MR Pleiotropy Residual Sum And Outlier Research Articles

Causal relationship between genetic proxies for calcium channel blockers and the risk of depression: a drug-target Mendelian randomization study

BackgroundCalcium channel blockers (CCBs) are widely used in the clinical management of hypertension. Depression, a common comorbidity of hypertension, is an important issue in the management of hypertension. However, the impact of CCBs on depression risk remains controversial. We aim to investigate the causal effect of CCBs on depression through drug-target Mendelian randomization (MR) analysis.MethodsTo proxy CCBs, we utilized the genetic variations located in or around drug target genes that were related to systolic blood pressure (SBP). Coronary artery disease (CAD) served as the positive control outcome. Genetic summary data of SBP, CAD, and depression were obtained from genome-wide association studies (GWAS) based on European population. Inverse variance weighted (IVW) method was applied as the main analysis to estimate the causal effect. Cochran’s Q test, MR-Egger intercept, MR pleiotropy residual sum and outlier (MR-PRESSO) and leave-one-out sensitivity analysis were used to test the robustness of the results. Meta-analysis was applied to further confirm whether causal relationships existed between CCBs and depression.ResultsThe IVW results failed to reveal any causal relationship between genetic proxies for CCBs and depression (P > 0.05). Cochran’s Q test showed no evidence of heterogeneity (P > 0.05). The MR-Egger intercept test suggested no evidence of directional pleiotropy, and the MR pleiotropy residual sum and outlier (MR-PRESSO) global test for horizontal pleiotropy was also not significant (P > 0.05). Leave-one-out analysis did not reveal any genetic variant that influenced the results. In addition, the meta-analysis further confirmed the absence of a causal relationship.ConclusionThe present study indicates no association of genetic proxies for CCBs with depression. Further studies are necessary to provide definitive evidence.

Uterine leiomyoma causes an increase in systolic blood pressure: a two-sample Mendelian randomization study

ObjectivesHypertension and hypertensive disorders of pregnancy (HDP) are common diseases in women at different stages, which affect women’s physical and mental health, and the impact of the latter on the offspring cannot not be ignored. Observational studies have investigated the correlation between uterine leiomyoma (UL) and the above conditions, but the relationship remains unclear. In this study, we employed two-sample Mendelian randomization (MR) analysis to assess the association between UL and hypertension, HDP, as well as blood pressure.MethodsWe collected genetic association data of UL (35,474 cases), hypertension (129,909 cases), HDP (gestational hypertension with 8,502 cases, pre-eclampsia with 6,663 cases and eclampsia with 452cases), systolic blood pressure (SBP) and diastolic blood pressure (DBP) (both 757,601 participants) from published available genome-wide association studies (GWAS). The single nucleotide polymorphisms (SNPs) associated with UL phenotype were used as instrumental variables, and hypertension, three sub-types of HDP, SBP and DBP were used as outcomes. The inverse-variance weighted (IVW) method was employed as the primary method of causal inference. Heterogeneity was assessed using Cochran’s Q test, and sensitivity analyses were conducted using MR-Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) tests to evaluate the pleiotropy of instrumental variables. PhenoScanner search was used to remove confounding SNP. Robustness and reliability of the results were assessed using methods such as the weighted median and weighted mode.ResultsThe IVW analysis revealed a positive correlation between genetically predicted UL and SBP [odds ratio (OR)= 1.67, 95% confidence interval (CI):1.24~2.25, P = 0.0007], and no statistical association was found between UL and hypertension, HDP, or DBP. The MR-Egger regression suggested that the above causal relationships were not affected by horizontal pleiotropy. The weighted median method and weighted model produced similar results to the IVW.ConclusionBased on large-scale population GWAS data, our MR analysis suggested a causal relationship between UL and SBP. Therefore, women with UL, especially pregnant women, should pay attention to monitoring their blood pressure levels. For patients with hypertension who already have UL, interventions for UL may serve as potential therapeutic methods for managing blood pressure.

Associations of systemic inflammatory regulators with CKD and kidney function: evidence from the bidirectional mendelian randomization study

BackgroundPrevious observational studies have reported that systemic inflammatory regulators are related to the development of chronic kidney disease (CKD); however, whether these associations are causal remains unclear. The current study aimed to investigate the potential causal relationships between systemic inflammatory regulators and CKD and kidney function.MethodWe performed bidirectional two-sample Mendelian randomization (MR) analyses to infer the underlying causal associations between 41 systemic inflammatory regulators and CKD and kidney function. The inverse-variance weighting (IVW) test was used as the primary analysis method. In addition, sensitivity analyses were executed via the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test and the weighted median test.ResultsThe findings revealed 12 suggestive associations between 11 genetically predicted systemic inflammatory regulators and CKD or kidney function in the forward analyses, including 4 for CKD, 3 for blood urea nitrogen (BUN), 4 for eGFRcrea and 1 for eGFRcys. In the other direction, we identified 6 significant causal associations, including CKD with granulocyte-colony stimulating factor (GCSF) (IVW β = 0.145; 95% CI, 0.042 to 0.248; P = 0.006), CKD with stem cell factor (SCF) (IVW β = 0.228; 95% CI, 0.133 to 0.323; P = 2.40 × 10− 6), eGFRcrea with SCF (IVW β =-2.90; 95% CI, -3.934 to -1.867; P = 3.76 × 10− 8), eGFRcys with GCSF (IVW β =-1.382; 95% CI, -2.404 to -0.361; P = 0.008), eGFRcys with interferon gamma (IFNg) (IVW β =-1.339; 95% CI, -2.313 to -0.366; P = 0.007) and eGFRcys with vascular endothelial growth factor (VEGF) (IVW β =-1.709; 95% CI, -2.720 to -0.699; P = 9.13 × 10− 4).ConclusionsOur findings support causal links between systemic inflammatory regulators and CKD or kidney function both in the forward and reverse MR analyses.

Causal roles of educational duration in bone mineral density and risk factors for osteoporosis: a Mendelian randomization study.

Educational duration might play a vital role in preventing the occurrence and development of osteoporosis(OP). To assess the causal effect of educational duration on bone mineral density(BMD) and risk factors for OP by Mendelian randomization(MR) study. The causal relationship was analyzed using data from genome-wide association study(GWAS). Inverse variance weighting (IVW) was used as the main analysis method. Horizontal pleiotropy was identified by MR-Egger intercept test, MR pleiotropy residual sum and outlier (MR-PRESSO) test. The leave-one-out method was used as a sensitivity analysis. The IVW results indicated that there was a positive causal relationship between educational duration and BMD (OR = 1.012, 95%CI:1.003-1.022), physical activity(PA) (OR = 1.156, 95%CI:1.032-1.295), calcium consumption (OR = 1.004, 95%CI:1.002-1.005), and coffee intake (OR = 1.019, 95%CI:1.014-1.024). There was a negative association between whole body fat mass (OR = 0.950, 95%CI:0.939-0.961), time for vigorous PA (OR = 0.955, 95%CI:0.939-0.972), sunbath (OR = 0.987, 95%CI:0.986-0.989), salt consumption (OR = 0.965, 95%CI:0.959-0.971), fizzy drink intake (OR = 0.985, 95%CI:0.978-0.992), smoking (OR = 0.969, 95%CI:0.964-0.975), and falling risk (OR = 0.976, 95%CI:0.965-0.987). There was no significant association between educational duration and lean mass, time for light-to-moderate PA, milk intake, and alcohol intake. Horizontal pleiotropy was absent in this study. The results were robust under sensitivity analyses. A longer educational duration was causally linked with increased BMD. No causal relationship had been found between educational duration and lean mass, time for light-to-moderate PA, milk intake, and alcohol consumption as risk factors for osteoporosis.

Association between adding salt in food and dementia in European descent: A mendelian randomization study.

High salt intake has been proposed as a risk factor for dementia. However, causal relationship between salt intake and dementia remains uncertain. The aim of this study was to employ a mendelian randomization (MR) design to investigate the causal impact of salt intake on the risk of dementia. Genome-wide association study (GWAS) data of exposures and outcomes (any dementia, cognitive performance, different types of dementia, Alzheimer's disease [AD], and Parkinson's disease) were obtained from the IEU database. MR estimates were generated though inverse-variance weighted model. MR-Egger, weighted median, and MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) method also used in our study. Sensitivity analyses included Cochran's Q test, MR-Egger intercept, MR-PRESSO global test and outlier test, leave-one-out analysis, and funnel plot assessment. Our MR analysis provided evidence of a causal association between high salt added to food and dementia (odds ratio [OR]=1.73, 95% confidence interval [CI]: 1.21-2.49, and p=.003), dementia in AD (OR=2.10, 95% CI: 1.15-3.83, and p=.015), and undefined dementia (OR=2.61, 95% CI: 1.26-5.39, and p=.009). Higher salt added was also associated with increased risk of AD (OR=1.80, 95% CI: 1.12-2.87, and p=.014) and lower cognitive performance (β=-.133, 95% CI: -.229 to -.038, and p=.006). This study provides evidence suggesting that high salt intake is causally associated with an increased risk of developing dementia, including AD and undefined dementia, highlighting the potential importance of reducing salt consumption as a preventive measure.

Causal associations between gut microbiota and synovitis–tenosynovitis: a two-sample Mendelian randomization study

BackgroundIncreasing evidence indicates that gut microbiota dysbiosis is related to synovitis and tenosynovitis. Nonetheless, whether these associations are causal is currently unknown.ObjectivesA two-sample Mendelian randomization (MR) study was performed to reveal the causality of gut microbiota with synovitis and tenosynovitis.MethodsThe summary statistical data from a large-scale genome-wide association study (GWAS) were applied as the basis for a two-sample MR analysis. The causal effect was estimated using inverse variance weighted (IVW), weighted median, simple mode, MR-Egger, and weighted mode methods, of which IVW was the important method. Meanwhile, the pleiotropy and heterogeneity were detected and measured using MR-Egger regression, Cochran’s Q statistics, funnel plots, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods.ResultsThe IVW technique demonstrated that genetically predicted five genera, namely Gordonibacter [odds ratio (OR) = 0.999, 95% confidence interval (CI): (0.9977, 0.9998), p = 0.019], Paraprevotella [OR = 0.999, 95% CI: (0.9971, 0.9999), p = 0.036], Lachnoclostridium [OR = 0.998, 95% CI: (0.9954, 0.9999), p = 0.041], RuminococcaceaeUCG003 [OR = 0.997, 95% CI: (0.9955, 0.9994), p = 0.011], and FamilyXIIIAD3011group [OR = 0.997, 95% CI: (0.9954, 0.9992), p = 0.006] were negatively correlated with the risk of synovitis and tenosynovitis, while two other genera, namely Ruminococcustorquesgroup [OR = 1.003, 95% CI: (1.0004, 1.0049), p = 0.019] and Parabacteroides [OR = 1.003, 95% CI: (1.0002, 1.0052), p = 0.035] were positively associated with synovitis and tenosynovitis risk. In addition, the data of sensitivity analyses demonstrated that there were no outliers, horizontal pleiotropy, or heterogeneity in the causal relationship of the above-mentioned gut microbiota on synovitis and tenosynovitis (p > 0.05).ConclusionThe results of the study suggested that the gut microbiota was causally involved in synovitis and tenosynovitis and identified specific bacterial taxa that affect synovitis and tenosynovitis, which provide new insights into the pathogenesis underlying the development of synovitis and tenosynovitis mediated by gut microbiota.

Obstructive sleep apnea and mental disorders: a bidirectional mendelian randomization study

BackgroundPrevious studies have reported associations between obstructive sleep apnea (OSA) and several mental disorders. However, further research is required to determine whether these associations are causal. Therefore, we evaluated the bidirectional causality between the genetic liability for OSA and nine mental disorders by using Mendelian randomization (MR).MethodWe performed two-sample bidirectional MR of genetic variants for OSA and nine mental disorders. Summary statistics on OSA and the nine mental disorders were extracted from the FinnGen study and the Psychiatric Genomics Consortium. The primary analytical approach for estimating causal effects was the inverse-variance weighted (IVW), with the weighted median and MR Egger as complementary methods. The MR Egger intercept test, Cochran’s Q test, Rucker’s Q test, and the MR pleiotropy residual sum and outlier (MR-PRESSO) test were used for sensitivity analyses.ResultMR analyses showed that genetic liability for major depressive disorder (MDD) was associated with an increased risk of OSA (odds ratio [OR] per unit increase in the risk of MDD, 1.29; 95% CI, 1.11–1.49; P < 0.001). In addition, genetic liability for OSA may be associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD) (OR = 1.26; 95% CI, 1.02–1.56; p = 0.032). There was no evidence that OSA is associated with other mental disorders.ConclusionOur study indicated that genetic liability for MDD is associated with an increased risk of OSA without a bidirectional relationship. Additionally, there was suggestive evidence that genetic liability for OSA may have a causal effect on ADHD. These findings have implications for prevention and intervention strategies targeting OSA and ADHD. Further research is needed to investigate the biological mechanisms underlying our findings and the relationship between OSA and other mental disorders.

Strengthening the Evidence for a Causal Link between Type 2 Diabetes Mellitus and Pancreatic Cancer: Insights from Two-Sample and Multivariable Mendelian Randomization.

This two-sample Mendelian randomization (MR) study was conducted to investigate the causal associations between type 2 diabetes mellitus (T2DM) and the risk of pancreatic cancer (PaCa), as this causal relationship remains inconclusive in existing MR studies. The selection of instrumental variables for T2DM was based on two genome-wide association study (GWAS) meta-analyses from European cohorts. Summary-level data for PaCa were extracted from the FinnGen and UK Biobank databases. Inverse variance weighted (IVW) and four other robust methods were employed in our MR analysis. Various sensitivity analyses and multivariable MR approaches were also performed to enhance the robustness of our findings. In the IVW and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analyses, the odds ratios (ORs) for each 1-unit increase in genetically predicted log odds of T2DM were approximately 1.13 for PaCa. The sensitivity tests and multivariable MR supported the causal link between T2DM and PaCa without pleiotropic effects. Therefore, our analyses suggest a causal relationship between T2DM and PaCa, shedding light on the potential pathophysiological mechanisms of T2DM's impact on PaCa. This finding underscores the importance of T2DM prevention as a strategy to reduce the risk of PaCa.

Causal impact of gut microbiota and associated metabolites on pulmonary arterial hypertension: a bidirectional Mendelian randomization study.

Patients with pulmonary arterial hypertension (PAH) exhibit a distinct gut microbiota profile; however, the causal association between gut microbiota, associated metabolites, and PAH remains elusive. We aimed to investigate this causal association and to explore whether dietary patterns play a role in its regulation. Summary statistics of gut microbiota, associated metabolites, diet, and PAH were obtained from genome-wide association studies. The inverse variance weighted method was primarily used to measure the causal effect, with sensitivity analyses using the weighted median, weighted mode, simple mode, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger methods. A reverse Mendelian randomisation analysis was also performed. Alistipes (odds ratio [OR] = 2.269, 95% confidence interval [CI]1.100-4.679, P = 0.027) and Victivallis (OR = 1.558, 95% CI 1.019-2.380, P = 0.040) were associated with an increased risk of PAH, while Coprobacter (OR = 0.585, 95% CI 0.358-0.956, P = 0.032), Erysipelotrichaceae (UCG003) (OR = 0.494, 95% CI 0.245-0.996, P = 0.049), Lachnospiraceae (UCG008) (OR = 0.596, 95% CI 0.367-0.968, P = 0.036), and Ruminococcaceae (UCG005) (OR = 0.472, 95% CI 0.231-0.962, P = 0.039) protected against PAH. No associations were observed between PAH and gut microbiota-derived metabolites (trimethylamine N-oxide[TMAO] and its precursors betaine, carnitine, and choline), short-chain fatty acids(SCFAs), or diet. Although inverse variance-weighted analysis demonstrated that elevated choline levels were correlated with an increased risk of PAH, the results were not consistent with the sensitivity analysis. Therefore, the association was considered insignificant. Reverse Mendelian randomisation analysis demonstrated that PAH had no causal impact on gut microbiota-derived metabolites but could contribute to increasedthelevels of Butyricicoccus and Holdemania, while decreasing the levels ofClostridium innocuum, Defluviitaleaceae UCG011, Eisenbergiella, and Ruminiclostridium 5. Gut microbiota were discovered suggestive evidence of the impacts of genetically predicted abundancy of certain microbial genera on PAH. Results of our study point that the production of SCFAs or TMAO does not mediate this association, which remains to be explained mechanistically.

The Association between Obstructive Sleep Apnea and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

Background Despite previous observational studies linking obstructive sleep apnea (OSA) to venous thromboembolism (VTE), these findings remain controversial. This study aimed to explore the association between OSA and VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), at a genetic level using a bidirectional two-sample Mendelian randomization (MR) analysis. Methods Utilizing summary-level data from large-scale genome-wide association studies (GWAS) in European individuals, we designed a bidirectional two-sample MR analysis to comprehensively assess the genetic association between OSA and VTE. The inverse variance weighting (IVW) was used as the primary method for MR analysis. In addition, MR-Egger, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for complementary analyses. Furthermore, a series of sensitivity analyses were performed to ensure the validity and robustness of the results. Results The initial and validation MR analyses indicated that genetically predicted OSA had no effects on the risk of VTE (including PE and DVT). Likewise, the reverse MR analysis did not find substantial support for a significant association between VTE (including PE and DVT) and OSA. Supplementary MR methods and sensitivity analyses provided additional confirmation of the reliability of the MR results. Conclusion Our bidirectional two-sample MR analysis did not find genetic evidence supporting a significant association between OSA and VTE in either direction.

Assessment of causal association between the socio-economic status and osteoporosis and fractures: a bidirectional Mendelian randomization study in European population.

The relationship between socio-economic status and bone-related diseases is attracting increasing attention. Therefore, a bidirectional Mendelian randomization (MR) analysis was performed in this study. Genetic data on factors associated with socio-economic status (average total household income before tax, years of schooling completed and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fracture (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses, and multivariable MR was performed to enhance the robustness of our findings. A higher educational attainment was associated with an increased level of eBMD (beta:0.06, 95% CI:0.01-0.10, P = 7.24 × 10-3), and decreased risk of osteoporosis (OR:0.78, 95% CI:0.65-0.94, P = 8.49 × 10-3), spine fracture (OR:0.76, 95% CI:0.66-0.88, P = 2.94 × 10-4), femur fracture (OR:0.78, 95% CI:0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR:0.79, 95% CI:0.70-0.88, P = 2.05 × 10-5), foot fracture (OR:0.78, 95% CI:0.66-0.93, P = 5.92 × 10-3) and wrist-hand fracture (OR:0.83, 95% CI:0.73-0.95, P = 7.15 × 10-3). Further, material deprivation seemed to harm the spine fracture (OR:2.63, 95% CI:1.43-4.85, P = 1.91 × 10-3). A higher level of FN-BMD positively affected increased household income (beta:0.03, 95% CI:0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index (BMI), type 2 diabetes, smoking initiation, and frequency of alcohol intake. The Mendelian randomization analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings offer valuable insights into the formulation of health guidelines and policy development.

Causal association between gut microbiomes and different types of aneurysms: a Mendelian randomization study.

Previous studies suggests that gut microbiomes are associated with the formation and progression of aneurysms. However, the causal association between them remains unclear. A two-sample Mendelian randomization was conducted to investigate whether gut microbiomes have a causal effect on the risk of intracerebral aneurysm (IA), thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA), and aortic aneurysm (AA). Single nucleotide polymorphisms (SNPs) smaller than the locus-wide significance level (1 × 10-5) were selected as instrumental variables. We used inverse-variance weighted (IVW) test as the primary method for the evaluation of causal association. MR-Egger, weighted median, weighted mode, and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods were conducted for sensitive analysis. The p-value was adjusted by the false discovery rate (FDR) which adjust the results of multiple comparisons, a p < 0.05 and q < 0.1 was considered a significant causal association. Additionally, a p < 0.05 and q > 0.1 was considered a suggestive causal effect. Additionally, reverse MR was also performed to exclude the possibility of reverse causality. The phylum Firmicutes (OR = 0.62; 95% CI, 0.48-0.81), class Lentisphaeria (OR = 0.75; 95% CI, 0.62-0.89), and order Victivallales (OR = 0.75; 95% CI, 0.62-0.89) have a causal protective effect on the risk of AAA. Additionally, class Verrucomicrobia, class Deltaproteobacteria, order Verrucomicrobiale, family Verrucomicrobiacea, genus Eubacterium rectale group, genus Akkermansia, and genus Clostridium innocuum group were negatively associated with the risk of different types of aneurysms, whereas class Negativicutes, order Selenomonadales, and genus Roseburia had positive causal association with different types of aneurysms (p < 0.05; q > 0.1). Further sensitivity analysis validated the robustness of our MR results, and no reverse causality was found with these gut microbiomes (p > 0.05). Our MR analysis confirmed the causal association of specific gut microbiomes with AAA, and these microbiomes were considered as protective factors. Our result may provide novel insights and theoretical basis for the prevention of aneurysms through regulation of gut microbiomes.

Gut microbiota's influence on erysipelas: evidence from a two-sample Mendelian randomization analysis.

Previous studies have suggested a link between gut microbiota and skin diseases, including erysipelas, an inflammatory skin condition. Despite this, the precise nature of the relationship between erysipelas and gut microbiota remains unclear and subject to debate. We conducted a Mendelian Randomization (MR) analysis using publicly available summary data from genome-wide association studies (GWAS) to explore the potential causal relationship between gut microbiota and erysipelas. Instrumental variables (IVs) were identified using a comprehensive set of screening methods. We then performed MR analyses primarily using the Inverse Variance Weighted (IVW) method, complemented by alternative approaches such as MR Egger, weighted median, simple mode, and weighted mode. A series of sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test, and a leave-one-out test, were executed to ensure the robustness and validity of our findings. We identified potential associations between erysipelas and various gut microbiota, including Alcaligenaceae (OR 1.23; 95% CI 1.06-1.43; p=0.006), Rikenellaceae (OR 0.77; 95% CI 0.67-0.90; p=0.001), and others. Notably, associations with Actinomyces, Lachnospiraceae NC2004 group, Ruminiclostridium 9, Ruminococcaceae UCG014, Odoribacter, and Actinobacteria were also observed. Sensitivity analyses confirmed the robustness of these associations. Our MR analysis suggests both potentially beneficial and harmful causal relationships between various gut microbiota and the incidence of erysipelas. This study provides new theoretical and empirical insights into the pathogenesis of erysipelas and underscores the potential for innovative preventive and therapeutic approaches.

Association of birth weight with type 2 diabetes mellitus and the mediating role of fatty acids traits: a two-step mendelian randomization study

BackgroundObservational studies have suggested an association between birth weight and type 2 diabetes mellitus, but the causality between them has not been established. We aimed to obtain the causal relationship between birth weight with T2DM and quantify the mediating effects of potential modifiable risk factors.MethodsTwo-step, two-sample Mendelian randomization (MR) techniques were applied using SNPs as genetic instruments for exposure and mediators. Summary data from genome-wide association studies (GWAS) for birth weight, T2DM, and a series of fatty acids traits and their ratios were leveraged. The inverse variance weighted (IVW) method was the main analysis approach. In addition, the heterogeneity test, horizontal pleiotropy test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, and leave-one-out analysis were carried out to assess the robustness.ResultsThe IVW method showed that lower birth weight raised the risk of T2DM (β: −1.113, 95% CI: −1.573 ∼ −0.652). Two-step MR identified 4 of 17 candidate mediators partially mediating the effect of lower birth weight on T2DM, including ratio of polyunsaturated fatty acids to monounsaturated fatty acids (proportion mediated: 7.9%), ratio of polyunsaturated fatty acids to total fatty acids (7.2%), ratio of omega-6 fatty acids to total fatty acids (8.1%) and ratio of linoleic acid to total fatty acids ratio (6.0%).ConclusionsOur findings supported a potentially causal effect of birth weight against T2DM with considerable mediation by modifiable risk factors. Interventions that target these factors have the potential to reduce the burden of T2DM attributable to low birth weight.

The Gut Microbiota-Constipation Connection: Insights from a Two Sample Bidirectional Mendelian Randomization Study

The dysbiosis of the gut microbiota has been implicated in various maladies. Research has identified an association between the dysbiosis of the gut microbiota and the risk of constipation, prompting this study to elucidate the potential causal relationship between gut microbiota imbalance with constipation through a two sample bidirectional Mendelian randomization (MR) study, shedding light on the genetic mechanisms underlying the connection between gut microbiota and constipation. The forward MR analysis aimed to scrutinize whether alterations in the composition and abundance of gut microbiota impact the risk of constipation, while the reverse MR analysis explored whether the genetic predisposition to constipation influences the abundance of gut microbiota. Genomic correlation data for the gut microbiota were sourced from the comprehensive statistics of the MiBioGen consortium. Genomic correlation data for constipation were obtained from the IEU database, encoded as the dataset ebi-a-GCST90018829. The correlation was assessed using various analytical techniques, including inverse variance weighting (IVW), Mendelian randomization-Egger regression (MR-Egger), and weighted median and mode methodologies. To ensure the robustness of the results, a meticulous sensitivity analysis was conducted, incorporating Cochran's Q test, MR-Egger intercept test, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and a Leave-one-out analysis. In the forward Mendelian randomization analyses, a negative correlation was discerned between the abundance of Coprococcus in the gut microbiota and the occurrence of constipation (IVW: OR = 0.74, 95% CI = 0.64-0.86, p = 0.0001), whereas a positive correlation was observed between the abundance of Bacteroidetes in the gut microbiota and constipation (IVW: OR = 1.22, 95% CI = 1.00-1.50, p = 0.04).In the forward Mendelian randomization analyses, we were unsuccessful in obtaining valid instrumental variables for scrutiny, and we deemed that constipation exerts no influence on the composition of the gut microbiota. Genetic predisposition towards increased abundance of Coprococcus and decreased abundance of Bacteroidetes is correlated with a diminished susceptibility to constipation. This investigation showed that alterations in the gut microbiota precipitated the onset of constipation, rather than constipation inducing modifications in the microbial flora.

The genetic causal relationship between type 2 diabetes, glycemic traits and venous thromboembolism, deep vein thrombosis, pulmonary embolism: a two-sample Mendelian randomization study

ObjectiveTo investigate the genetic underpinnings of the association between type 2 diabetes (T2D), glycemic indicators such as fasting glucose (FG), fasting insulin (FI), and glycated hemoglobin (GH), and venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), thereby contributing novel insights to the scholarly discourse within this domain.MethodsGenome-wide association study (GWAS) summary data pertaining to exposures (T2D, FG, FI, GH) and outcomes (VTE, DVT, PE) were acquired from the IEU Open GWAS database, encompassing participants of European descent, including both male and female individuals. Two-sample Mendelian randomization (MR) analyses were conducted utilizing the TwoSampleMR and MRPRESSO packages within the R programming environment. The primary analytical approach employed was the random-effects inverse variance weighted (IVW) method. Heterogeneity was assessed via Cochran’s Q statistic for MR-IVW and Rucker’s Q statistic for MR-Egger. Horizontal pleiotropy was evaluated using the intercept test of MR Egger and MR pleiotropy residual sum and outlier (MR-PRESSO) analysis, with the latter also employed for outlier detection. Additionally, a “Leave one out” analysis was conducted to ascertain the influence of individual single nucleotide polymorphisms (SNPs) on MR results.ResultsThe random-effects IVW analysis revealed a negative genetic causal association between T2D) and VTE (P = 0.008, Odds Ratio [OR] 95% confidence interval [CI] = 0.896 [0.827–0.972]), as well as between FG and VTE (P = 0.002, OR 95% CI = 0.655 [0.503–0.853]), GH and VTE (P = 0.010, OR 95% CI = 0.604 [0.412–0.884]), and GH and DVT (P = 0.002, OR 95% CI = 0.413 [0.235–0.725]). Conversely, the random-effects IVW analysis did not detect a genetic causal relationship between FI and VTE (P > 0.05), nor between T2D, FG, or FI and DVT (P > 0.05), or between T2D, FG, FI, or GH and PE (P > 0.05). Both the Cochran’s Q statistic for MR-IVW and Rucker’s Q statistic for MR-Egger indicated no significant heterogeneity (P > 0.05). Moreover, the intercept tests of MR Egger and MR-PRESSO suggested the absence of horizontal pleiotropy (P > 0.05). MR-PRESSO analysis identified no outliers, while the “Leave one out” analysis underscored that the MR analysis was not influenced by any single SNP.ConclusionOur investigation revealed that T2D, FG, and GH exhibit negative genetic causal relationships with VTE at the genetic level, while GH demonstrates a negative genetic causal relationship with DVT at the genetic level. These findings furnish genetic-level evidence warranting further examination of VTE, DVT, and PE, thereby making a contribution to the advancement of related research domains.

Causal associations between human gut microbiota and hemorrhoidal disease: A two-sample Mendelian randomization study.

Hemorrhoidal disease (HEM) is a common condition affecting a significant proportion of the population. However, the causal relationship between the gut microbiota and hemorrhoids remains unclear. In this study, we employed a Mendelian randomization (MR) approach to investigate the potential associations between them. In this study, the exposure factor was determined by selecting summary statistics data from a large-scale gut microbiome whole-genome association study conducted by the MiBioGen Consortium, which involved a sample size of 18,340 individuals. The disease outcome data consisted of 218,920 cases of HEM and 725,213 controls of European ancestry obtained from the European Bioinformatics Institute dataset. Two-sample MR analyses were performed to assess the causalities between gut microbiota and hemorrhoids using various methods, including inverse-variance weighting, MR-Egger regression, MR Pleiotropy Residual Sum and Outlier (MR-PRESSO), simple mode, and weighted median. Reverse MR analyses were performed to examine reverse causal association. Our findings suggest phylum Cyanobacteria (OR = 0.947, 95% CI: 0.915-0.980, P = 2.10 × 10 - 3), genus Phascolarctobacterium (OR = 0.960, 95% CI: 0.924-0.997, P = .034) and family FamilyXI (OR = 0.974, 95% CI: 0.952-0.997, P = .027) have potentially protective causal effects on the risk of HEM, while genus Ruminococcaceae_UCG_002 (OR = 1.036, 95% CI: 1.001-1.071, P = .042), family Peptostreptococcaceae (OR = 1.042, 95% CI: 1.004-1.082, P = .029), genus Oscillospira (OR = 1.048, 95% CI: 1.005-1.091, P = .026), family Alcaligenaceae (OR = 1.048, 95% CI: 1.005-1.091, P = .036) and order Burkholderiales (OR = 1.074, 95% CI: 1.020-1.130, P = 6.50 × 10-3) have opposite effect. However, there was a reverse causal relationship between HEM and genus Oscillospira (OR = 1.140, 95% CI: 1.002-1.295, P = .046) This is the first MR study to explore the causalities between specific gut microbiota taxa and hemorrhoidal disease, which may offer valuable insights for future clinical interventions for hemorrhoidal disease.

Metformin treatment reduces the incidence of osteoporosis: a two-sample Mendelian randomized study.

We utilize a MR approach to investigate the association between metformin treatment and the risk of OP. Metformin treatment was selected as exposures. Outcomes included OP; BMD at the forearm (FA), femoral neck (FN), and lumbar spine (LS); estimated heel bone mineral density (eBMD); and fracture. Summary statistics for exposures and outcomes were obtained from corresponding genome-wide association studies. Inverse variance-weighted (IVW) analysis was mainly applied; the weighted median (WM), penalized weighted median (PWM), maximum likelihood (ML), and MR-Egger regression (MR-Egger) method were also used to obtain robust estimates. A series of sensitivity analyses including Cochran's Q test, MR-Egger regression, leave-one-out analysis, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were used to detect pleiotropy or heterogeneity. In the main analysis, IVW estimates demonstrated that metformin treatment had a definite causal effect on the risk of OP (odds ratio (OR): 0.859, 95% CI: 0.774-0.953, P = 0.004), LS-BMD (OR: 1.063, 95% CI: 1.023-1.105, P = 0.002), FN-BMD (OR: 1.034, 95% CI: 1.000-1.069, P = 0.049), eBMD (OR: 1.035, 95% CI: 1.023-1.047, P ≤ 0.001), and fracture(OR: 0.958, 95% CI: 0.928-0.989, P = 0.008). However, it did not have an effect on FA-BMD(OR: 1.050, 95% CI: 0.969-1.138, P = 0.237). This study indicated that metformin treatment is significantly associated with a reduction in the risk of OP, fracture and higher LS-BMD, FN-BMD, and eBMD. However, there was no significant association with FA-BMD.

Causal effects of glycemic traits and endometriosis: a bidirectional and multivariate mendelian randomization study

BackgroundObservational studies have suggested an association between endometriosis and glycemic traits, but causality remains unclear. We used bidirectional and multivariate Mendelian randomization (MR) to examine the causal effect of glycemic traits on endometriosis and vice versa.MethodsWe obtained genome-wide association studies summary data of endometriosis and glycemic traits in our study. Inverse variance weighted (IVW), Weighted median, MR-Egger and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were applied in bidirectional two-sample MR analyses. MVMR was implemented to estimate the causal effect for fasting insulin (FI), fasting glucose (FG), and glycosylated hemoglobin A1c (HbA1c) on endometriosis. To test the validity of our findings, a number of sensitivity analyses were conducted.ResultsThe risk of endometriosis was significantly increased by genetically predicted T1DM (OR = 1.02, 95% CI 1.00-1.04, p = 0.0171, q = 0.0556) and GDM (OR = 1.01, 95% CI 1.01–1.02, p = 1.34 × 10− 8, q = 1.74 × 10− 7). Endometriosis had a suggestive association with HbA1c (Beta = 0.04, 95% CI 0.00-0.08, p = 0.0481, q = 0.1251). Using multivariate Mendelian randomization (MVMR), a significant causal effect of FI on genetically predicted endometriosis was found (OR = 2.18, 95% CI 1.16–4.09, p = 0.0154, q = 0.0547). Moreover, no causal associations between endometriosis and other glycemic traits were detected.ConclusionOur findings supported the significant causal associations of T1DM, GDM and FI with endometriosis, respectively. Additionally, a suggestive association was found of endometriosis on HbA1c. Importantly, our study may shed light on etiology studies and clinical management of endometriosis.

Periodontitis and Sjogren’s syndrome: a bidirectional two-sample mendelian randomization study

ObjectivesObservational studies indicated a controversial relationship between periodontitis (PD) and Sjogren’s syndrome (SS). To overcome restrictions in conventional observational studies, we conducted a two-sample Mendelian randomization (MR) analysis to assess the potential bidirectional relationship between PD and SS.MethodsWe utilized the largest available genome-wide association study (GWAS) of European ancestry on both PD (17,353 cases-28,210 controls) and SS (2495 cases-365,533 controls) for MR genetic instrument selection. The random-effect inverse-variance weighted (IVW) method complemented by Causal Analysis Using Summary Effect (CAUSE), weighted median, weighted mode, simple mode, MR-Egger regression, and MR-pleiotropy residual sum and outlier (MR-PRESSO) was used for MR analysis. Subsequent pleiotropy and heterogeneity tests were conducted.ResultsIVW analysis exhibited neither an effect of PD on SS (OR = 0.939, 95%CI = 0.525–1.677, P = 0.8304) nor that of SS on PD (OR = 1.007, 95%CI = 0.977–1.038, P = 0.6440). The other five complementary methods further recognized the null association with an effect size close to one. No significant pleiotropy was detected in the relationship between PD and SS (P > 0.05). Heterogeneity existed in the effect of PD on SS but not vice versa.ConclusionsNo genetic causality between PD and SS or vice versa was supported by our results under MR assumptions and limitations. The study results provided new insights into the relationship between periodontal status and sjogren’s syndrome, highlighting the need for a more prudent medical intervention.