Search

Background: Migraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this study to explore whether immune diseases are causally associated with migraine and its subtypes. Methods: We conducted a two-sample bidirectional multivariate Mendelian randomization study. Single-nucleotide polymorphisms (SNP) for six immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), allergic rhinitis (AR), asthma and psoriasis, were used as genetic instrumental variables. Summary statistics for migraine were obtained from 3 databases: the International Headache Genetics Consortium (IHGC), UK Biobank, and FinnGen study. MR analyses were performed per outcome database for each exposure and subsequently meta-analyzed. Reverse MR analysis was performed to determine whether migraine were risk factors for immune diseases. In addition, we conducted a genetic correlation to identify shared genetic variants for these two associations. Results: No significant causal relationship was found between immune diseases and migraine and its subtypes. These results were robust with a series of sensitivity analyses. Using the linkage disequilibrium score regression method (LDSC), we detected no genetic correlation between migraine and immune diseases. Conclusion: The evidence from our study does not support a causal relationship between immune diseases and migraine. The mechanisms underlying the frequent comorbidity of migraine and several immune diseases need to be further elucidated. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is common in patients with autoimmune diseases (ADs); however, the causal associations between ADs and sarcopenia remain unclear. Therefore, this study investigated the causal associations using bi-directional Mendelian randomization analysis. Methods: Exposure-related single-nucleotide polymorphisms (SNPs) were extracted from genome-wide association studies (GWASs). GWAS statistics for common ADs [Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis (PSO), and multiple sclerosis (MS)] and sarcopenia-related traits [hand grip strength (HGS), appendicular fatfree mass (FFM), and walking pace] were obtained from public datasets. Inverse-variance weighting as the main method was used to evaluate the causal effect. Results: Genetically predicted CD had causal effects on whole-body FFM (β = -0.005, p = 0.001), leg FFM (βleft = -0.006, p = 1.8E-4; βright = -0.007, p = 2.0E-4), and arm FFM (βleft = -0.005, p = 0.005; βright = -0.005, p = 0.001), while RA had causal effects on 8 sarcopenia-related traits, namely, HGS (βleft = -2.06, p = 2.8E-38; βright = -2.311, p = 2E-20), whole-body FFM (β = -0.842, p = 4.7E-10), leg FFM (βleft = -0.666, p = 2.6E-6; βright = -0.073, p = 2.1E-3), arm FFM (βleft = -0.63, p = 4.4E-6; βright = -0.736, p = 4.4E-8), and walking pace (β = -1.019, p = 6.2E-14). In the reverse direction, HGS (odds ratio [OR]left = 10.257, p = 3.6E-5; ORright = 16.445, p = 3.7E-7) had causal effects on CD, while HGS (ORleft = 0.994, p = 0.004; ORright = 0.993, p = 1.4E-4), leg FFM (ORleft = 1.003, p = 0.005; ORright = 1.005, p = 1.9E-4), and walking pace (OR = 0.985, p = 5.7E-5) were causally associated with RA. No evidence showed causal associations of UC, SLE, PSO, or MS with sarcopenia-related traits. Conclusion: Our study demonstrated that the genetic susceptibility to CD and RA was associated with high risk of sarcopenia, and some sarcopenia-related traits had causal effects on CD or RA. [ABSTRACT FROM AUTHOR]

Background: Recently, observational studies have reported that gastroesophageal reflux disease (GERD) is commonly associated with irritable bowel syndrome (IBS), but the causal relationship is unclear. Methods: We conducted a two-sample Mendelian randomization study using summary data from genome-wide association studies (GWASs) to explore a causal relationship between GERD (N cases = 129,080) and IBS (N cases = 4,605) of European ancestry. Furthermore, the inverse-variance weighted (IVW) method and a series of sensitivity analyses were used to assess the accuracy and confidence of our results. Results: We found a significant association of GERD with IBS (NSNP = 74; OR: 1.375; 95% CI: 1.164-1.624; p < 0.001). Reverse MR analysis showed no evidence of a causal association for IBS with GERD (NSNP = 6; OR: 0.996; 95% CI: 0.960-1.034; p = 0.845). Conclusion: This study provides evidence that the presence of GERD increases the risk of developing IBS, and it is observed from the reverse MR results that IBS did not increase the risk of GERD. [ABSTRACT FROM AUTHOR]

Aim: Mendelian randomization (MR) analysis has been used in the exploration of the role of gut microbiota (GM) in type 2 diabetes mellitus (T2DM); however, it was limited to the genus level. This study herein aims to investigate the relationship of GM, especially at the species level, with T2DM in order to provide some evidence for further exploration of more specific GM taxa and pathway abundance in T2DM. Methods: This two-sample MR study was based on the summary statistics of GM from the available genome-wide association study (GWAS) meta-analysis conducted by the MiBioGen consortium as well as the Dutch Microbiome Project (DMP), whereas the summary statistics of T2DM were obtained from the FinnGen consortium released data. Inverse variance weighted (IVW), MREgger, strength test (F), and weighted median methods were used to examine the causal association between GM and the onset of T2DM. Cochran’s Q statistics was employed to quantify the heterogeneity of instrumental variables. Bonferroni’s correction was conducted to correct the bias of multiple testing. We also performed reverse causality analysis. Results: The corrected IVW estimates suggested the increased relative abundance of family Oxalobacteraceae (OR = 1.0704) and genus Oxalobacter (OR = 1.0874), respectively, were associated with higher odds of T2DM, while that of species faecis (OR = 0.9460) had a negative relationship with T2DM. The relationships of class Betaproteobacteria, family Lactobacillaceae, species finegoldii, and species longum with T2DM were also significant according to the IVW results (all P < 0.05) Conclusions: GM had a potential causal association with T2DM, especially species faecis, finegoldii, and longum. Further studies are still needed to clarify certain results that are contradictory with previous findings. [ABSTRACT FROM AUTHOR]

To explore the genetic causal association between pulmonary artery hypertension (PAH) and iron status through Mendelian randomization (MR), we conducted MR analysis using publicly available genome‐wide association study (GWAS) summary data. Five indicators related to iron status (serum iron, ferritin, total iron binding capacity (TIBC), soluble transferrin receptor (sTfR), and transferrin saturation) served as exposures, while PAH was the outcome. The genetic causal association between these iron status indicators and PAH was assessed using the inverse variance weighted (IVW) method. Cochran's Q statistic was employed to evaluate heterogeneity. We assessed pleiotropy using MR‐Egger regression and MR‐Presso test. Additionally, we validated our results using the Weighted median, Simple mode, and Weighted mode methods. Based on the IVW method, we found no causal association between iron status (serum iron, ferritin, TIBC, sTfR, and transferrin saturation) and PAH (pβ > 0.05). The Weighted median, Simple mode, and Weighted mode methods showed no potential genetic causal association (pβ > 0.05 in the three analyses). Additionally, no heterogeneity or horizontal pleiotropy was detected in any of the analyses. Our results show that there are no genetic causal association between iron status and PAH. [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin (mTOR) signal pathway plays a crucial role in the development of nonalcoholic fatty liver disease (NAFLD). However, the causal effect of mTOR downstream proteins on NAFLD remains unknown. We conducted a two-sample Mendelian randomization (MR) study to investigate whether the mTOR-dependent circulating proteins, including Eukaryotic Initiation Factor 4E Binding Proteins (eIF4EBPs), Ribosomal Protein S6K kinase 1 (RP-S6K), Eukaryotic Initiation Factor 4E (eIF4E), Eukaryotic Initiation Factor 4A (eIF4A) and Eukaryotic Initiation Factor 4 G (eIF4G), have causal effects on the risk of NAFLD. The causal estimate was evaluated with the inverse-variance weighted (IVW) method in discovery stage and validation stage. The single-nucleotide polymorphisms (SNPs) were selected to genetically predict exposures from Genome-Wide Association Studies (GWAS). Exposures with statistically significant effects in the discovery dataset would be further validated in the validation dataset. MR study revealed that eIF4E had a causal effect on NAFLD in both discovery stage (OR = 1.339, P = 0.037) and validation stage (OR = 1.0007, P = 0.022). Sensitivity analyses confirmed robustness of the results. The genetically predicted higher level of mTOR-dependent eIF4E in plasma might have a causal effect on the occurrence of NAFLD. [ABSTRACT FROM AUTHOR]

Background: Increasing numbers of people are suffering from sleep disorders. The gut microbiota of these individuals differs significantly. However, no reports are available on the causal associations between specific gut microbiota and sleep disorders. Methods: Data on gut genera were obtained from the MiBioGen consortium. Twenty-four cohorts with 18,340 individuals of European origin were included. Sleep disorder data, which included 216,454 European individuals, were retrieved from the FinnGen Biobank. Subsequently, two-sample Mendelian randomization was performed to analyze associations between sleep disorders and specific components of the gut microbiota. Results: Inverse variance weighting (IVW) revealed a negative correlation between Coprobacter and sleep disorders (OR = 0.797, 95% CI = 0.66-0.96, and p = 0.016), a positive correlation between Lachnospiraceae and sleep disorders (OR = 1.429, 95% CI = 1.03-1.98, and p = 0.032), a negative association between Oscillospira and sleep disorders (OR = 0.745, 95% CI = 0.56-0.98, and p = 0.038), and a negative association between Peptococcus and sleep disorders (OR = 0.858, 95% CI = 0.74-0.99, p = 0.039). Conclusion: A significant causal relationship was found between four specific gut microbiota and sleep disorders. One family, Lachnospiraceae, was observed to increase the risk of sleep disorders, while three genera, namely, Coprobacter, Oscillospira, and Peptococcus, could reduce the risk of sleep disorders. However, further investigations are needed to confirm the specific mechanisms by which the gut microbiota affects sleep. [ABSTRACT FROM AUTHOR]

Introduction: Circulating cytokines were considered to play a critical role in the initiation and propagation of sarcopenia and frailty from observational studies. This study aimed to find the casual association between circulating cytokines and sarcopenia and frailty from a genetic perspective by two-sample Mendelian randomization (MR) analysis. Methods: Data for 41 circulating cytokines were extracted from the genome-wide association study dataset of 8,293 European participants. Inverse-variance weighted (IVW) method, MR-Egger, and weighted median method were applied to assess the relationship of circulating cytokines with the risk of aging-related syndromes and frailty. Furthermore, MR-Egger regression was used to indicate the directional pleiotropy, and Cochran's Q test was used to verify the potential heterogeneity. The "leave-one-out" method was applied to visualize whether there was a causal relationship affected by only one anomalous single-nucleotide polymorphisms. Results: Genetic predisposition to increasing levels of interleukin-10 (IL-10), IL-12, and vascular endothelial growth factor (VEGF) was associated with the higher risk of low hand grip strength according to the IVW method [R = 1.05, 95% CI = 1.01-1.10, P = 0.028, false discovery rate (FDR)-adjusted P = 1.000; OR = 1.03, 95% CI = 1.00-1.07, P = 0.042, FDR-adjusted P = 0.784; OR = 1.02, 95% CI = 1.00-1.05, P = 0.038, FDR-adjusted P = 0.567]. Furthermore, genetically determined higher macrophage colony-stimulating factors (M-CSFs) were associated with a lower presence of appendicular lean mass (OR = 1.01, 95% CI = 1.00-1.02, P = 0.003, FDR-adjusted P = 0.103). Monokine induced by interferon-g (MIG) and tumor necrosis factor-beta (TNF-β) were associated with a higher risk of frailty (OR = 1.03, 95% CI = 1.01-1.05, P < 0.0001, FDR-adjusted P = 0.012; OR = 1.01, 95% CI = 1.00-1.03, P = 0.013, FDR-adjusted P = 0.259). In this study, we did not find heterogeneity and horizontal pleiotropy between the circulating cytokines and the risk of frailty and sarcopenia. Conclusion: Genetic predisposition to assess IL-10, IL-12, and VEGF levels was associated with a higher risk of low hand grip strength and M-CSF with the presence of appendicular lean mass. The high levels of TNF-β and MIG were associated with a higher risk of frailty. More studies will be required to explore the molecular biological mechanisms underlying the action of inflammatory factors. [ABSTRACT FROM AUTHOR]

Objective: Observational research has indicated a potential link between dietary salt intake and susceptibility to dementia. However, it is important to note that these types of studies are prone to the issues of reverse causation and residual confounding. Therefore, we conducted a two-sample Mendelian randomization (MR) study to explore the causality. Method: To explore the causal relationship between them, this Mendelian randomization (MR) study incorporated summary statistics of dietary salt intake and dementia. We estimated the causality between salt intake and the risk of overall dementia and various subtypes of dementia, including Alzheimer's disease (AD), Vascular dementia (VaD), and Lewy body dementia (LBD). The inverse variance-weighted (IVW) method was the major MR analysis. To conduct sensitivity analyses, we employed various MR methods, the pleiotropy residual sum and outlier (MR-PRESSO) method, and the leave-one-out approach. The MR-Egger intercept and Cochran's Q test were conducted to test pleiotropy and heterogeneity respectively. Results: A suggestive association was observed for genetically predicted higher dietary salt intake and increased risk of overall dementia in the European ancestry [odds ratio (OR): 1.542; 95% confidence interval (95% CI): 1.095–2.169; P = 0.013]. The causal relationship between dietary salt intake and overall dementia is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Meanwhile, no clear heterogeneity or pleiotropy was identified. However, we failed to detect a causal effect of dietary salt intake on the risk of various dementia subtypes. Conclusion: The results of this research present strong evidence that established a significant association between dietary salt intake and the likelihood of developing dementia. These findings reinforce the notion that the amount of dietary salt intake plays a crucial role in determining the risk of acquiring this cognitive condition. By establishing a definitive correlation, this study highlights the importance of reducing salt consumption as a preventive measure against dementia. [ABSTRACT FROM AUTHOR]

Background: Sex difference in the incidence rate of idiopathic pulmonary fibrosis (IPF) indicates that estrogen has a certain protective effect on the disease. Nevertheless, there is a dearth of study investigating the association between factors pertaining to endogenous estrogen exposure level, such as age at menarche (AAM) in women, and IPF. Our study intended to employ Mendelian randomization (MR) method to elucidate the causal association between AAM and IPF. Methods: Our study utilized AAM as a measure of endogenous estrogen exposure and investigated its causal effect on the risk of IPF through MR. We employed the inverse variance weighted (IVW) method to assess the causal relationship between AAM and IPF risk, with supplementary analyses conducted using the weighted median estimator (WME) and MR-Egger method. Several sensitivity analyses were performed to assess the dependability of MR estimates. Results: A total of 9 selected single nucleotide polymorphisms (SNPs) significantly associated with AAM were selected as instrumental variables. The IVW method showed that genetically later AAM was associated with an increased risk of IPF (odds ratio [OR] = 1.0014, 95%confidence interval [CI] = 1.0005–1.0023, p = 0.001). The median weighting method and the MR-Egger method obtained similar estimates, and no heterogeneity or pleiotropy was found, indicating that the results were robust. Conclusions: Our MR study suggested a causal relationship between a later onset of menarche and a heightened susceptibility to IPF. [ABSTRACT FROM AUTHOR]

Background: Numerous observational studies have identified a linkage between the gut microbiota and gastroesophageal reflux disease (GERD). However, a clear causative association between the gut microbiota and GERD has yet to be definitively ascertained, given the presence of confounding variables. Methods: The genome-wide association study (GWAS) pertaining to the microbiome, conducted by the MiBioGen consortium and comprising 18,340 samples from 24 population-based cohorts, served as the exposure dataset. Summary-level data for GERD were obtained from a recent publicly available genome-wide association involving 78 707 GERD cases and 288 734 controls of European descent. The inverse variance-weighted (IVW) method was performed as a primary analysis, the other four methods were used as supporting analyses. Furthermore, sensitivity analyses encompassing Cochran's Q statistics, MR-Egger intercept, MR-PRESSO global test, and leave-one-out methodology were carried out to identify potential heterogeneity and horizontal pleiotropy. Ultimately, a reverse MR assessment was conducted to investigate the potential for reverse causation. Results: The IVW method's findings suggested protective roles against GERD for the Family Clostridiales Vadin BB60 group (P = 0.027), Genus Lachnospiraceae UCG004 (P = 0.026), Genus Methanobrevibacter (P = 0.026), and Phylum Actinobacteria (P = 0.019). In contrast, Class Mollicutes (P = 0.037), Genus Anaerostipes (P = 0.049), and Phylum Tenericutes (P = 0.024) emerged as potential GERD risk factors. In assessing reverse causation with GERD as the exposure and gut microbiota as the outcome, the findings indicate that GERD leads to dysbiosis in 13 distinct gut microbiota classes. The MR results' reliability was confirmed by thorough assessments of heterogeneity and pleiotropy. Conclusions: For the first time, the MR analysis indicates a genetic link between gut microbiota abundance changes and GERD risk. This not only substantiates the potential of intestinal microecological therapy for GERD, but also establishes a basis for advanced research into the role of intestinal microbiota in the etiology of GERD. [ABSTRACT FROM AUTHOR]

Background: Previous observational studies indicated that atrial fibrillation may increase the risk of breast cancer. Following a breast cancer diagnosis, the chance of developing atrial fibrillation may increase as well. However, it is uncertain whether the link is causal or just due to confounding factors. Objective: Using bidirectional Mendelian randomization (MR) analysis, we sought to assess the bidirectional causal relationship between atrial fibrillation and breast cancer from a genetic level. Methods: Large genome‐wide association studies yielded summary‐level data for atrial fibrillation and breast cancer. The preliminary estimate was inverse variance weighted (IVW) under a random model. MR–Egger, weighted median, simple mode, weighted mode, and multivariable MR (adjusting body mass index, smoking, and alcohol drinking) were performed as sensitivity analyses. Results: Genetically predicted atrial fibrillation presented no statistically significant association with overall breast cancer (odds ratio [OR] = 1.00; 95% confidence interval [CI]: 0.97–1.04; p = 0.79), estrogen receptor (ER) + (OR = 1.00; 95% CI: 0.96–1.03; p = 0.89) or ER− subtypes (OR = 1.00; 95% CI: 0.97–1.04; p = 0.89). Similarly, genetically predicted overall breast cancer (OR = 1.01; 95% CI: 0.98–1.04; p = 0.37), ER+ (OR = 1.02; 95% CI: 0.99–1.05; p = 0.16) or ER− (OR = 0.98; 95% CI: 0.93–1.02; p = 0.32) subtypes had no causal effect on atrial fibrillation. Sensitivity analyses yielded similar results. Individual single nucleotide polymorphism had little effect on the total estimate. We did not observe any evidence of horizontal pleiotropy. Conclusions: Our bidirectional MR studies revealed that there may be no causal links between atrial fibrillation and breast cancer. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis is one of the most common skin disorders. Evidence has suggested an association between skin disorders, such as atopic dermatitis, and Parkinson's disease (PD). However, whether atopic dermatitis has a causal effect on PD remains unknown. Methods: The study aimed to determine whether their association between atopic dermatitis and PD is causal, using a bidirectional two‐sample Mendelian randomization method. Genetic variants from the public genome‐wide association studies for atopic dermatitis (n = 10788 cases and 30047 controls) were selected to evaluate their causal effects on the risk of PD (33,674 cases and 449,056 controls). The inverse variance weighted (IVW) method was used as the primary analysis. Results: The IVW results indicated that atopic dermatitis was associated with decreased risk of PD {fixed effects: odds ratio [OR] [95% confidence interval (CI)]:.905 [.832–.986], p =.022; OR [95% CI]:.905 [.827–.991], p =.032}. However, we failed to detect the causal effects of PD on risk of atopic dermatitis in the reverse causation analysis. Conclusion: This study indicated causal association of genetically proxied atopic dermatitis with the risk of PD. Future studies are warranted to explore the underlying mechanism and investigate the targeting effect of atopic dermatitis on PD. [ABSTRACT FROM AUTHOR]

Evidence from prospective cohort studies has revealed an inverse association between cheese consumption and the development of atherosclerosis (AS), atherosclerotic cardiovascular diseases (ASCVD), and their complications. However, it remains unclear whether this observed association is influenced by potential confounding factors that may arise during the long-term development process of AS, ASCVD, and its complications. Therefore, to further clarify the causal relationship between cheese consumption and AS, ASCVD, and its complications, we conducted a two-sample Mendelian randomization (MR) analysis to explore the causal association between cheese intake and the aforementioned health outcomes. We employed a two-sample MR analysis based on publicly available genome-wide association studies (GWAS) to infer the causal relationship, with no overlap between their participating populations. The effect estimates were calculated using the random-effects inverse-variance-weighted method. Sensitivity analyses were conducted using Cochran's Q statistic, funnel plot, leave-one-out analysis, and MR-Egger intercept tests. The genetically predicted cheese intake was found to be associated with lower risks of coronary AS (odds ratio [OR] = 0.72, 95 % confidence interval [CI] 0.59–0.88, P = 0.001), peripheral vascular AS (OR = 0.56, 95 % CI 0.37–0.84, P = 0.006), other vascular AS (OR = 0.66, 95 % CI 0.44–0.99, P = 0.043), coronary artery disease (OR = 0.64, 95 % CI 0.56–0.74, P = 1.57e-09), angina pectoris (OR = 0.70, 95 % CI 0.58–0.84, P = 4.92e-05), myocardial infarction (OR = 0.63, 95 % CI 0.52–0.77, P = 3.56e-06), heart failure (OR = 0.62, 0.49–0.79, P = 1.20e-04), total ischemic stroke (OR = 0.76, 95 % CI 0.63–0.91, P = 0.003), peripheral artery disease (OR = 0.64, 95 % CI 0.43–0.95, P = 0.028), and cognitive impairment (OR = 0.65, 95 % CI 0.56–0.74, P = 3.40e-10). However, no associations were observed for cerebrovascular AS, arrhythmia, cardiac death, ischemic stroke (large artery AS), ischemic stroke (small vessel), ischemic stroke (cardioembolic), and transient ischemic attack. This two-sample MR analysis reveals a causally inverse association between cheese intake and multi-vascular AS (including coronary AS, peripheral vascular AS, and other vascular AS), as well as multiple types of ASCVD and its complications (such as coronary artery disease, angina pectoris, myocardial infarction, heart failure, total ischemic stroke, and peripheral artery disease). The findings from this study may lay a stronger theoretical foundation and present new opportunities for the dietary management of future atherosclerotic cardiovascular diseases. • Genetically predicted cheese consumption lowered the risks of coronary atherosclerosis (AS), peripheral vascular AS, other vascular AS. • Genetically predicted cheese consumption lowered the risks of coronary heart disease, angina pectoris, myocardial infarction, heart failure, total ischemic stroke, peripheral artery disease, and cognitive impairment. • The findings from this study may lay a stronger theoretical foundation and present new opportunities for the dietary management of future atherosclerotic cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Prevention & Treatment For Stomatological Diseases is the property of Journal of Prevention & Treatment For Stomatological Diseases Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BackgroundObservational studies have reported an association between body mass index (BMI) as well as height and the risk of pneumothorax. However, it has long been unclear whether BMI or height are causally associated with pneumothorax.MethodsGenetic summary data for BMI, height and pneumothorax were retrieved from multiple independent large genome-wide association studies (GWAS). A series of quality control steps were conducted to select instruments. Four independent two-sample Mendelian randomization (MR) analyzes were performed to adequately assess the causal relationship between BMI or height on pneumothorax, and the robustness of the results was assessed by a series of sensitivity analyzes.ResultsHeight increased the risk of pneumothorax with an OR of 1.5181 (95%CI 1.3092–1.7604; p = 3.28e-08); there was no evidence of a causal effect of BMI on the risk of pneumothorax with an OR of 0.8979 (95%CI 0.7417–1.0869; p = 0.269). Height increased the risk of spontaneous pneumothorax with an OR of 1.0010 (95%CI 1.0002–1.0018; p = 0.012); the results showed no significant causal relationship between BMI and spontaneous pneumothorax either with an OR of 0.9992 (95%CI 0.9983–1.0002; p = 0.112).ConclusionOur results supported a genetic association between height and pneumothorax. We found that height increased the risk of pneumothorax. However, no evidence was found to suggest a causal relationship between BMI and pneumothorax risk. The relationship between BMI and pneumothorax requires further in-depth analysis.

BackgroundChronic heart failure (CHF) patients exhibit alterations in cerebral cortical structure and cognitive function. However, the mechanisms by which CHF affects cortical structure and functional regions remain unknown. This study aims to investigate potential causal relationship between CHF and cerebral cortical structure through Mendelian randomization (MR).MethodsThe research utilized genome-wide association studies (GWAS) to explore the causal association between CHF and cerebral cortical structure. The results were primarily analyzed using the inverse-variance weighted (IVW). The reliability of the data was verified through horizontal pleiotropy and heterogeneity analysis by MR-Egger intercept test and Cochran's Q-test, respectively. Replication analysis was conducted in the Integrative Epidemiology Unit (IEU) OpenGWAS project for further validation. In addition, we collected mediator genes that mediate causality to reveal potential mechanisms. Integrated bioinformatics analysis was conducted using the Open Target Genetics platform, the STRING database, and Cytoscape software.ResultsThe IVW results did not reveal any significant causal association between genetically predicted CHF and the overall structure of the cerebral cortex or the surface area (SA) of the 34 functional regions of the cerebral cortex (P > 0.05). However, the results revealed that CHF increased the thickness (TH) of pars opercularis (IVW: β = 0.015, 95% CI: 0.005–0.025, P = 3.16E-03). Replication analysis supported the causal association between CHF and pars opercularis TH (IVW: β = 0.02, 95% CI: 0.010–0.033, P = 1.84E-04). We examined the degree centrality values of the top 10 mediator genes, namely CDKN1A, CELSR2, NME5, SURF4, PSMA5, TSC1, RPL7A, SURF6, PRDX3, and FTO.ConclusionGenetic evidence indicates a positive correlation between CHF and pars opercularis TH.

BackgroundObservational studies have indicated that obesity is a risk factor for anorectal abscess (ARB). However, it remains unclear whether a causal genetic relationship exists between obesity and ARB.MethodsUnivariate and multivariate Mendelian randomization (MR) were conducted using data from a large, published genome-wide association study (GWAS) of European ancestry to infer a causal relationship between obesity and ARB. Inverse variance weighted (IVW) analysis served as the primary analysis method, with results reported as odds ratios (OR).ResultsMR analysis revealed that body mass index (BMI) positively affects ARB (OR 1.974, 95% confidence interval (CI) 1.548–2.519, p = 4.34 × 10−8). The weighted median method (OR = 1.879, 95% CI 1.248–2.829, p = 0.002) and Bayesian model averaging (BMA) (OR = 1.88, 95% CI 1.477–2.392, p = 2.85 × 10−7) also demonstrated consistent results. Subsequently, the impact of several obesity-related characteristics on ARB was assessed. Body fat percentage (BF), whole body fat mass (FM), waist circumference (WC), and hip circumference (HC) were found to be causally associated with an increased risk of ARB. However, these associations vanished after adjusting for BMI effects.ConclusionThe study confirms a positive causal effect of obesity on ARB, highlighting that reasonable weight control is an important strategy to reduce the incidence of ARB.

BackgroundSeveral observational studies suggested an association between rheumatoid arthritis (RA) and bronchiectasis. Nevertheless, the presence of a causal relationship between these conditions is yet to be determined. This study aimed to investigate whether genetically predicted RA is associated with the risk of bronchiectasis and vice versa.MethodsWe obtained RA genome-wide association study (GWAS) data from FinnGen consortium, and bronchiectasis GWAS data from IEU Open GWAS project. Univariate Mendelian randomization (MR) analysis was performed using inverse variance weighted (IVW) estimation as the main method. Furthermore, bidirectional and replication MR analysis, multivariate MR (MVMR), Mediation analysis, and sensitivity analyses were conducted to validate the findings.ResultsIn the UVMR analysis, the IVW results revealed that RA had an increased risk of bronchiectasis (OR = 1.18, 95% CI = 1.10–1.27; p = 2.34 × 10−6). In the reverse MR analysis, no evidence of a causal effect of bronchiectasis on the risk of RA was detected. Conversely, in the replication MR analysis, RA remained associated with an increased risk of bronchiectasis. Estimates remained consistent in MVMR analyses after adjusting for the prescription of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids. Immunosuppressants were found to mediate 58% of the effect of the RA on bronchiectasis. Sensitivity analyses confirmed the stability of these associations.ConclusionThis study demonstrated a positive causal relationship between RA and an increased risk of bronchiectasis, offering insights for the early prevention of bronchiectasis in RA patients and shedding new light on the potential role of immunosuppressants as mediators in promoting the effects of RA on bronchiectasis.

Li An,1,2,&ast; Xiaomei Ren,1,&ast; Ye Pan,2 Wei Gao,1 Liqun Ren,1 Jing Wang,3 Yao Wang2 1Department of Geriatrics, ZhongDa Hospital, Southeast University School of Medicine, Nanjing, 210009, People’s Republic of China; 2Department of Endocrine, ZhongDa Hospital, Southeast University School of Medicine, Nanjing, 210009, People’s Republic of China; 3Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng, 211400, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Wang; Yao Wang, Tel/Fax +86-25- 83272111, Email wang_yao100@163.com; yz3466599@hotmail.comBackground: The impact of inflammatory factors on the risk of diabetic nephropathy (DN) is inconsistent. Two-sample Mendelian randomization (MR) analyses were used to detect the causal role of inflammatory factors in DN risk.Methods: Inflammatory factor GWAS summary data were collected from a meta-analysis including 8,293 Finnish participants, and DN information was extracted from a GWAS of 213,746 individuals from FinnGen. The MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) outlier test was used for the removal of horizontal pleiotropic outliers. Multivariable MR analysis was also used to adjust for pleiotropy.Results: IFN-γ [ORIVW: 1.33; 95% CI: 1.09– 1.63; p=0.005] and SCF [ORIVW: 1.25, 1.02– 1.52; p = 0.027] were associated with an increased risk of DN. MIP1b [ORIVW: 0.92; 95% CI: 0.85– 0.98; p = 0.022] and IL-16 [ORIVW: 0.89, 0.81– 0.99; p = 0.043] showed negative associations with the risk of DN. We validated our MR results with MR-PRESSO analyses. Significant horizontal pleiotropy was not found. Moreover, in the multivariable MR analysis, the associations between cytokines and DN risk remained.Conclusion: Our MR results based on genetic data contribute to a better understanding of the pathogenesis of DN and provide evidence for a causal effect of inflammatory factors on DN. These findings support targeting specific inflammatory factors to alleviate DN risk.Keywords: causal association, diabetic nephropathy, inflammatory factors, Mendelian randomization

Abstract Background Several researches have demonstrated that patients with sarcoidosis accompanied with the abnormality in blood glucose and/or lipids, however, the causal relationship between them remains uncertain. To elucidate the potential association and causality of blood glucose and lipids with sarcoidosis, we conducted a propensity score matching (PSM)-based observational study combined with mendelian randomization (MR) analysis. Methods All subjects in this study were retrospectively collected from Tongji Hospital during 2010 and 2023. 1:1 PSM was employed to control the potential confounders as appropriate. Univariable and multivariable logistic regression analyses were performed to estimate the associations of sarcoidosis with fasting glucose, high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), total cholesterol (TC), and total triglyceride (TG). The further subtype analysis was also conducted. Afterwards, a bidirectional MR analysis based on public data deeply explored the causality among the 5 candidate traits and sarcoidosis, for which the inverse-variance weighted (IVW) method was utilized as the main inferring approach. Results In the observational study, a total number of 756 subjects were enrolled, with 162 sarcoidosis patients and 594 non-sarcoidosis participants, while 160 pairs of subjects were matched after PSM. Multivariable logistic regression analysis indicated that HDLC (OR: 0.151; 95% CI: 0.056–0.408; P

Abstract Objective Observational studies have shown an association between COVID‐19 and epilepsy. However, causality remains unproven. This study aimed to investigate the causative effect of genetically predicted COVID‐19 phenotypes on epilepsy risk using a two‐sample Mendelian randomization (MR) analysis. Methods We retrieved summary‐level datasets for three COVID‐19 phenotypes (COVID‐19 susceptibility, COVID‐19 hospitalization, and COVID‐19 severity) and epilepsy from the genome‐wide association studies conducted by the COVID‐19 Host Genetics Initiative (COVID‐19 HGI) and International League Against Epilepsy (ILAE) consortium, respectively. To analyze the final results, nine MR analytic methods were utilized. The inverse‐variance weighted (IVW) method was chosen as the primary approach for data analysis to evaluate the potential causal effect. Other MR analytic methods (MR‐Egger regression, weighted median estimator, mode based‐estimator, and MR‐PRESSO) were used as a supplement to IVW to ensure the robustness of the results. Results The IVW approach demonstrated no causal association between any genetically predicted COVID‐19 phenotype and the risk of epilepsy [COVID‐19 susceptibility: odds ratio (OR) = 0.99, 95% confidence interval (CI) = 0.86–1.14, p = 0.92; COVID‐19 hospitalization: OR = 1.00, 95% CI = 0.96–1.04, p = 0.95; COVID‐19 severity: OR = 0.99, 95% CI = 0.96–1.01, p = 0.25]. Other MR complementary methods revealed consistent results. Additionally, no evidence for heterogeneity and horizontal pleiotropy was found. Significance This MR study revealed no genetically predicted causal relationship between COVID‐19 phenotypes and epilepsy.

Background and Purpose: Evaluating the causal association effect of risk factors is essential in estimating the mortality rate among COVID-19 patients. Much research has been conducted to assess the impact of COVID-19 on death in various countries worldwide. However, few studies have addressed the effect of causal association of risk factors. This study aims to address this gap by estimating the impact of COVID-19 on death by evaluating the causal association with the risk factors. Materials and Methods: The research population included all inpatients with initial COVID-19 symptoms, confirmed by their PCR test results. They were admitted to hospitals affiliated with Golestan University of Medical Science, Golestan, Iran, in 2020. We employed the propensity score method, an effective statistical technique for evaluating the causal association effect of risk factors in observational studies. We also used the student and chi-squared tests to compare the differences between the two study groups. Results: We used the propensity score matching estimation approach and logistic regression analysis for comparison. Of 6379 inpatients, 5581 (87.5%) were discharged or recovered, and 798 (12.5%) died. The causal association between treatment results (discharged vs died) and variables of PCR test, SpO2, gender, age, and hospitalization duration in ICU were statistically significant. Conclusion: The propensity score matching estimation method revealed a high risk of death in patients with PCR+ test diagnosis. Specifically, using this approach, the above-measured risk factors increased the chance of death in patients with PCR+ to 72%. However, the traditional multiple logistic regression model estimated the risk of death at 46%, suggesting potential underestimation. This disparity might be due to better control of the effect of the above-measured risk factors by the propensity score matching. Therefore, the former estimating approach is more effective in assessing the impact of COVID-19 on death.

Background: Although observational studies have suggested a bidirectional relation between depression and intracranial aneurysms (IAs), their causal relations remain unclear. Thus we aimed to assess the causal association between depression and IAs. Methods: We conducted a bidirectional two-sample Mendelian randomization (MR) study using summary-level data from publicly available genome-wide association studies of depression (n = 500,199), IAs (n = 79,429), unruptured intracranial aneurysm (uIA) (n = 74,004), and subarachnoid hemorrhage (SAH) (n = 77,074). MR analyses included the inverse-variance weighted (IVW) method as the primary analytic, plus weighted-median, simple mode, weighted mode, MR-Egger, and MR PRESSO. Results: Genetically predicted depression was strongly positively related to IAs (odds ratio [OR] = 1.69, 95% confidence interval [CI] 1.19-2.39, p = 0.003), uIA (OR = 1.96, 95% CI 1.06-3.64, p = 0.032), and SAH (OR = 1.73, 95% CI 1.14-2.61, p = 0.009). Reverse MR analyses showed that while genetically predicted uIA was positively related to depression (OR = 1.02, 95% CI 1.00-1.05, p = 0.044), no causal relations were observed for either IAs or SAH for depression. Conclusion: Our findings provide evidence of a causal effect of depression on IAs, uIA, and SAH. For the reverse MR analyses, we found a causal impact of uIA on depression, but no causal influence of either IAs or SAH for depression. [ABSTRACT FROM AUTHOR]

Background: Previous research has indicated that there may be a link between Crohn's disease (CD) and breast cancer (BC), but the causality remains unclear. This study aimed to investigate the causal association between CD and BC using Mendelian randomization (MR) analysis. Methods: The summary data for CD (5,956 cases/14,927 controls) was obtained from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). And the summary data for BC (122,977 cases/105,974 controls) was extracted from the Breast Cancer Association Consortium (BCAC). Based on the estrogen receptor status, the cases were classified into two subtypes: estrogen receptor-positive (ER+) BC and estrogen receptor-negative (ER-) BC. We used the inverse variance weighted method as the primary approach for two-sample MR. MR-PRESSO method was used to rule out outliers. Heterogeneity and pleiotropy tests were carried out to improve the accuracy of results. Additionally, multivariable MR was conducted by adjusting for possible confounders to ensure the stability of the results. Results: The two-sample MR indicated that CD increased the risks of overall (OR: 1.020; 95% CI: 1.010-1.031; p=0.000106), ER+ (OR: 1.019; 95%CI: 1.006-1.034; p=0.006) and ER- BC (OR: 1.019; 95%CI: 1.000-1.037; p=0.046) after removal of outliers by MR-PRESSO. This result was reliable in the sensitivity analysis, including Cochran's Q and MR-Egger regression. In multivariate MR analyses, after adjusting for smoking and drinking separately or concurrently, the positive association between CD and the risks of overall and ER+ BC remained, but it disappeared in ER- BC. Furthermore, reverse MR analysis suggested that BC did not have a significant impact on CD risk. Conclusion: Our findings provide evidence for a possible positive association between CD and the risk of BC. However, further studies are needed to fully understand the underlying mechanisms and establish a stronger causal relationship. [ABSTRACT FROM AUTHOR]

Objectives: This Mendelian randomization (MR) study identified modifiable risk factors for isolated rapid eye movement sleep behavior disorder (iRBD). Methods: Genome-wide association study (GWAS) datasets for 29 modifiable risk factors for iRBD in discovery and replication stages were used. GWAS data for iRBD cases were obtained from the International RBD Study Group. The inverse variance weighted (IVW) method was primarily employed to explore causality, with supplementary analyses used to verify the robustness of IVW findings. Co-localization analysis further substantiated causal associations identified via MR. Genetic correlations between mental illness and iRBD were identified using trait covariance, linkage disequilibrium score regression, and co-localization analyses. Results: Our study revealed causal associations between sun exposure-related factors and iRBD. Utilizing sun protection (odds ratio [OR] = 0.31 [0.14, 0.69], p = 0.004), ease of sunburn (OR = 0.70 [0.57, 0.87], p = 0.001), childhood sunburn occasions (OR = 0.58 [0.39, 0.87], p = 0.008), and phototoxic dermatitis (OR = 0.78 [0.66, 0.92], p = 0.003) decreased iRBD risk. Conversely, a deep skin color increased risk (OR = 1.42 [1.04, 1.93], p = 0.026). Smoking, alcohol consumption, low education levels, and mental illness were not risk factors for iRBD. Anxiety disorders and iRBD were genetically correlated. Conclusion: Our study does not corroborate previous findings that identified smoking, alcohol use, low education, and mental illness as risk factors for iRBD. Moreover, we found that excessive sun exposure elevates iRBD risk. These findings offer new insights for screening high-risk populations and devising preventive measures. [ABSTRACT FROM AUTHOR]

Background and objectives: As indicated by observational and genetic variation studies, age at first sexual intercourse (AFS) may be associated with migraine attack, but there is a lack of evidence from real-world studies due to ethical concerns. Therefore, we conducted a Mendelian randomization study to determine the causal relationship between AFS and migraine. Methods: We extracted instrumental variables from summary data of a genomewide association study (GWAS) on AFS and migraine and then conducted twosample Mendelian randomization analyses. GWAS data for AFS and migraine were obtained from 397,338 unrelated individuals (214,547 females and 182,791 males) and 306,314 individuals (18,477 patients and 287,837 control individuals), respectively. Results: There was a causal relationship between AFS and risk for migraine (odds ratio (OR) = 0.73, 95% confidence interval (CI) [0.61 to 0.86]), both for migraine with aura (MWA; OR = 0.72, 95% CI [0.58 to 0.89]) and migraine without aura (MOA; OR = 0.66, 95% CI [0.51 to 0.86]). Stratified analyses provided suggestive evidence of the causal relationship between delayed AFS and a decreased risk of migraine for both males (OR = 0.71, 95% CI [0.59 to 0.84]) and females (OR = 0.73, 95% CI [0.61 to 0.89]). Reverse Mendelian randomization did not reveal any effect of migraine on AFS (p > 0.05). No pleiotropy was detected. Discussion: A delayed AFS is a protective factor against migraine (for both MWA and MOA) in both males and females. This causal relationship indicates the presence of extracranial regulatory pathways of migraine. [ABSTRACT FROM AUTHOR]

Aims: Observational studies have reported that autoimmune diseases are associated with gestational diabetes mellitus (GDM), but the causality is unknown. The study aimed to evaluate the potential causal effect of autoimmune diseases on GDM. Methods: A two-sample Mendelian randomization (MR) study was designed using the summary statistics of GDM (123,579 individuals) and three common autoimmune diseases, including inflammatory bowel disease (IBD, 59,957 individuals), rheumatoid arthritis (RA, 80,799 individuals) and systemic lupus erythematosus (SLE, 14,267 individuals), from the genome-wide association study (GWAS). The fixed-effects inverse variance weighted (IVW) was used to deduce the causal association between autoimmune diseases and GDM, and sensitivity analyses were further performed. Results: The inverse variance weighting (IVW) method showed that RA and SLE increased the risk of GDM (RA: OR = 1.076, 95%CI = 1.033–1.122, P = 4.649E-04; SLE: OR = 1.025, 95%CI = 1.001–1.049, P = 0.044). But there were no any associations of IBD with GDM (P > 0.05). No significant horizontal pleiotropy was found by MR Egger regression (IBD: P for intercept = 0.905; RA: P for intercept = 0.103; SLE = P for intercept = 0.608). Conclusion: This two-sample MR study found that both SLE and RA are positively associated with the risk of GDM. Our findings provide help for the future prevention and treatment of GDM to reduce associated maternal and fetal complications. However, more research is needed to obviate the role of the GC and the HCQ to ensure this relationship is causal. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IVDD) is a common degenerative condition, which is thought to be a major cause of lower back pain (LBP). However, the etiology and pathophysiology of IVDD are not yet completely clear. To examine potential causal effects of modifiable risk factors on IVDD. Bidirectional Mendelian randomization (MR) study. Genome-wide association studies (GWAS) with sample sizes between 54,358 and 766,345 participants. Outcomes included (1) modifiable risk factors associated with IVDD use in the forward MR; and (2) modifiable risk factors that were determined to have a causal association with IVDD in the reverse MR, including smoking, alcohol intake, standing height, education level, household income, sleeplessness, hypertension, hip osteoarthritis, HDL, triglycerides, apolipoprotein A-I, type 2 diabetes, fasting glucose, HbA1c, BMI and obesity trait. We obtained genetic variants associated with 33 exposure factors from genome-wide association studies. Summary statistics for IVDD were obtained from the FinnGen consortium. The risk factors of IVDD were analyzed by inverse variance weighting method, MR-Egger method, weighted median method, MR-PRESSO method and multivariate MR Method. Reverse Mendelian randomization analysis was performed on risk factors found to be caustically associated with IVDD in the forward Mendelian randomization analysis. The heterogeneity of instrumental variables was quantified using Cochran's Q statistic. Genetic predisposition to smoking (OR=1.221, 95% CI: 1.068–1.396), alcohol intake (OR=1.208, 95% CI: 1.056–1.328) and standing height (OR=1.149, 95% CI: 1.072–1.231) were associated with increased risk of IVDD. In addition, education level (OR=0.573, 95%CI: 0.502–0.654)and household income (OR=0.614, 95%CI: 0.445–0.847) had a protective effect on IVDD. Sleeplessness (OR=1.799, 95%CI: 1.162–2.783), hypertension (OR=2.113, 95%CI: 1.132–3.944) and type 2 diabetes (OR=1.069, 95%CI: 1.024–1.115) are three important risk factors causally associated with the IVDD. In addition, we demonstrated that increased levels of triglycerides (OR=1.080, 95%CI:1.013–1.151), fasting glucose (OR=1.189, 95%CI:1.007–1.405), and HbA1c (OR=1.308, 95%CI:1.017–1.683) could significantly increase the odds of IVDD. Hip osteoarthritis, HDL, apolipoprotein A-I, BMI and obesity trait factors showed bidirectional causal associations with IVDD, therefore we considered the causal associations between these risk factors and IVDD to be uncertain. This MR study provides evidence of complex causal associations between modifiable risk factors and IVDD. It is noteworthy that metabolic disturbances appear to have a more significant effect on IVDD than biomechanical alterations, as individuals with type 2 diabetes, elevated triglycerides, fasting glucose, and elevated HbA1c are at higher risk for IVDD, and the causal association of obesity-related characteristics with IVDD incidence is unclear. These findings provide new insights into potential therapeutic and prevention strategies. Further research is needed to clarify the mechanisms of these risk factors on IVDD. [ABSTRACT FROM AUTHOR]

Background: Frequent hand washing and disinfection during the corona virus disease (COVID‐19) pandemic may lead to skin‐related disability. The causal relationship between atopic dermatitis (AD), the most common chronic, noninfectious, inflammatory skin disease, and COVID‐19 remains unclear. We used Mendelian randomization (MR) to explore the causal inference of atopic dermatitis with COVID‐19 outcomes. Methods: Genome‐wide association study (GWAS) data for AD, consisting of 8383 cases and 236,162 controls of European ethnicity, were provided by the FinnGen database. The GWAS outcome data were derived from the COVID‐19 Host Genetics Initiative and consisted of COVID‐19 susceptibility (122,616 cases and 2,475,240 controls), hospitalization (32,519 cases and 2,062,805 controls), and very severe respiratory disease (13,769 cases and 1,072,442 controls). The inverse variance weighted with a fixed effects model (IVW (fe)) was used as the main statistical approach to assess the causality between AD and COVID‐19 in this study. Several other analytical methods have also been used to complement or identify pleiotropy and heterogeneity. Results: MR analysis showed no causality between AD and COVID‐19 outcomes. The odds ratios (OR) were 1.00 (95% confidence interval (CI), 0.99–1.02) for susceptibility, 1.00 (95% CI, 0.96–1.04) for hospitalization, 0.97 (95% CI, 0.92–1.03) for very severe respiratory disease by the method of IVW (fe). Conclusion: In conclusion, we found no causal relationship between AD and COVID‐19 outcomes. This study provides additional ideas for the exploration of the risk factors for COVID‐19. [ABSTRACT FROM AUTHOR]

Background: Cerebral aneurysms (CAs) are a significant cerebrovascular ailment with a multifaceted etiology influenced by various factors including heredity and environment. This study aimed to explore the possible link between different types of immune cells and the occurrence of CAs. Methods: We analyzed the connection between 731 immune cell signatures and the risk of CAs by using publicly available genetic data. The analysis included four immune features, specifically median brightness levels (MBL), proportionate cell (PC), definite cell (DC), and morphological attributes (MA). Mendelian randomization (MR) analysis was conducted using the instrumental variables (IVs) derived from the genetic variation linked to CAs. Results: After multiple test adjustment based on the FDR method, the inverse variance weighted (IVW) method revealed that 3 immune cell phenotypes were linked to the risk of CAs. These included CD45 on HLA DR+NK (odds ratio (OR), 1.116; 95% confidence interval (CI), 1.001-1.244; p = 0.0489), CX3CR1 on CD14-CD16- (OR, 0.973; 95% CI, 0.948-0.999; p = 0.0447). An immune cell phenotype CD16- CD56 on NK was found to have a significant association with the risk of CAs in reverse MR study (OR, 0.950; 95% CI, 0.911-0.990; p = 0.0156). Conclusion: Our investigation has yielded findings that support a substantial genetic link between immune cells and CAs, thereby suggesting possible implications for future clinical interventions. [ABSTRACT FROM AUTHOR]

Background: Several researches have demonstrated that patients with sarcoidosis accompanied with the abnormality in blood glucose and/or lipids, however, the causal relationship between them remains uncertain. To elucidate the potential association and causality of blood glucose and lipids with sarcoidosis, we conducted a propensity score matching (PSM)-based observational study combined with mendelian randomization (MR) analysis. Methods: All subjects in this study were retrospectively collected from Tongji Hospital during 2010 and 2023. 1:1 PSM was employed to control the potential confounders as appropriate. Univariable and multivariable logistic regression analyses were performed to estimate the associations of sarcoidosis with fasting glucose, high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), total cholesterol (TC), and total triglyceride (TG). The further subtype analysis was also conducted. Afterwards, a bidirectional MR analysis based on public data deeply explored the causality among the 5 candidate traits and sarcoidosis, for which the inverse-variance weighted (IVW) method was utilized as the main inferring approach. Results: In the observational study, a total number of 756 subjects were enrolled, with 162 sarcoidosis patients and 594 non-sarcoidosis participants, while 160 pairs of subjects were matched after PSM. Multivariable logistic regression analysis indicated that HDLC (OR: 0.151; 95% CI: 0.056–0.408; P < 0.001) and TC (OR: 3.942; 95% CI: 2.644–5.877; P < 0.001) were strongly associated with sarcoidosis. Subtype analysis showed that low HDLC was independently correlated to risk of lesions in bronchus and lungs, and mediastinal lymph nodes, while high TC was to cervical lymph nodes. In MR analysis, high fasting glucose, low HDLC, and high TC were identified as the causal factors of sarcoidosis. Conclusion: HDLC and TC had the potential to influence the risk of sarcoidosis, which could be regarded as predictors and may provide new diagnostic and therapeutic targets for sarcoidosis. [ABSTRACT FROM AUTHOR]

Background: Fibromyalgia (FM) is a syndrome characterized by chronic and widespread musculoskeletal pain. A number of studies have implied a potential association between gut microbiota and FM. However, the casual association between gut microbiota and FM remains unknown. Method: Mendelian randomization (MR) study was conducted using the summary statistics of genetic variants from the genome-wide association study (GWAS). Inverse variance weighted (IVW), combined with MR-Egger and weighted median were used to investigate the causal association between 119 gut microbiota genera and FM. Sensitivity analyses were performed on the MR results, including heterogeneity test, leave-one-out test and pleiotropy test. Results: A total of 1,295 single nucleotide polymorphism (SNPs) were selected as instrumental variables (IVs), with no significant heterogeneity and pleiotropy according to the sensitivity analyses. Five gut microbiota genera were found to have significant casual association with FM. Coprococcus2 (OR = 2.317, pvalue = 0.005, 95% CI: 1.289-4.167), Eggerthella (OR = 1.897, p-value = 0.001, 95% CI: 1.313-2.741) and Lactobacillus (OR = 1.576, p-value =0.020, 95% CI: 1.073-2.315) can increase the risk of FM. FamillyXIIIUCG001 (OR = 0.528, pvalue = 0.038, 95% CI: 0.289-0.964) and Olsenella (OR = 0.747, p-value = 0.050, 95% CI: 0.557-1.000) can decrease the risk of FM. Conclusion: This MR study found that gut microbiota is casually associated with FM. New insights into the mechanisms of FM mediated by gut microbiota are provided. [ABSTRACT FROM AUTHOR]

Introduction: Glaucoma may be related to ischemic stroke (IS) and poor outcomes after IS in observational studies, while the causal association remains unclear. Methods: We obtained single-nucleotide polymorphisms (SNPs) related to glaucoma from the genome-wide association study (GWAS) conducted by the FinnGen consortium. The GWAS included a total of 13,614 cases and 295,540 controls. The summary-level datasets regarding IS were collected from the MEGASTROKE consortium, including 34,217 cases and 406,111 controls. Furthermore, we acquired summary statistics datasets for functional outcomes following IS from the GWAS meta-analysis conducted by the GISCOME consortium, which involved 6,021 individuals. The genetic association estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Score (mRS), including 3,741 cases with good functional outcomes (mRS = 0–2) and 2,280 subjects with poor functional outcomes post-stroke (mRS = 3–6). Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. Results: Genetically, glaucoma is associated with an increased risk of IS (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.02–1.14, p = 0.0039), as well as poor prognosis after IS with adjustment for severity (OR = 1.64; 95% CI = 1.27–2.13, p = 0.0001) and functional outcome after IS (OR = 1.45, 95% CI = 1.12–1.87, p = 0.0038). Through sensitivity analyses, we confirmed the robustness of the results. In addition, we did not identify any causal association between IS, functional outcome after IS, and glaucoma in reverse analysis. Conclusion: Our study provides evidence suggesting potential genetic causal effects of glaucoma on an increased risk of IS, as well as a poor functional outcome following IS. Future studies are necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

Prior research has demonstrated equivocal associations between selenium (Se) concentrations and osteoporosis (OP), yielding inconclusive findings. The purpose of the current study was to examine the potential correlation between Se levels and the risk of OP by using the Mendelian randomization (MR) study design. The genetic variants related to Se levels were obtained from a meta-analysis of a Genome-Wide Association Study (GWAS) conducted on toenail Se levels (n = 4162) and blood Se levels (n = 5477). The data summary for OP and bone mineral density (BMD) was obtained by utilizing the GWAS database. To examine the association between Se levels and BMD and OP, we employed three statistical methods: inverse variance weighted, weighted median, and MR-Egger. The reliability of the analysis was verified by sensitivity testing. All three methods of MR analysis revealed that Se levels had no effect on OP risk. In addition, the sensitivity analysis revealed no heterogeneity or pleiotropy, and the significance of the overall effect remained unaffected by single-nucleotide polymorphisms (SNPs), as determined by the leave-one-out analysis, indicating that our findings are relatively reliable. The results of our study indicate that there is no causal association between Se levels and the risk of OP. However, additional investigation is necessary to ascertain whether there is a potential association between these variables. [ABSTRACT FROM AUTHOR]

Objective: According to the 2020 data from the World Health Organization (WHO), cancers stand as one of the foremost contributors to global mortality. Revealing novel cancer risk factors and protective factors is of paramount importance in the prevention of disease occurrence. Studies on the relationship between chemokines and cancer are ongoing; however, due to the coordination of multiple potential mechanisms, the specific causal association remains unclear. Methods: We performed a bidirectional Mendelian randomization analysis to explore the causal association between serum chemokines and pancarcinoma. All data is from the GWAS catalog and IEU Open GWAS database. The inverse-variance weighted (IVW) method is primarily employed for assessing the statistical significance of the findings. In addition, the significance threshold after the multiple hypothesis test (Bonferroni) was 0.0013, and the evidence of a potential association was considered if the p-value < 0.05, but remained greater than Bonferroni’s threshold. Results: The results indicate that CCL1 (odds ratio, OR = 1.18), CCL2 (OR = 1.04), CCL8 (OR = 1.36), CCL14 (Colorectal, OR = 1.08, Small intestine, OR = 0.77, Lung, OR = 1.11), CCL15 (OR = 0.85), CCL18 (Breast, OR = 0.95, Prostate, OR = 0.96), CCL19 (Lung, OR = 0.66, Prostate, OR = 0.92), CCL20 (Lung, OR = 0.53, Thyroid, OR = 0.76), CCL21 (OR = 0.62), CCL22 (OR = 2.05), CCL23 (OR = 1.31), CCL24 (OR = 1.06), CCL27 (OR = 1.49), CCL28 (OR = 0.74), CXCL5 (OR = 0.95), CXCL9 (OR = 3.60), CXCL12 (Breast, OR = 0.87, Small intestine, OR = 0.58), CXCL13 (Breast, OR = 0.93, Lung, OR = 1.29), CXCL14 (Colon, OR = 1.40) and CXCL17 (OR = 1.07) are potential risk factors for cancers. In addition, there was a reverse causal association between CCL1 (OR = 0.94) and CCL18 (OR = 0.94) and breast cancer. Sensitivity analysis results were similar. The results of the other four MR Methods were consistent with the main results, and the leave-one-out method showed that the results were not driven by a Single nucleotide polymorphism (SNP). Moreover, there was no heterogeneity and pleiotropy in our analysis. Conclusion: Based on the two-sample MR Analysis method, we found that chemokines might be upstream factors of cancer pathogenesis. These results might provide new insights into the future use of chemokines as potential targets for cancer prevention and treatment. Our results also provide important clues for tumor prevention, and changes of serum chemokine concentration may be recognized as one of the features of precancerous lesions in future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Despite the well-established findings of a higher incidence of retina-related eye diseases in patients with diabetes, there is less investigation into the causal relationship between diabetes and non-retinal eye conditions, such as age-related cataracts and glaucoma. Methods: We performed Mendelian randomization (MR) analysis to examine the causal relationship between type 2 diabetes mellitus (T2DM) and 111 ocular diseases. We employed a set of 184 single nucleotide polymorphisms (SNPs) that reached genome-wide significance as instrumental variables (IVs). The primary analysis utilized the inverse variance-weighted (IVW) method, with MR-Egger and weighted median (WM) methods serving as supplementary analyses. Results: The results revealed suggestive positive causal relationships between T2DM and various ocular conditions, including "Senile cataract" (OR= 1.07; 95% CI: 1.03, 1.11; P=7.77×10-4), "Glaucoma" (OR= 1.08; 95% CI: 1.02, 1.13; P=4.81×10-3), and "Disorders of optic nerve and visual pathways" (OR= 1.10; 95% CI: 0.99, 1.23; P=7.01×10-2). Conclusion: Our evidence supports a causal relationship between T2DM and specific ocular disorders. This provides a basis for further research on the importance of T2DM management and prevention strategies in maintaining ocular health. [ABSTRACT FROM AUTHOR]

Background: Previous observational studies have reported inconsistent findings regarding the incidence of cancer in patients with schizophrenia compared to the general population. The causal relationship between schizophrenia and cancer remains unclear and requires further investigation. Objective: To investigate the causal relationship between schizophrenia and cancer. Methods: In this study, a two-sample Mendelian randomization (MR) analysis was conducted using publicly available genome-wide association studies to determine the causal relationship. The effect estimates were calculated using the random-effects inverse-variance-weighted method. Results: We determined a causal relationship between genetic predisposition to schizophrenia and cancer, with schizophrenia increasing lung cancer (odds ratio (OR) = 1.0007; 95% confidence interval (CI), 1.0001-1.0013; p = 0.0192), thyroid cancer (OR = 1.5482; CI, 1.1112-2.1569; p =0.0098), colorectal cancer (OR = 1.0009; CI, 1.0001-1.0018; p = 0.0344), ovarian cancer (OR = 1.0770; CI, 1.0352- 1.1203; p = 0.0002), breast cancer (OR = 1.0011; CI, 1.0001- 1.0022; p =0.0352) and reduced the risk of malignant neoplasm of the stomach (OR = 0.8502; CI, 0.7230-0.9998; p = 0.0496). Conclusions: This study conducted a two-sample MR analysis and discovered a positive causal relationship between schizophrenia and breast, ovarian, thyroid, lung, and colorectal cancers. On the other hand, an inverse causal relationship was found between schizophrenia and malignant neoplasm of the stomach. [ABSTRACT FROM AUTHOR]

Objective: Previous studies have demonstrated an association between sex hormone-related traits and systemic lupus erythematosus (SLE). However, because of the difficulties in determining sequential temporality, the causal association remains elusive. In this study, we used two-sample Mendelian randomization (MR) to explore the genetic causal associations between sex hormone-related traits and SLE. Methods: We used a two-sample MR to explore the causal association between sex hormone-related traits and SLE. The summarized data for sex hormone-related traits (including testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), and bioavailable testosterone (BT)) originated from large genome-wide association studies (GWASs) of European descent. Aggregated data for SLE were derived from the FinnGen consortium (835 cases and 300,162 controls). Random-effects inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, weighted mode, and fixed-effects IVW methods were used for the MR analysis. Random-effects IVW was the primary method used to analyze the genetic causal association between sex hormone-related traits and SLE. Heterogeneity of the MR results was detected using the IVW Cochran's Q estimates. The pleiotropy of MR results was detected using MR-Egger regression and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. Finally, leave-one-out analysis was performed to determine whether MR results were affected by a single single-nucleotide polymorphism (SNP). Results: Random-effects IVW as the primary method showed that testosterone (odds ratio (OR), 0.87; 95% confidence interval (CI), 0.41–1.82; P = 0.705), E2 (OR, 0.95; 95% CI, 0.73–1.23; P = 0.693), SHBG (OR, 1.25; 95% CI, 0.74–2.13; P = 0.400), and BT (OR, 0.99; 95% CI, 0.67–1.47; P = 0.959) had no potential causal association with SLE. The MR-Egger, weighted median, simple mode, weighted mode, and fixed-effects IVW methods all indicated consistent results. The results of the MR-Egger regression showed that there was no pleiotropy in our MR analysis (P > 0.05). The IVW Cochran's Q estimates showed that the MR analysis results of E2, SHBG, and BT on SLE had no heterogeneity (P > 0.05), but testosterone and SLE had heterogeneity (P < 0.05). The leave-one-out analysis confirmed that a single SNP did not affect the MR results. Conclusions: Our MR analysis demonstrated that genetically predicted testosterone, E2, SHBG, and BT levels were not associated with SLE risk, but the roles of other non-genetic pathways cannot be ruled out. Key Points • This is the first MR study to explore the causal association of sex hormone-related traits with SLE. • No evidence to support causal associations between sex hormone-related traits and SLE. • Our MR analysis may provide novel insights into the causal association between sex hormone-related traits and SLE risk. [ABSTRACT FROM AUTHOR]

Background: An increasing number of cohort studies have indicated a correlation between lung diseases and esophageal cancer, but the exact causal relationship has not been definitively established. Therefore, the objective of this study is to assess the causal relationship between lung diseases and esophageal cancer. Methods: Single-nucleotide polymorphisms (SNPs) related to lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF), along with outcomes data on esophageal cancer, were extracted from public genome-wide association studies (GWAS). A two-sample Mendelian randomization (MR) analysis was then performed using publicly available GWAS data to investigate the potential causal relationship. The effect estimates were primarily calculated using the fixed-effects inverse-variance-weighted method. Results: Totally, 81 SNPs related to asthma among 218,792 participants in GWAS. Based on the primary causal effects model using MR analyses with the inverse variance weighted (IVW) method, asthma was demonstrated a significantly related to the risk of esophageal cancer (OR 1.0006; 95% CI 1.0003–1.0010, p = 0.001), while COPD (OR 1.0306; 95% CI 0.9504–1.1176, p = 0.466), lung cancer (OR 1.0003, 95% CI 0.9998–1.0008, p = 0.305), as well as IPF (OR 0.9999, 95% CI 0.9998–1.0000, p = 0.147), showed no significant correlation with esophageal cancer. Conclusions: The two-sample MR analysis conducted in this study revealed a positive causal relationship between asthma and esophageal cancer. In contrast, esophageal cancer demonstrated no significant correlation with COPD, lung cancer, or IPF. Further large-sample prospective studies are needed to validate these findings and to provide appropriate recommendations regarding esophageal cancer screening among patients with asthma. [ABSTRACT FROM AUTHOR]

Objective: Observational studies have shown an association between COVID‐19 and epilepsy. However, causality remains unproven. This study aimed to investigate the causative effect of genetically predicted COVID‐19 phenotypes on epilepsy risk using a two‐sample Mendelian randomization (MR) analysis. Methods: We retrieved summary‐level datasets for three COVID‐19 phenotypes (COVID‐19 susceptibility, COVID‐19 hospitalization, and COVID‐19 severity) and epilepsy from the genome‐wide association studies conducted by the COVID‐19 Host Genetics Initiative (COVID‐19 HGI) and International League Against Epilepsy (ILAE) consortium, respectively. To analyze the final results, nine MR analytic methods were utilized. The inverse‐variance weighted (IVW) method was chosen as the primary approach for data analysis to evaluate the potential causal effect. Other MR analytic methods (MR‐Egger regression, weighted median estimator, mode based‐estimator, and MR‐PRESSO) were used as a supplement to IVW to ensure the robustness of the results. Results: The IVW approach demonstrated no causal association between any genetically predicted COVID‐19 phenotype and the risk of epilepsy [COVID‐19 susceptibility: odds ratio (OR) = 0.99, 95% confidence interval (CI) = 0.86–1.14, p = 0.92; COVID‐19 hospitalization: OR = 1.00, 95% CI = 0.96–1.04, p = 0.95; COVID‐19 severity: OR = 0.99, 95% CI = 0.96–1.01, p = 0.25]. Other MR complementary methods revealed consistent results. Additionally, no evidence for heterogeneity and horizontal pleiotropy was found. Significance: This MR study revealed no genetically predicted causal relationship between COVID‐19 phenotypes and epilepsy. [ABSTRACT FROM AUTHOR]

BackgroundHemorrhagic stroke (HS), a leading cause of death and disability worldwide, has not been clarified in terms of the underlying biomolecular mechanisms of its development. Circulating metabolites have been closely associated with HS in recent years. Therefore, we explored the causal association between circulating metabolomes and HS using Mendelian randomization (MR) analysis and identified the molecular mechanisms of effects.MethodsWe assessed the causal relationship between circulating serum metabolites (CSMs) and HS using a bidirectional two-sample MR method supplemented with five ways: weighted median, MR Egger, simple mode, weighted mode, and MR-PRESSO. The Cochran Q-test, MR-Egger intercept test, and MR-PRESSO served for the sensitivity analyses. The Steiger test and reverse MR were used to estimate reverse causality. Metabolic pathway analyses were performed using MetaboAnalyst 5.0, and genetic effects were assessed by linkage disequilibrium score regression. Significant metabolites were further synthesized using meta-analysis, and we used multivariate MR to correct for common confounders.ResultsWe finally recognized four metabolites, biliverdin (OR 0.62, 95% CI 0.40–0.96, PMVMR = 0.030), linoleate (18. 2n6) (OR 0.20, 95% CI 0.08–0.54, PMVMR = 0.001),1-eicosadienoylglycerophosphocholine* (OR 2.21, 95% CI 1.02–4.76, PMVMR = 0.044),7-alpha-hydroxy-3 -oxo-4-cholestenoate (7-Hoca) (OR 0.27, 95% CI 0.09–0.77, PMVMR = 0.015) with significant causal relation to HS.ConclusionWe demonstrated significant causal associations between circulating serum metabolites and hemorrhagic stroke. Monitoring, diagnosis, and treatment of hemorrhagic stroke by serum metabolites might be a valuable approach.

Abstract To explore the genetic causal association between pulmonary artery hypertension (PAH) and iron status through Mendelian randomization (MR), we conducted MR analysis using publicly available genome‐wide association study (GWAS) summary data. Five indicators related to iron status (serum iron, ferritin, total iron binding capacity (TIBC), soluble transferrin receptor (sTfR), and transferrin saturation) served as exposures, while PAH was the outcome. The genetic causal association between these iron status indicators and PAH was assessed using the inverse variance weighted (IVW) method. Cochran's Q statistic was employed to evaluate heterogeneity. We assessed pleiotropy using MR‐Egger regression and MR‐Presso test. Additionally, we validated our results using the Weighted median, Simple mode, and Weighted mode methods. Based on the IVW method, we found no causal association between iron status (serum iron, ferritin, TIBC, sTfR, and transferrin saturation) and PAH (pβ > 0.05). The Weighted median, Simple mode, and Weighted mode methods showed no potential genetic causal association (pβ > 0.05 in the three analyses). Additionally, no heterogeneity or horizontal pleiotropy was detected in any of the analyses. Our results show that there are no genetic causal association between iron status and PAH.

Introduction: Malnutrition is strongly associated with heart failure (HF); however, the causal link remains unclear. We used Mendelian randomization (MR) to infer causal associations between different nutritional assessment phenotypes and HF and to analyze whether these associations were mediated by common HF risk factors. Methods: Two-sample bidirectional MR was used to infer causal associations between nutritional assessment phenotypes and HF. Mutual influences between different nutritional assessment phenotypes and potential correlations were estimated using multivariate MR methods. Two-step MR was used to quantify the mediating effects of common HF risk factors on the causal associations. Results: Three phenotypes were positively associated with the development of HF: waist circumference (WC) (odds ratio [OR] = 1.74; 95% confidence interval [CI], 1.60–1.90; P = 3.95 × 10−39), body mass index (BMI) (OR = 1.70; 95%CI, 1.60–1.80; P = 1.35 × 10−73), and whole body fat mass (WBFM) (OR = 1.54; 95%CI, 1.44–1.65; P = 4.82 × 10−37). Multivariate MR indicated that WBFM remained positively associated with HF after conditioning on BMI and WC (OR = 2.05; 95%CI, 1.27–3.31; P = 0.003). Three phenotypes were negatively correlated with the development of HF: usual walking pace (UWP) (OR = 0.40; 95%CI, 0.27–0.60; P = 8.41 × 10−6), educational attainment (EA) (OR = 0.73; 95%CI, 0.67–0.79; P = 2.27 × 10−13), and total cholesterol (TC) (OR = 0.90; 95%CI, 0.84–0.96; P = 4.22 × 10−3). There was a bidirectional causality between HF and UWP (Effect estimate = −0.03; 95%CI, −0.05 to −0.01; P = 1.95 × 10−3). Mediation analysis showed that common risk factors for HF (hypertension, coronary artery disease, cardiomyopathy, and valvular heart disease) mediated these causal associations (all P

Abstract Background Atopic dermatitis is one of the most common skin disorders. Evidence has suggested an association between skin disorders, such as atopic dermatitis, and Parkinson's disease (PD). However, whether atopic dermatitis has a causal effect on PD remains unknown. Methods The study aimed to determine whether their association between atopic dermatitis and PD is causal, using a bidirectional two‐sample Mendelian randomization method. Genetic variants from the public genome‐wide association studies for atopic dermatitis (n = 10788 cases and 30047 controls) were selected to evaluate their causal effects on the risk of PD (33,674 cases and 449,056 controls). The inverse variance weighted (IVW) method was used as the primary analysis. Results The IVW results indicated that atopic dermatitis was associated with decreased risk of PD {fixed effects: odds ratio [OR] [95% confidence interval (CI)]: .905 [.832–.986], p = .022; OR [95% CI]: .905 [.827–.991], p = .032}. However, we failed to detect the causal effects of PD on risk of atopic dermatitis in the reverse causation analysis. Conclusion This study indicated causal association of genetically proxied atopic dermatitis with the risk of PD. Future studies are warranted to explore the underlying mechanism and investigate the targeting effect of atopic dermatitis on PD.

Abstract The incidences of periodontitis and osteoporosis are rising worldwide. Observational studies have shown that periodontitis is associated with increased risk of osteoporosis. We performed a Mendelian randomization (MR) study to genetically investigate the causality of periodontitis on osteoporosis. We explored the causal effect of periodontitis on osteoporosis by MR analysis. A total of 9 single nucleotide polymorphisms (SNP) were related to periodontitis. The primary approach in this MR analysis was the inverse variance-weighted (IVW) method. Simple median, weighted median, and penalized weighted median were used to analyze sensitivity. The fixed-effect IVW model and random-effect IVW model showed no significant causal effect of genetically predicted periodontitis on the risk of osteoporosis (OR=1.032; 95%CI: 0.923-1.153; P=0.574; OR=1.032; 95%CI: 0.920-1.158; P=0.588, respectively). Similar results were observed in simple mode (OR=1.031; 95%CI: 0.780-1.361, P=0.835), weighted mode (OR=1.120; 95%CI: 0.944-1.328, P=0.229), simple median (OR=1.003; 95%CI: 0.839-1.197, P=0.977), weighted median (OR=1.078; 95%CI: 0.921-1.262, P=0.346), penalized weight median (OR 1.078; 95%CI: 0.919-1.264, P=0.351), and MR-Egger method (OR=1.360; 95%CI: 0.998-1.853, P=0.092). There was no heterogeneity in the IVW and MR-Egger analyses (Q=7.454, P=0.489 and Q=3.901, P=0.791, respectively). MR-Egger regression revealed no evidence of a pleiotropic influence through genetic variants (intercept: -0.004; P=0.101). The leave-one-out sensitivity analysis indicated no driven influence of any individual SNP on the association between periodontitis and osteoporosis. The Mendelian randomization analysis did not show a significant detrimental effect of periodontitis on the risk of osteoporosis.

Abstract Background Previous observational studies indicated that atrial fibrillation may increase the risk of breast cancer. Following a breast cancer diagnosis, the chance of developing atrial fibrillation may increase as well. However, it is uncertain whether the link is causal or just due to confounding factors. Objective Using bidirectional Mendelian randomization (MR) analysis, we sought to assess the bidirectional causal relationship between atrial fibrillation and breast cancer from a genetic level. Methods Large genome‐wide association studies yielded summary‐level data for atrial fibrillation and breast cancer. The preliminary estimate was inverse variance weighted (IVW) under a random model. MR–Egger, weighted median, simple mode, weighted mode, and multivariable MR (adjusting body mass index, smoking, and alcohol drinking) were performed as sensitivity analyses. Results Genetically predicted atrial fibrillation presented no statistically significant association with overall breast cancer (odds ratio [OR] = 1.00; 95% confidence interval [CI]: 0.97–1.04; p = 0.79), estrogen receptor (ER) + (OR = 1.00; 95% CI: 0.96–1.03; p = 0.89) or ER− subtypes (OR = 1.00; 95% CI: 0.97–1.04; p = 0.89). Similarly, genetically predicted overall breast cancer (OR = 1.01; 95% CI: 0.98–1.04; p = 0.37), ER+ (OR = 1.02; 95% CI: 0.99–1.05; p = 0.16) or ER− (OR = 0.98; 95% CI: 0.93–1.02; p = 0.32) subtypes had no causal effect on atrial fibrillation. Sensitivity analyses yielded similar results. Individual single nucleotide polymorphism had little effect on the total estimate. We did not observe any evidence of horizontal pleiotropy. Conclusions Our bidirectional MR studies revealed that there may be no causal links between atrial fibrillation and breast cancer.

Background: Increasing evidence has shown a link between immune cells and Alzheimer's disease (AD). Comprehensive two-sample Mendelian randomization (MR) analysis was performed to determine the causal association between 731 immune cell signatures and AD in this study. Methods: We extracted genetic variants of 731 immune cell traits and AD from the publicly available GWAS dataset. The immune features included median fluorescence intensity (MFI), relative cellular (RC), absolute cellular (AC) and morphological parameters (MP). The inverse variance weighted (IVW) method was the main MR analysis method, and sensitivity analyses were used to validate the robustness, heterogeneity and horizontal pleiotropy of the results. Results: After FDR adjustment, seven immune phenotypes were found to be associated significantly with AD risk: HLA DR on CD33− HLA DR+ (OR = 0.938, PFDR = 0.001), Secreting Treg %CD4 (OR = 0.972, PFDR = 0.021), HLA DR+ T cell AC (OR = 0.928, PFDR = 0.041), Activated & resting Treg % CD4 Treg (OR = 1.031, PFDR = 0.002), CD33 on CD33dim HLA DR+ CD11b+ (OR = 1.025, PFDR = 0.025), CD33 on CD14+ monocyte (OR = 1.026, PFDR = 0.027) and CD33 on CD66b++ myeloid cell (OR = 1.027, PFDR = 0.036). Conclusions: These findings demonstrated seven immune phenotypes were significantly associated with AD risk. This may provide researchers with a new perspective in exploring the biological mechanisms of AD and may lead to the exploration of earlier treatment.

Abstract Background The relationship between aging and osteoporosis is well established. However, the relationship between the body's physiological age, i.e. epigenetic age, and osteoporosis is not known. Our goal is to analyze the bidirectional causal relationship between epigenetic clocks and osteoporosis using a bidirectional Mendelian randomization study. Methods We used SNPs closely associated with GrimAge, Hannum, PhenoAge, and HorvathAge in epigenetic age and SNPs closely associated with femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density as instrumental variables, respectively, using the inverse variance weighting method and several other MR methods to assess the bidirectional causal relationship between epigenetic age and osteoporosis. Result There was no evidence of a clear causal relationship of epigenetic age (GrimAge, Hannum, PhenoAge, and HorvathAge) on femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density. In reverse Mendelian randomization analysis showed a significant causal effect of lumbar spine bone mineral density on GrimAge: odds ratio (OR) = 0.692, 95% confidence interval (CI) = (0.538–0.890), p = 0.004. The results suggest that a decrease in lumbar spine bone mineral density promotes an acceleration of GrimAge. Conclusion There was no significant bidirectional causal relationship between epigenetic age and osteoporosis A decrease in lumbar spine bone density may lead to an acceleration of the epigenetic clock "GrimAge". Our study provides partial evidence for a bidirectional causal effect between epigenetic age and Osteoporosis.