Inverse-variance Weighted Analysis Research Articles

Causal associations between gastroesophageal reflux disease and essential hypertension: A bidirectional Mendelian randomization study.

Clinical studies have reported that patients with gastroesophageal reflux disease (GERD) have a higher prevalence of hypertension. To performed a bidirectional Mendelian randomization (MR) analysis to investigate the causal link between GERD and essential hypertension. Eligible single nucleotide polymorphisms (SNPs) were selected, and weighted median, inverse variance weighted (IVW) as well as MR egger (MR-Egger) regression were used to examine the potential causal association between GERD and hypertension. The MR-Pleiotropy RESidual Sum and Outlier analysis was used to detect and attempt to reduce horizontal pleiotropy by removing outliers SNPs. The MR-Egger intercept test, Cochran's Q test and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of single instrumental variable. IVW analysis exhibited an increased risk of hypertension (OR = 1.46, 95%CI: 1.33-1.59, P = 2.14E-16) in GERD patients. And the same result was obtained in replication practice (OR = 1.002, 95%CI: 1.0008-1.003, P = 0.000498). Meanwhile, the IVW analysis showed an increased risk of systolic blood pressure (β = 0.78, 95%CI: 0.11-1.44, P = 0.021) and hypertensive heart disease (OR = 1.68, 95%CI: 1.36-2.08, P = 0.0000016) in GERD patients. Moreover, we found an decreased risk of Barrett's esophagus (OR = 0.91, 95%CI: 0.83-0.99, P = 0.043) in essential hypertension patients. We found that GERD would increase the risk of essential hypertension, which provided a novel prevent and therapeutic perspectives of essential hypertension.

Inflammatory cytokines and oral lichen planus: a Mendelian randomization study.

Inflammatory cytokines have long been considered closely related to the development of oral lichen planus (OLP), and we further explored the causal relationship between the two by Mendelian randomization (MR) method. We performed bidirectional MR analyses by large genome-wide association studies (GWAS). The data included a large-scale OLP dataset, as well as datasets of 41 inflammatory cytokines. All data were obtained from the University of Bristol database, which includes 41 inflammatory cytokines, and the GWAS Catalog database, which includes 91 inflammatory cytokines. OLP data were obtained from the Finngen database, which includes 6411 cases and 405770 healthy controls. We used the inverse variance weighted (IVW) method, MR-Egger method, weighted median method, simple mode method and weighted mode method to analyze the causal relationship between inflammatory cytokines and OLP, and we also combined with sensitivity analysis to further verify the robustness of the results. We performed a meta-analysis of positive or potentially positive results for the same genes to confirm the reliability of the final results. We primarily used the IVW analysis method, corrected using the Benjamin Hochberg (BH) method. When p<0.00038 (0.05/132), the results are significantly causal; when 0.00038<p<0.05, the results are potentially causal. We found a total of 7 inflammatory cytokines with significant or potential associations with OLP (University of Bristol database: 2, GWAS Catalog database: 5). In the reverse analysis, we found that a total of 30 inflammatory cytokines were significantly or potentially associated with OLP (University of Bristol database: 5, GWAS Catalog database: 25). After sensitivity analysis and meta-analysis, we finally determined that there was a causal relationship between a total of 3 inflammatory cytokines and OLP in the forward analysis, the most significant of which was FGF21 (p=0.02954, odds ratio (OR): 1.113, 95% confidence interval (95%CI): 1.011-1.226). In the reverse analysis, 14 inflammatory cytokines were causally associated with OLP, the most significant of which was PLAU (p=0.00002, OR: 0.951, 95%CI: 0.930-0.973). There is a causal association between OLP and some inflammatory cytokines, which may play an important role in the pathogenesis of OLP and require further attention.

Sjögren’s Disease and Oral Health: A Genetic Instrumental Variable Analysis

Epidemiological studies have consistently shown that Sjögren’s disease (SjD) increases the risk of dental caries. Despite similar evidence indicating an elevated risk of periodontitis, SjD remains a disputed risk factor for this disease. The risk of bias in observational research is a major impediment to confirming this link. Within an instrumental variable framework, genetic variants associated with a risk factor can be used to proxy its effect on an outcome while avoiding common sources of observational study bias. In this study, we leveraged an instrumental variable approach to investigate whether SjD affects the risk of caries and periodontitis. A total of 57 genetic variants strongly associated with SjD were identified from a genome-wide association study of 2,247 European descent cases and 332,115 controls. We tested for associations of these genetic instruments with caries (measured as the number of decayed, missing, and filled surfaces in 26,792 individuals) and periodontitis (17,353 clinical periodontitis cases and 28,210 European controls). Several sensitivity analyses were used to further validate the primary inverse variance weighted (IVW) estimate. IVW analysis revealed an adverse effect of SjD on caries (β = 0.039, P = 6.3e-16) and periodontitis (odds ratio = 1.033, P = 2.3e-05). Sensitivity analyses, conducted to assess the robustness to potential violations of instrumental variable assumptions, further support these findings. Our results showed that SjD has a detrimental effect on caries and also suggest that SjD promotes periodontitis.

Anxiety disorder and cardiovascular disease: a two-sample Mendelian randomization study.

Cardiovascular disease is the leading cause of death worldwide. Anxiety disorders are common psychiatric conditions associated with cardiovascular outcomes. This two-sample Mendelian randomization (MR) study investigated the causal relationship between anxiety disorders and coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). Single nucleotide polymorphisms (SNPs) associated with anxiety disorders (16730 cases; 101021 controls) were obtained from the UK Biobank genome-wide association study (GWAS). Cardiovascular outcome data were derived from the FinnGen study (CHD: 21012 cases and 197780 controls; MI: 12801 cases and 187840 controls; HF: 23397 cases and 194811 controls; and AF: 22068 cases and 116926 controls). Inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode analyses examined causality. IVW analysis demonstrated significant causal relationships between anxiety disorders and increased risk of CHD [odds ratio (OR): 4.496; 95% confidence interval (CI): 1.777-11.378; P=0.002], MI (OR: 5.042; 95% CI: 1.451-17.518; P=0.011), and HF (OR: 3.255; 95% CI: 1.461-7.252; P=0.004). No relationship was observed with AF (OR: 1.775; 95% CI: 0.612-5.146; P=0.29). Other methods showed non-significant associations. Two-way analysis indicated no reverse causality. Anxiety disorders were causally associated with greater risk of CHD, MI, and HF but not AF among individuals of European descent. Further research on mediating mechanisms and in diverse populations is warranted.

Causal associations between circulating inflammatory cytokines and blinding eye diseases: a bidirectional Mendelian randomization analysis.

Previous studies have explored the associations between circulating inflammatory cytokines and blinding eye diseases, including glaucoma, cataract and macular degeneration. However, the causality of these associations remains controversial. This study employs a bidirectional Mendelian randomization (MR) study to investigate the causal relationships between 41 circulating inflammatory cytokines and these blinding eye diseases. Summary data for glaucoma, cataract, macular degeneration and 41 circulating inflammatory cytokines were publicly available. The inverse variance weighted (IVW) method was employed as the main analysis method. Additionally, various sensitivity tests, including MR-Egger regression, weighted median, weight mode, Cochran's Q test, MR pleiotropy Residual Sum and Outlier test, and leave-one-out test, were conducted to evaluate sensitivity and stability of results. The IVW analysis identified six circulating inflammatory cytokines causally associated with the risk of blinding eye diseases: Monokine induced by interferon-gamma (MIG) for glaucoma, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-10, and platelet derived growth factor BB (PDGFbb) for cataract, and MIG and hepatocyte growth factor (HGF) for macular degeneration. However, it is noteworthy that none of these associations remained significant after Bonferroni correction (p < 0.0004). Reverse MR analyses indicated that cataract may lead to a decrease in vascular endothelial growth factor (VEGF) levels (OR: 3.326 × 10-04, 95% CI: 5.198 × 10-07 - 2.129 × 10-01, p = 0.0151). This study highlights the potential roles of specific inflammatory cytokines in the development of glaucoma, cataract and macular degeneration. Moreover, it suggests that VEGF is likely to be involved in cataract development downstream. These findings offer insights for early prevention and novel therapeutic strategies for these blinding eye diseases.

Causal association between kynurenine and depression investigated using two-sample mendelian randomization.

As research progresses, the intricate metabolic connections between depression and tryptophan, as well as kynurenine (KYN), have become increasingly evident. In studies investigating the relationship between KYN and depression, the conclusions reached thus far have been inconsistent. Therefore, we propose employing a two-sample mendelian randomization (MR) approach to further elucidate the relationship between KYN and depression. We utilized extensive data from large-scale genome-wide association studies to identify single nucleotide polymorphisms that act as instrumental variables for kynurenine and depression in European ancestry populations, ensuring compliance with MR assumptions. We employed five MR algorithms, namely, weighted median, MR-Egger, inverse variance weighted (IVW), simple mode, and weighted mode, with IVW as the primary analysis method. Sensitivity tests were conducted using Cochran's Q test, MR-Egger intercept test, MR Pleiotropy Residual Sum and Outlier, and Leave-one-out analysis.The IVW analysis revealed that each standard deviation increase in kynurenine corresponded to a 1.4-fold increase in the risk of depression (OR = 1.351, 95% CI 1.110-1.645, P = 0.003). The direction of the effect size (positive or negative) was consistent with the findings from the other four algorithms. Sensitivity tests indicated no heterogeneity or horizontal pleiotropy among the instrumental variables. Elevated levels of kynurenine have a causal relationship with an increased risk of developing depression.

Late age at first birth is a protective factor for oesophageal cancer and gastro-oesophageal reflux: the evidence from the genetic study.

The primary objective of this research endeavor was to examine the underlying genetic causality between the age at first birth (AFB) and four prevalent esophageal diseases, namely oesophageal obstruction (OO), oesophageal varices (OV), gastro-oesophageal reflux (GOR), and oesophageal cancer (OC). We conducted a two-sample Mendelian randomization (MR) analysis to examine the causal association between AFB and four prevalent esophageal disorders. We employed eight distinct MR analysis techniques to evaluate causal relationships, encompassing random-effects inverse variance weighted (IVW), MR Egger, weighted median, simple mode, weighted mode, maximum likelihood, penalized weighted median, and fixed-effects IVW. The random-effects IVW method served as the primary approach for our analysis. Furthermore, we executed several sensitivity analyses to assess the robustness of the genetic causal inferences. The random-effects IVW analysis revealed a significant negative genetic causal association between AFB and both GOR (P < 0.001, Odds Ratio [OR] 95% Confidence Interval [CI] = 0.882 [0.828-0.940]) and OC (P < 0.001, OR 95% CI = 0.998 [0.998-0.999]). Conversely, there was insufficient evidence support to substantiate a genetic causal link between AFB and OO (P = 0.399, OR 95% CI = 0.873 [0.637-1.197]) or OV (P = 0.881, OR 95% CI = 0.978 [0.727-1.314]). The results of sensitivity analyses underscore the robustness and reliability of our MR analysis. The findings of this investigation substantiate the notion that elevated AFB confers a protective effect against GOR and OC. In addition, no causative association was discerned between AFB and OO or OV at the genetic level.

The potential causal association between systemic lupus erythematosus and endocrine and metabolic disorders in the East Asian population: A bidirectional two-sample Mendelian randomization study.

Observational studies indicate a significant correlation between systemic lupus erythematosus (SLE) and endocrine and metabolic disorders, but the causal association between SLE and endocrine and metabolic disorders remains unclear due to the reverse causality and confounding biases commonly presented in conventional observational research. This study endeavors to uncover the causal association between SLE and three common endocrine and metabolic disorders, including Graves' disease (GD), type 2 diabetes mellitus (T2DM), and osteoporosis (OP). We used genome-wide association study data for SLE and three endocrine and metabolic disorders in an East Asian population, employing bidirectional two-sample Mendelian randomization (MR) analysis and sensitivity analysis to ascertain the causal association between SLE and endocrine and metabolic disorders. A multiplicative random-effect inverse-variance weighted approach revealed a significant positive correlation between SLE and an elevated risk of GD with an odds ratio (OR) of 1.12 (95% CI: 1.04-1.22, p < .01), and inverse-variance weighted (IVW) analysis also indicated that SLE increased the risk of OP with an OR of 1.035 (95% CI: 1.003-1.068, p < .05). Additionally, GD causally affected SLE in an IVW analysis after Bonferroni correction, with an OR of 1.33 (95% CI: 1.19-1.49, p < .05/3), but the application of multivariable MR analysis resulted in the absence of a causal association of GD on SLE (OR 1.047, 95% CI: 0.952-1.151, p > .05). Lastly, the robustness and validity of the findings were verified through a sensitivity analysis. We confirmed that SLE has a causal effect on GD as well as OP, but no evidence exists to substantiate a causal link between SLE and T2DM. Our study offers valuable contributions for uncovering the etiology of SLE and endocrine and metabolic disorders and furthering disease risk research while providing potential targets for disease monitoring and therapeutic intervention.

Periodontitis and thyroid function: A bidirectional Mendelian randomization study.

Previous studies suggest interaction between periodontitis and thyroid function, while the causality has not yet been established. We applied the Mendelian randomization (MR) method to assess bidirectional causal association between periodontitis and thyroid-related traits, including free thyroxine (FT4), thyroid stimulating hormone (TSH), hypothyroidism, hyperthyroidism and autoimmune thyroid disease (AITD). Genetic instruments were extracted from large-scale genome-wide association studies on normal-range FT4 (N = 49 269) and TSH (N = 54 288) levels, TSH in full range (N = 119 715); hypothyroidism (discovery/replication cohorts: N = 53 423/334 316), hyperthyroidism (discovery/replication cohorts: N = 51 823/257 552), AITD (N = 755 406) and periodontitis (N = 45 563). Here, the inverse variance weighted (IVW) method was applied as the primary analysis, and robustness of results were assessed by several pleiotropic-robust methods. Results were adjusted for Bonferroni correction thresholds with significant p < .004 (0.05/13) and suggestive p between .004 and .05. The IVW analysis revealed a suggestively causal linkage between genetic predisposition to periodontitis and the increased risk of hypothyroidism (discovery cohort: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.05-1.46, p = .012; replication cohort: OR = 1.06, 95% CI = 1.01-1.11, p = .011). No evidence was found for supporting the impact of periodontitis on hyperthyroidism and AITD risks (associated p ≥ .209), as well as thyroid-related traits on periodontitis risk (associated p ≥ .105). These findings were robust and consistent through sensitivity analysis with other MR models. This bidirectional MR reveals periodontitis should not be attributed to variations in thyroid function but it has potential causal effect on hypothyroidism risk, which provides a better understanding of the relationship between periodontitis and thyroid function, and potential evidence for the clinical intervention of hypothyroidism. Further investigations are warranted to elucidate the nature and underlying mechanisms of this finding.

The causal association of specific gut microbiota on the risk of membranous nephropathy: a Mendelian randomization study.

Gut microbiota transplantation has been reported to improve the renal function of membranous nephropathy (MN). However, whether there is a causal effect of gut microbiota on MN remained unclear. We performed two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method was used as the main approach to evaluate the causal relationship between gut microbiota and MN. Additional methods including MR-Egger regression, weighted median, and MR-weighted mode were also conducted. Cochrane's Q test, MR-Egger regression, and MR-PRESSO were employed to detect heterogeneity and pleiotropy, respectively. A total of 196 gut microbiota were examined. After IVW and sensitivity analysis, eight gut bacteria taxa were observed causal effects on the risk of MN. Specifically, Genus. Oscillibacter was a protective factor (OR: 0.57; 95% CI 0.328-0.979; P = 0.042), while Class. Melainabacteria (OR: 1.51; 95% CI 1.004-2.277; P = 0.048), Genus. Butyricicoccus (OR: 2.16; 95% CI 1.005-4.621; P = 0.048), Genus. Catenibacterium (OR: 1.49; 95% CI 1.043-2.134; P = 0.028), Genus.Ruminiclostridium5 (OR: 1.74; 95% CI 1.053-2.862; P = 0.030), Genus. Ruminococcaceae UCG-003 (OR: 1.73; 95% CI 1.110-2.692; P = 0.015), Order. Bacillales (OR: 1.52; 95% CI 1.135-2.025; P = 0.0048) and Order. Gastranaerophilales (OR: 1.45; 95% CI 1.010-2.085; P = 0.044) were risk factors. Heterogeneity was not significant for most single-nucleotide polymorphisms, and no statistical difference in pleiotropy. This study first indicated the causal association between specific gut microbiota and MN, which would be of great significance to guide clinical prevention and treatment in MN.

Causal effects of gut microbiota on diabetic neuropathy: a two-sample Mendelian randomization study.

Previous observational studies have suggested an association between gut microbiota and diabetic neuropathy (DN). However, confounding factors and reverse causality make the causal relationship between gut microbiota and DN uncertain. We aimed to investigate the interactive causal relationships between the abundance of gut microbiota and DN. We conducted a Mendelian randomization (MR) analysis to examine the causal relationship between gut microbiota and DN. Genomic data on gut microbiota at the genus level were obtained from the MiBioGen Consortium, including 18,340 individuals of European descent. Data on diabetic polyneuropathy (DPN) were obtained from the FinnGen Consortium, which included 1,048 cases and 374,434 controls, while data on diabetic autonomic neuropathy (DAN) were also obtained from the FinnGen Consortium, including 111 cases and 374,434 controls. Causal effects were primarily estimated using inverse variance weighted (IVW) analysis, supplemented with four validation methods, and additional sensitivity analyses to assess the pleiotropy, heterogeneity, and robustness of instrumental variables. The IVW analysis indicated that Prevotella 9 had a protective effect on DPN (OR = 0.715, 95% CI: 0.521-0.982, P = 0.038), and Bacteroides also showed a protective effect (OR = 0.602, 95% CI: 0.364-0.996, P = 0.048). On the other hand, Ruminococcus 2 had a promoting effect on DPN (OR = 1.449, 95% CI: 1.008-2.083, P = 0.045). Blautia (OR = 0.161, 95% CI: 0.035-0.733, P = 0.018), Clostridium innocuum group (OR = 3.033, 95% CI: 1.379-6.672, P = 0.006), and Howardella (OR = 2.595, 95% CI: 1.074-6.269, P = 0.034) were causally associated with DAN in the IVW analysis, with no evidence of heterogeneity or pleiotropy. Sensitivity analyses showed no significant pleiotropy or heterogeneity. Our study identified a causal relationship between gut microbiota and the increased or decreased risk of diabetic neuropathy. These findings underscore the importance of adopting a comprehensive approach that combines gut microbiota modulation with other therapeutic interventions in the management of diabetic neuropathy.

Assessing the role of statin therapy in bladder cancer: evidence from a Mendelian Randomization study.

Statins, which are medications that lower lipid levels, are extensively used to decrease cardiovascular disease risk. Recently, the use of statins in cancer prevention has attracted considerable interest. However, it is still unclear whether the use of statins has a causal effect on bladder cancer. The two-sample Mendelian Randomization (MR) was performed to infer the causal relationship between statin therapy (atorvastatin, simvastatin, and rosuvastatin) and bladder cancer. Single-nucleotide polymorphisms (SNP)-based genome-wide association studies (GWAS) of statins (atorvastatin, simvastatin, and rosuvastatin) were gathered from the UK Biobank, involving 462,933 participants. We acquired summary-level genetic data on bladder cancer from a European cohort of 175,121 individuals. The inverse variance weighted (IVW) method was the main analytical technique used, supplemented by MR-Egger, weighted median, weighted mode, and simple mode to estimate causal effects. Additionally, sensitivity analyses were conducted to verify the robustness and reliability of our findings. Based on the IVW analysis, we identified a significant causal association between rosuvastatin use and a decreased risk of bladder cancer, with genetic analysis inferring the substantial reduction in odds (OR = 3.52E-19, 95% CI: 5.48E-32-2.26E-06, p = 0.005). In contrast, the IVW results did not reveal a statistically significant relationship between the genetically estimated use of atorvastatin (OR = 7.42E-03, 95% CI: 6.80E-06-8.084, p = 0.169) or simvastatin (OR = 0.135, 95% CI: 0.008-2.330, p = 0.168) and bladder cancer risk. We investigated the causal link between statin therapy (atorvastatin, simvastatin, and rosuvastatin) and bladder cancer using a two-sample Mendelian Randomization analysis among the European population. Our findings indicated that genetically predicted use of rosuvastatin was associated with a decreased risk of bladder cancer, whereas no significant genetically predicted causal effects were observed for atorvastatin and simvastatin use.

Assessment of causal associations between obesity and peripheral artery disease: a bidirectional Mendelian randomization study.

Several observational studies have documented a potential link between obesity and peripheral artery disease (PAD), although conflicting findings exist. The causal relationship between obesity and PAD continues to be a subject of ongoing debate in the medical community. In this study, we employed a bidirectional Mendelian randomization (MR) analysis to explore the potential causal relationship between obesity and the risk of PAD. To investigate these causal relationships, we conducted bidirectional MR analysis using publicly available genome-wide association study (GWAS) data. Effect estimates were calculated using the random-effects inverse variance-weighted (IVW) method. We identified eight independent single nucleotide polymorphisms (SNPs) associated with obesity in 218,735 samples involving 16,380,465 SNPs, all of which met the genome-wide significance threshold (p < 5 × 10-⁸). The IVW analysis indicates a significant positive association between genetic obesity and multiple datasets with PAD as the outcome: Queue-1 (GWAS ID: finn-b-I9_PAD) (OR = 1.138, 95% CI: 1.027-1.261, p = 0.013), Queue-2 (GWAS ID: bbj-a-144) (OR = 1.190, 95% CI: 1.019-1.390, p = 0.028), Queue-3 (GWAS ID: ebi-a-GCST90018670) (OR = 1.174, 95% CI: 1.014-1.360, p = 0.032), and Queue-4 (GWAS ID: ebi-a-GCST90018890) (OR = 1.194, 95% CI: 1.099-1.296, p < 0.001). However, we did not observe a significant genetic-level association between obesity and PAD for Queue-5 (GWAS ID: ukb-d-I9_PAD) (OR = 1.001, 95% CI: 1.000-1.002, p = 0.071). Furthermore, we conducted a reverse causal MR analysis to explore the potential reverse causal relationship between obesity and PAD. This comprehensive analysis did not provide evidence of a reverse causal association between these two factors. In summary, our study offers genetic evidence suggesting a possible causal link between obesity and PAD. While we did not find evidence supporting the "obesity paradox", prudent weight management remains crucial, as lower weight does not necessarily guarantee better outcomes. As with any study, caution is required in interpreting the findings. Further research is essential to assess the clinical relevance of weight in preventing PAD, which could inform the development of more precise intervention strategies.

Causal Relationship between PECAM-1 Level and Cardiovascular Diseases: A Mendelian Randomization Study

Background: Platelet endothelial cell adhesion molecule (PECAM-1) is present in the vascular endothelium and plays important roles in various biological processes. Several recent studies have reported associations between PECAM-1 and certain subtypes of cardiovascular diseases (CVDs). However, further research is necessary to clarify the causal effects of PECAM-1 on CVDs. To determine whether PECAM-1 and CVDs are causally associated, we conducted a two-sample Mendelian randomization (TSMR) study. Methods: Single nucleotide polymorphisms (SNPs) associated with PECAM-1 were used as instrumental variants (IVs) to estimate the causal effects of PECAM-1 on CVDs. Six SNPs were included in our TSMR study. The inverse-variance weighted (IVW) method was applied in the primary analysis. To confirm the initial results, we conducted several complementary analyses and pleiotropy analyses. Results: In the IVW analysis, higher genetically predicted PECAM-1 levels were associated with lower risk of coronary artery disease (CAD) (OR, 0.835; CI, 0.757–0.92; P = 3 × 10−4) and myocardial infarction (MI) (OR, 0.79; CI, 0.709–0.881; P = 2.03 × 10−5). Conclusions: The findings confirmed that elevated PECAM-1 levels may decrease the risk of CAD and MI. These results confirm the causal effect of PECAM-1 on CVDs and may facilitate further investigation of the mechanism of PECAM-1 in CVD pathogenesis.

Genetic association of serum lipids and lipid-modifying targets with endometriosis: Trans-ethnic Mendelian-randomization and mediation analysis.

Prior observational research identified dyslipidemia as a risk factor for endometriosis (EMS) but the causal relationship remains unestablished due to inherent study limitations. Genome-wide association study data for high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC) from European (EUR) and East Asian (EAS) ancestries were sourced from the Global Lipids Genetics Consortium. Multi-ancestry EMS data came from various datasets. Univariable Mendelian randomization (MR) examined causal links between serum lipids and EMS. Multivariable and mediation MR explored the influence of seven confounding factors and mediators. Drug-target MR investigates the association between lipid-lowering target genes identified in positive results and EMS. The primary method was inverse-variance weighted (IVW), with replication datasets and meta-analyses reinforcing causal associations. Sensitivity analyses included false discovery rate (FDR) correction, causal analysis using summary effect estimates (CAUSE), and colocalization analysis. IVW analysis in EUR ancestry showed a significant causal association between TG and increased EMS risk (OR = 1.112, 95% CI 1.033-1.198, P = 5.03×10-3, PFDR = 0.03), supported by replication and meta-analyses. CAUSE analysis confirmed unbiased results (P < 0.05). Multivariable and mediation MR revealed that systolic blood pressure (Mediation effect: 7.52%, P = 0.02) and total testosterone (Mediation effect: 10.79%, P = 0.01) partly mediated this relationship. No causal links were found between other lipid traits and EMS (P > 0.05 & PFDR > 0.05). In EAS ancestry, no causal relationships with EMS were detected (P > 0.05 & PFDR > 0.05). Drug-target MR indicated suggestive evidence for the influence of ANGPTL3 on EMS mediated through TG (OR = 0.798, 95% CI 0.670-0.951, P = 0.01, PFDR = 0.04, PP.H4 = 0.85%). This MR study in EUR ancestry indicated an increased EMS risk with higher serum TG levels.

Association between cheese intake and risk of atherosclerosis: a two-sample Mendelian randomization phenome-wide study

Background and purpose: Previous observational studies have yielded conflicting results regarding the association between cheese intake and atherosclerosis. Also, relative contribution to each subtype (coronary atherosclerosis, peripheral atherosclerosis, cerebral atherosclerosis, and arterial stiffness) remains unclear. The primary objective of this investigation was to assess the causal association between cheese intake and atherosclerosis. Methods: A two-sample Mendelian randomization (MR) study was conducted based on summary statistics from published genome-wide associations of cheese intake (n = 451,486 individuals), coronary atherosclerosis (n = 14,334 cases, 346,860 controls), peripheral atherosclerosis (n = 6,631 cases, 162,201 controls), arterial stiffness (n = 151,053 individuals, no available cases/controls), cerebral atherosclerosis (n = 104 cases, 218,688 controls), and atherosclerosis (excluding cerebral, coronary, and peripheral arterial disease [PAD]) (n = 6,599 cases, 212,193 controls). Primary analysis was conducted using an inverse-variance weighted (IVW) method. Sensitivity analyses included weighted median, MR Egger, and weighted mode analyses. Results are shown as odds ratio (OR) and 95% confidence interval (CI). Results: In the IVW analysis, genetically predicted cheese intake was inversely associated with coronary atherosclerosis (OR: 0.98, 95% CI: 0.97–0.99; P = 0.002), peripheral atherosclerosis (OR: 0.56, 95% CI: 0.37–0.84; P = 0.006), arterial stiffness (OR: 0.87, 95% CI: 0.81–0.94; P = 0.001), and atherosclerosis (excluding cerebral, coronary, and PAD) (OR: 0.65, 95% CI: 0.43–0.98; P = 0.037), but not with cerebral atherosclerosis (OR; 0.91, 95% CI: 0.07–11.28: P = 0.941). The sensitivity analyses supported an association of cheese intake with coronary atherosclerosis, peripheral atherosclerosis, arterial stiffness, and atherosclerosis (excluding cerebral, coronary, and PAD), but not cerebral atherosclerosis. Conclusions: This study suggested that cheese intake is inversely associated with coronary atherosclerosis, peripheral atherosclerosis, arterial stiffness, and atherosclerosis (excluding cerebral, coronary, and PAD), but not cerebral atherosclerosis. These findings support dietary interventions, especially increasing cheese intake, in subjects with high risk to cardiovascular diseases.

Genetic analyses of the bidirectional associations between common mental disorders and asthma.

Although extensive research has explored the link between mental disorders and asthma, the characteristics and patterns of this association are still unclear. Our study aims to examine the genetic causal links between common mental disorders (specifically, anxiety and depression) and asthma. We conducted genetic analyses including linkage disequilibrium score regression (LDSC) and bidirectional two-sample Mendelian randomization (MR) analyses, and utilized summary statistics from recent large-scale Genome-Wide Association Studies (GWASs) in European populations, covering sensation of anxiety or depression, anxiety sensation, depression sensation, anxiety disorders, major depression disorder (MDD), and asthma. LDSC revealed significant genetic correlations among sensation of anxiety or depression, MDD and asthma (P < 0.017), highlighting potential genetic correlation between anxiety disorders and asthma (P < 0.05 yet > 0.017). In bidirectional two-sample MR, inverse-variance weighted (IVW) analyses suggested that genetic liability to asthma was significantly associated with an increased risk of sensation of anxiety or depression (OR = 4.760, 95%CI: 1.645-13.777), and MDD (OR = 1.658, 95%CI: 1.477-1.860). Conversely, IVW analyses indicated that genetic liability to anxiety disorders was not associated with an increased risk of asthma (P > 0.01), nor was genetic liability to asthma associated with an increased risk of anxiety disorders (P > 0.01). Furthermore, no significant genetic causal relationships were observed for other studied traits. Multivariate MR, after adjusting for body mass index and alcohol consumption, further corroborated the independent causal effect of genetic predisposition to MDD on the risk of asthma (OR = 1.460, 95% CI: 1.285-1.660). Our study establishes MDD as a predisposing factor for asthma. Meanwhile, anxiety disorders are not causal risk factors for asthma, nor is the reverse true. It is recommended to closely monitor asthma symptoms in patients with MDD.

Causal association of smoking, blood lipids, and bladder cancer: Insights from a multivariable and mediation mendelian randomization investigation.

We used Mendelian randomization (MR) to examine the relationship between smoking, various categories of blood lipids, and bladder cancer (BLCA). Data for this study were drawn from the genome-wide association studies of the GSCAN consortium (~1.2 million participants), a subset of the UK Biobank (~120,000 participants), and the FinnGen consortium (2,072 cases and 307,082 controls). Initially, we utilized inverse variance weighted (IVW), complementary and sensitivity analyses, multivariable MR, and meta-analysis to confirm the association between blood lipids and BLCA. We then performed mediation MR to elucidate the relationship between smoking, blood lipids, and BLCA. Our analysis identified five lipids, including triglycerides in very large HDL, cholesterol in small VLDL, free cholesterol in very large HDL, total free cholesterol, and apolipoprotein B, as having strong and inverse associations with BLCA. These lipids demonstrated no heterogeneity or pleiotropy and exhibited consistent direction and magnitude across IVW, weighted median, and MR-Egger analyses. Our mediation MR further revealed that triglycerides in very large HDL and cholesterol in small VLDL could reduce the impact of smoking on BLCA, mediating -4.3% and -4.5% of the effect, respectively. In conclusion, our study identified five lipids exhibiting a robust inverse relationship with BLCA, two of which can buffer the impact of smoking on BLCA.

Periodontitis and osteoporosis: a two-sample Mendelian randomization analysis.

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.

Chronic Obstructive Pulmonary Disease and Osteoporosis: A Two-Sample Mendelian Randomization Analysis.

There is a global increase in the prevalence of osteoporosis and chronic obstructive pulmonary disease (COPD). Studies based on observation revealed a higher incidence of osteoporosis in patients with COPD. We looked into the genetic relationship between COPD and osteoporosis using the Mendelian randomization (MR) technique. The inverse variance-weighted (IVW) method was the primary technique used in this MR investigation. The sensitivity was assessed using the simple median, weighted median, penalized weighted median, and MR Egger regression analysis. The IVW model demonstrated that genetically determined COPD is causally associated with an elevated risk of osteoporosis (odds ratio [OR] fixed-effect, 1.010; 95% confidence interval [CI], 1.001-1.019, P=0.021; OR random-effect, 1.010; 95% CI, 1.001-1.020, P=0.039). It was also found that this correlation held valid for the simple and weighted median, Penalized weighted, MR-Egger, and MR Egger (bootstrap) approaches. No heterogeneity was found in the IVW or MR-Egger analysis results (Q=131.374, P=0.061 and Q=128.895, P=0.069, respectively). Furthermore, no pleiotropic influence via genetic variations was revealed by MR-Egger regression (intercept, -0.0002; P=0.160). No one single nucleotide polymorphism was found to have a substantial impact on the relationship between COPD and osteoporosis by the leave-one-out sensitivity analysis. Our MR analysis demonstrated a substantial positive impact of COPD on the risk of osteoporosis.