal association between HM and serum nutrient levels, suggesting that differences of nutrients in HM patients may not be directly attributed to the mole. ConclusionThis MR study provides evidence that vitamin B6 may protect against HM, and suggests potential roles for folate and magnesium in HM development, while highlighting the need for further research to confirm these findings.

Thyroid function, physical activity and sedentary behaviour: A bidirectional two-sample Mendelian randomisation study.

The interinfluence of thyroid function and daily physical activity (PA) remains unclear. We examined the causal relationship between genetically proxied thyroid-related traits; hypothyroidism, hyperthyroidism, thyroid stimulating hormone (TSH) and free thyroxine (FT4), and daily PA measures; leisure screen time (LST) and moderate-to-vigorous physical activity (MVPA), using Mendelian randomisation (MR) analysis. We used genome-wide association study (GWAS) data from the ThyroidOmics Consortium and the most comprehensive meta-analysis on PA, comprising data on hypothyroidism (n = 53 423), hyperthyroidism (n = 51 823), TSH within the reference range (n = 54 288), fT4 within the reference range (n = 49 269), LST (n = 526 725), and MVPA (n = 608 595) to conduct a bidirectional two-sample MR analysis. The inverse variance weighted (IVW) method was employed as the primary result. Sensitivity analyses included MR-Egger, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) regression. Similar investigations were conducted in the reverse direction. Finally, we analysed a multivariable MR using body mass index (BMI)-related traits GWAS data. In the primary IVW analysis, an increase in genetically proxied TSH levels significantly increased LST (correlation coefficient (β) = 0.040; 95% confidence interval (CI) = 0.020-0.061, P = 9.776 × 10-5). The multivariable MR analysis indicated that the positive causal effect still existed when considering the influence of BMI (MVMR-IVW: β = 0.042; 95% CI = 0.011-0.073, P = 0.007). Conversely, there was no evidence to suggest that PA impacts thyroid function. The results of this MR analysis suggest that thyroid function influences daily PA. The positive association between TSH and LST is not confounded or mediated by BMI.