Multivariable Mendelian Randomization Research Articles

Disentangling the causal effects of education and participation bias on Alzheimer's disease using Mendelian Randomization.

People with university degrees have a lower incidence of Alzheimer's Disease (AD). However, the relationship between education and AD could be due to selection, collider, and ascertainment biases, such as lower familiarity with cognitive testing or the fact that those with degrees are more likely to participate in research. Here, we use two-sample Mendelian randomization (MR) to investigate the causal relationships between education, participation, and AD. We used genome-wide association study (GWAS) summary statistics for educational attainment, three different measures of participation, AD (clinically diagnosed AD), and AD/ADRD (clinical diagnosis and family history of AD and related dementias). Independent genome-wide significant single nucleotide polymorphisms (SNPs) were extracted from the exposure summary statistics and harmonized with the outcome SNPs. Fixed-effects inverse variance weighted meta-analysis was the primary MR method; Cochran's Q statistic and MR Egger intercept were used to test for heterogeneity and pleiotropy, and Radial-MR was used to identify outliers. Sensitivity analyses included MR Egger, Weighted Median, and Weighted mode. Bidirectional analyses were used to test if AD pathology affects participation and multivariable MR (MVMR) assessed independent exposure-outcome effects. Educational attainment reduced the risk of AD (OR IVW 95% CI= 0.70 [0.63, 0.79], p = 8e-10), and the results were robust based on sensitivity analyses. However, education increased the risk of AD/ADRD, though the results were not robust to sensitivity analyses (OR IVW 95% CI= 1.09 [1.02, 1.15], p = 0.006). Participation in MHQ reduced the odds of AD (OR IVW 95% CI= 0.325 [0.128, 0.326], p = 0.01). When adjusting for participation in MVMR, education remained associated with a reduced risk of AD (OR IVW 95% CI= 0.76 [0.62, 0.92], p = 0.006). Univariate MR analyses indicated that education and participation reduced the risk of AD. However, MR also suggested that education increased the risk of AD/ADRD, highlighting the inconsistencies between clinical and proxy diagnoses of AD, as proxy-AD may be affected by selection, collider, or ascertainment bias. MVMR indicated that participation is unlikely to explain the effect of education on AD identified in MR, and the protective effect of educational attainment may be due to other biological mechanisms, such as cognitive reserve.

The effect of coffee consumption on three main bone disorders: a Mendelian randomization trial.

Despite a large number of observational studies examining the effect of coffee consumption(CC) on bone disorders(BDs), particularly, osteoarthritis(OA), osteoportic fracture(OF), and rheumatoid arthritis(RA), the conclusions are highly controversial. Thus, it is essential to examine the causal association between CC and BDs. Mendelian randomization (MR) analysis was performed to assess the causal influence of CC on OF, RA, and OA. The main endpoint was the odds ratio (OR) of the inverse variance weighted (IVW) approach. In addition, the weighted median (WM), MR-Egger regressions, MR-pleiotropy residual sum and outlier (MR-PRESSO) and multivariable MR (MVMR) were included in sensitivity analyses. Furthermore, the function of causal SNPs was evaluated by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction networks. Primary MR analysis based on the IVW method suggested that changes in CC alter risk of OF (OR = 1.383, 95%CI 1.079-1.853, P = 0.039), RA(OR: 1.623, 95%CI 1.042-2.527, P = 0.032) and HOA (hip osteoarthritis, OR = 1.536, 95% CI 1.044-2.259, P = 0.021). However, these causal relationships were not robust in sensitivity analyses. In contrast, there is a positive causal relationship between increased CC and the risk of KOA (knee osteoarthritis, OR: 2.094, 95%CI: 1.592-2.754, P = 1.41 × 10-7), as evidenced by the IVW using random effect. A similar effect size was observed across all MR sensitivity analyses, with no evidence of horizontal pleiotropy. Based on our MR analysis, increased CC was causally linked to an increase in the risk of KOA. Genetic predictions suggested that CC reduction may have benefits for bone health.

Obesity and adiposity promote the development of non-suppurative otitis media: a Mendelian randomization study.

Observational studies have found that obesity is associated with the development of non-suppurative otitis media (NSOM), but the causality and pathogenesis are unclear. This study aimed to investigate the association between obesity, lipid metabolism, and NSOM at the genetic level. We performed a bidirectional two-sample Mendelian randomization (MR) study to examine the causal relationship between obesity, lipid metabolism-related factors, and NSOM by using the datasets obtained from the IEU Open genome-wide association studies (GWAS) Project. Furthermore, a multivariate MR (MVMR) analysis on lipid indicators was conducted to validate the results. We then used obesity or body mass index (BMI) as the exposure and NSOM as the outcome to search for possible mediators in lipids and adipokines. Using NSOM as the outcome, we found nine positive exposure results related to obesity and lipid metabolism. Among them, obesity, BMI, body fat percentage, waist circumference, hip circumference, and resistin were risk factors, while apolipoprotein A1 (apoA1), high-density lipoprotein cholesterol (HDL-C), and nerve growth factor (NGF) were protective factors. Then, we used the obesity and lipid metabolism-related factors as outcomes and NSOM as the exposure to perform the MR analysis, which failed to obtain positive results. In the MVMR analysis, we found that HDL cholesterol and apoA1 remained causally associated with NSOM after correction for other potential confounders. Simultaneously, when obesity or BMI was used as the exposure and NSOM as the outcome, HDL cholesterol or apoA1 served as mediators through a two-step MR analysis. The MR analysis for mediation, obesity, and BMI reduced the production of HDL or apoA1, which served as protective factors affecting the development of NSOM. At the genetic level, obesity and adiposity may promote the development of NSOM, while NSOM has no effect on obesity and adiposity. Obesity can also encourage the progress of NSOM by reducing HDL cholesterol/apoA1. Resistin may be a potential risk factor for NSOM, whereas NGF may be a potential protective factor.

Causal inference of the effect of blood proteome on the risk of head and neck cancer: two-sample Mendelian randomization

Early diagnosis of head and neck cancer can improve therapeutic outcomes but remains a challenge. The blood proteome can comprise a key source of biomarkers that enable the early diagnosis and precision medicine in head and neck cancer, but blood protein biomarkers of head and neck cancer are not well delineated. Here we applied two-sample Mendelian randomization to a GWAS dataset of 1478 blood proteins and large dataset of head and neck cancer cases and controls to identify blood proteome traits associated with head and neck cancer. Multiple two-sample Mendelian randomization (MR) methods were used to assess causal effects of the exposures, including: Inverse-variance weighted (IVW), Mendelian randomization-Egger method, Weight Median method, simple mode, weight mode. Sensitivity analysis was performed by using heterogeneity test, pleiotropy test and one-by-one exclusion test. Multivariable MR analyses were performed to assess the effects of obesity, diabetes mellitus, and smoking. A significant causal association between A Disintegrin and metalloproteinase domain-containing protein 23 (ADAM23) and head and neck cancer was noted. The sensitivity analysis indicated no significant bias. Multivariate analysis showed that the effect for ADAM23 remained significant after adjusting for the indirect effects of obesity, diabetes mellitus and smoking. In sum, this study showed a significant causal role of genetically dysregulated ADAM23 protein with head and neck cancer risk. The specific mechanisms underlying the role of ADAM23 in mediating head and neck cancer risk, and its role as a potential therapeutic target and biomarker, need further investigation.

Genetic correlation and causal relationship between sleep and myopia: a mendelian randomization study.

To investigate the genetic correlation and causal links between sleep traits (including sleep duration, chronotype, and insomnia) and myopia. Summary data on three sleep traits (sleep duration, chronotype and insomnia) and myopia from FinnGen (n = 214,211) and UK Biobank (n = 460,536) were analyzed using linkage disequilibrium score regression (LD Score), univariable and multivariable mendelian randomization (MR) experiments and Causal Analysis Using Summary Effect (CAUSE) estimation. LD Score regression detected candidate genetic correlation between sleep traits and myopia, such as sleep duration, chronotype (Genetic Correlation Z-score >10.00, h2_observed_p < 0.005, Lambda GC > 1.05, p > 0.05). Univariable MR analyses indicated that increased sleep duration has a promotional effect on the occurrence of myopia (p = 0.046 < 0.05, P_FDR = 0.138 < 0.2, OR = 2.872, 95% CI: 1.018-8.101). However, after accounting for potential confounding factors, multivariable MR and CAUSE analysis did not provide evidence for a causal effect of the three sleep traits on myopia. There may be a potential genetic correlation between sleep duration, chronotype and myopia. However, neither of sleep duration, chronotype or insomnia had causal effect on myopia.

Association between primary biliary cholangitis with diabetes and cardiovascular diseases: A bidirectional multivariable Mendelian randomization study

Background and aimsPrimary biliary cholangitis (PBC) is an autoimmune disease often accompanied by multisystem damage. This study aimed to explore the causal association between genetically predicted PBC and diabetes, as well as multiple cardiovascular diseases (CVDs). MethodsGenome-wide association studies (GWAS) summary data of PBC in 24,510 individuals of European ancestry from the European Association for the Study of the Liver was used to identify genetically predicted PBC. We conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to estimate the impacts of PBC on diabetes (N = 17,685 to 318,014) and 20 CVDs from the genetic consortium (N = 171,875 to 1,030,836). ResultsSVMR provided evidence that genetically predicted PBC is associated with an increased risk of type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), heart failure (HF), hypertension, atrial fibrillation (AF), stroke, ischemic stroke, and small-vessel ischemic stroke. Additionally, there was no evidence of a causal association between PBC and coronary atherosclerosis. In the MVMR analysis, PBC maintained independent effects on T1D, HF, MI, and small-vessel ischemic stroke in most models. ConclusionOur findings revealed the causal effects of PBC on diabetes and 7 CVDs, and no causal relationship was detected between PBC and coronary atherosclerosis.

Genetic evidence for the causal impact of insomnia on gastrointestinal diseases and the mediating effects of adiposity traits.

Insomnia has been implicated in gastrointestinal diseases (GIs), but the causal effect between insomnia and GIs and underlying mechanisms remain unknown. By using the released summary-level data, we conducted a two-step Mendelian randomization (MR) analysis to examine the relationship between insomnia and four GIs and estimate the mediating role of candidate mediators. The first step was to investigate the causal association between insomnia and GIs using univariable MR analysis. The second step was to estimate the mediation proportion of selected mediators in these associations using multivariable MR analysis. Subsequently, results from different datasets were combined using the fixed-effect meta-analysis. Univariable MR analysis provided strong evidence for the causal effects of insomnia on four GIs after Bonferroni correction for multiple comparisons, including peptic ulcer disease (PUD) (odds ratio [OR]=1.15, 95% interval confidence [CI]=1.10-1.20, P=1.83×10-9), gastroesophageal reflux (GORD) (OR=1.19, 95% CI=1.16-1.22, P=5.95×10-42), irritable bowel syndrome (IBS) (OR=1.18, 95% CI=1.15-1.22, P=8.69×10-25), and inflammatory bowel disease (IBD) (OR=1.09, 95% CI=1.03-1.05, P=3.46×10-3). In the mediation analysis, body mass index (BMI) and waist-to-hip ratio (WHR) were selected as mediators in the association between insomnia and PUD (BMI: mediation proportion [95% CI]: 13.61% [7.64%-20.70%]; WHR: 8.74% [5.50%-12.44%]) and GORD (BMI: 11.82% [5.94%-18.74%]; WHR: 7.68% [4.73%-11.12%]). Our findings suggest that genetically instrumented insomnia has causal effects on PUD, GORD, IBS, and IBD, respectively. Adiposity traits partially mediated the associations between insomnia and GIs. Further clinical studies are warranted to evaluate the protective effect of insomnia treatment on GIs.

Mendelian randomization analysis reveals higher whole body water mass may increase risk of bacterial infections

Background and purposeThe association of water loading with several infections remains unclear. Observational studies are hard to investigate definitively due to potential confounders. In this study, we employed Mendelian randomization (MR) analysis to assess the association between genetically predicted whole body water mass (BWM) and several infections.MethodsBWM levels were predicted among 331,315 Europeans in UK Biobank using 418 SNPs associated with BWM. For outcomes, we used genome-wide association data from the UK Biobank and FinnGen consortium, including sepsis, pneumonia, intestinal infections, urinary tract infections (UTIs) and skin and soft tissue infections (SSTIs). Inverse-variance weighted MR analyses as well as a series of sensitivity analyses were conducted.ResultsGenetic prediction of BWM is associated with an increased risk of sepsis (OR 1.34; 95% CI 1.19 to 1.51; P = 1.57 × 10− 6), pneumonia (OR: 1.17; 95% CI 1.08 to 1.29; P = 3.53 × 10− 4), UTIs (OR: 1.26; 95% CI 1.16 to 1.37; P = 6.29 × 10− 8), and SSTIs (OR: 1.57; 95% CI 1.25 to 1.96; P = 7.35 × 10− 5). In the sepsis and pneumonia subgroup analyses, the relationship between BWM and infection was observed in bacterial but not in viral infections. Suggestive evidence suggests that BWM has an effect on viral intestinal infections (OR: 0.86; 95% CI 0.75 to 0.99; P = 0.03). There is limited evidence of an association between BWM levels and bacteria intestinal infections, and genitourinary tract infection (GUI) in pregnancy. In addition, MR analyses supported the risk of BWM for several edematous diseases. However, multivariable MR analysis shows that the associations of BWM with sepsis, pneumonia, UTIs and SSTIs remains unaffected when accounting for these traits.ConclusionsIn this study, the causal relationship between BWM and infectious diseases was systematically investigated. Further prospective studies are necessary to validate these findings.

Exploring potential causal links between air pollutants and congenital malformations: A two-sample Mendelian Randomization study

Observational studies have suggested an association between air pollutants and congenital malformations; however, conclusions are inconsistent and the causal associations have not been elucidated. In this study, based on publicly available genetic data, a two-sample Mendelian randomization (MR) was applied to explore the associations between particulate matter 2.5 (PM2.5), NOX, NO2 levels and 11 congenital malformations. Inverse variance weighted (IVW), MR-Egger and weighted median were used as analytical methods, with IVW being the main method. A series of sensitivity analyses were used to verify the robustness of the results. For significant associations, multivariable MR (MVMR) was utilized to explore possible mediating effects. The IVW results showed that PM2.5 was associated with congenital malformations of digestive system (OR = 7.72, 95 %CI = 2.33–25.54, P = 8.11E−4) and multiple systems (OR = 8.63, 95 %CI = 1.02–73.43, P = 0.048) risks; NOX was associated with circulatory system (OR = 4.65, 95 %CI = 1.15–18.86, P = 0.031) and cardiac septal defects (OR = 14.09, 95 %CI = 1.62–122.59, P = 0.017) risks; NO2 was correlated with digestive system (OR = 27.12, 95 %CI = 1.81–407.07, P = 0.017) and cardiac septal defects (OR = 22.57, 95 %CI = 2.50–203.45, P = 0.005) risks. Further MVMR analyses suggest that there may be interactions in the effects of these air pollutants on congenital malformations. In conclusion, this study demonstrated a causal association between air pollution and congenital malformations from a genetic perspective.

Causal relationship between bone mineral density and intervertebral disc degeneration: a univariate and multivariable mendelian randomization study

BackgroundAlthough previous studies have suggested a possible association between bone mineral density (BMD) and intervertebral disc degeneration (IDD), the causal relationship between them remains unclear. Evidence from accumulating studies indicates that they might mutually influence one another. However, observational studies may be affected by potential confounders. Meanwhile, Mendelian randomization (MR) study can overcome these confounders to assess causality.ObjectivesThis Mendelian randomization (MR) study aimed to explore the causal effect of bone mineral density (BMD) on intervertebral disc degeneration (IDD).MethodsSummary data from genome-wide association studies of bone mineral density (BMD) and IDD (the FinnGen biobank) have been acquired. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach. Weighted median, MR-Egger regression, weighted mode, and simple mode were used as supplements. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were performed to assess horizontal pleiotropy. Cochran’s Q test evaluated heterogeneity. Leave-one-out sensitivity analysis was further conducted to determine the reliability of the causal relationship. Multivariate MR (MVMR) analyses used multivariable inverse variance-weighted methods to individually and jointly adjust for four potential confounders, body mass index (BMI), Type2 diabetes, hyperthyroidism and smoking. A reverse MR analysis was conducted to assess potential reverse causation.ResultsIn the univariate MR analysis, femoral neck bone mineral density (FNBMD), heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) had a direct causal effect on intervertebral disc degeneration (IDD) [FNBMD-related analysis: OR(95%CI) = 1.17 (1.04 to 1.31), p = 0.008, eBMD-related analysis: OR(95%CI) = 1.06 (1.01 to 1.12), p = 0.028, LSBMD-related analysis: OR(95%CI) = 1.20 (1.10 to 1.31), p = 3.38E-7,TB BMD-related analysis: OR(95%CI) = 1.20 (1.12 to 1.29), p = 1.0E-8]. In the MVMR analysis, it was revealed that, even after controlling for confounding factors, heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) still maintained an independent and significant causal association with IDD(Adjusting for heel bone mineral density: beta = 0.073, OR95% CI = 1.08(1.02 to 1.14), P = 0.013; Adjusting for lumbar spine bone mineral density: beta = 0.11, OR(95%CI) = 1.12(1.02 to 1.23), P = 0.03; Adjusting for total body bone mineral density: beta = 0.139, OR95% CI = 1.15(1.06 to 1.24), P = 5.53E − 5). In the reverse analysis, no evidence was found to suggest that IDD has an impact on BMD.ConclusionsThe findings from our univariate and multivariable Mendelian randomization analysis establish a substantial positive causal association between BMD and IDD, indicating that higher bone mineral density may be a significant risk factor for intervertebral disc degeneration. Notably, no causal effect of IDD on these four measures of bone mineral density was observed. Further research is required to elucidate the underlying mechanisms governing this causal relationship.

Appetitive Lifestyles and Obesity with Risk of Senile Cataract: An Univariable and Multivariable Mendelian Randomization Study

Objective: To estimate the causal effects of appetitive lifestyles (cigarette smoking, alcohol use, coffee consumption) and obesity on risk of senile cataract (SC) using genetically based approaches. Methods: Single nucleotide polymorphisms selected to be instrumental variables for exposures were identified at the level of genome-wide significance (P&lt;5×10-8) from genome-wide association studies. Summary-level genetic statistics for SC was derived from the FinnGen consortium. Univariable and multivariable Mendelian randomization (MR) with inverse-variance weighted (IVW) method as main analysis were performed. Directional pleiotropy and heterogeneity were tested. Results: For univariable MR, genetically determined predisposition to smoking initiation was associated with elevated risk of SC (IVW odds ratio (OR))=1.1241, 95% confidence interval (CI) (CI: 1.0240-1.2339, P=0.0140). Also, genetically predicted higher coffee consumption and body mass index (BMI) was associated with increased risk of SC (IVW OR=1.0050, 95% CI: 1.0012-1.0088, P=0.0101; IVW OR=1.1925, 95% CI: 1.0954-1.2982, P=4.8099×10-5, respectively). For multivariable MR, genetically predicted higher BMI still exerted a causal effect on SC risk (IVW OR=1.1712, 95% CI: 1.0786-1.2717, P&lt;0.001). Nevertheless, the associations of smoking initiation and coffee consumption with SC risk disappeared. No directional pleiotropy was detected in both univariable and multivariable MR. Conclusion: Our findings provide evidence for an adverse effect of higher BMI on SC risk, while no evidence supporting independent causal associations of appetitive lifestyles with SC risk. Improving the management of obesity may serve as a useful strategy protecting against SC.

Causality of metabolites and metabolic pathways on cholestatic liver diseases: a Mendelian randomization study.

Blood metabolite abnormalities have revealed an association with cholestatic liver diseases (CLDs), while the underlying metabolic mechanisms have remained sluggish yet. Accordingly, the present evaluation aims to investigate the causal relationship between blood metabolites and the risk of two major CLDs, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Univariable and multivariable Mendelian randomization (MR) approaches were employed to uncover potential causal associations between blood metabolites and 2 CLDs, including PBS and PSC, through extracting instrumental variables (IVs) for metabolites from genome-wide association studies (GWAS) conducted on European individuals. The GWAS summary data of PBC or PSC were sourced from two distinct datasets. The initial analysis employed inverse variance weighted (IVW) and an array of sensitivity analyses, followed by replication and meta-analysis utilizing FinnGen consortium data. Finally, a multivariable MR analysis was carried out to ascertain the independent effects of each metabolite. Furthermore, the web-based tool MetaboAnalyst 5.0 was used to perform metabolic pathway examination. A genetic causality between 15 metabolites and CLDs was recognized after preliminary analysis and false discovery rate (FDR) correction. Subsequently, 9 metabolites consistently represented an association through replication and meta-analysis. Additionally, the independent causal effects of 7 metabolites were corroborated by multivariable MR analysis. Specifically, the metabolites isovalerylcarnitine (odds ratio [OR] = 3.146, 95% confidence intervals [CI]: 1.471-6.726, p = 0.003), valine (OR = 192.44, 95%CI: 4.949-7483.27, p = 0.005), and mannose (OR = 0.184, 95%CI: 0.068-0.499, p < 0.001) were found to have a causal relationship with the occurrence of PBC. Furthermore, erythrose (OR = 5.504, 95%CI: 1.801-16.821, p = 0.003), 1-stearoylglycerophosphocholine (OR = 6.753, 95%CI: 2.621-17.399, p = 7.64 × 10-5), X-11847 (OR = 0.478, 95%CI: 0.352-0.650, p = 2.28 × 10-6), and X-12405 (OR = 3.765, 95%CI: 1.771-8.005, p = 5.71 × 10-4) were independently associated with the occurrence of PSC. Furthermore, the analysis of metabolic pathways identified seven significant pathways in two CLDs. The findings of the present study have unveiled robust causal relationships between 7 metabolites and 2 CLDs, thereby providing novel insights into the metabolic mechanisms and therapeutic strategies for these disorders.

The causal relationship between immune cells and Sjögren's syndrome: a univariate, multivariate, bidirectional Mendelian randomized study.

Immune cells are involved in the onset and progression of Sjögren's syndrome (SS). This study explored the causal relationship between immune signature cells and SS, which has not been fully elucidated. We conducted univariate, multivariate, and bidirectional Mendelian randomization to investigate the causal relationship between 731 immunological feature characteristic cells and SS pairs and explore the interaction of immune cells in SS. After false discovery rate correction, six immune cells were significantly associated with SS risk. Among them, four contributed to SS (CD24 on memory B cell, CD27 on IgD + CD24 + B cell, CD28 on CD39+ secreting CD4 Treg cell, and CD80 on CD62L + mDC); two appeared to reduce SS risk (CD3 on CD39 + CD8 + T cell and CD38 on IgD + CD38 + B cell). Pleiotropy and heterogeneity were not observed. Three immune cells exerted independent effects for SS (CD27 on IgD + CD24 + B cell, CD80 on CD62L + mDC, and CD38 on IgD + CD38 + B cell); two were risk factors (CD27 on IgD + CD24 + B cell and CD80 on CD62L + mDC); and one was a protective factor (CD38 on IgD + CD38 + B cell). Twenty-three immune cells showed a reverse causal relationship with SS. These findings demonstrate the influence of immune cells on SS risk and the effects of SS on immune cells, providing new clues for further research on the mechanisms underlying SS.

HDL-C mediates the causal relationship between serum urate and aortic aneurysm: a Mendelian randomization study

Background and purpose: Studies have indicated a close relationship between serum urate and an increased risk of aortic aneurysm or aortic dissection. However, the causality between them and the mediators of this association have not been identified. This study employs bidirectional and multivariable Mendelian randomization (MR) to investigate the causality between serum urate and aortic aneurysm or dissection and identify mediators of this relationship. Methods: We first investigated the causal association between serum urate and aortic aneurysm or aortic dissection using two-sample bidirectional MR, with the inverse-variance-weighted method as the principal analysis technique. Subsequently, we applied multivariable MR to determine probable mediators. Results: Genetically serum urate levels were linked to an increased risk of aortic aneurysm (odds ratio [OR]: 1.160, 95% confidence interval [95% CI]: 1.011–1.332, P = 0.034), with high-density lipoprotein cholesterol (HDL-C) mediating this causal relationship, accounting for 10.2% of the effect. No causal relationship was found between serum urate and aortic dissection. Conclusions: Serum urate is a risk factor for aortic aneurysm, and this causal relationship is mediated through HDL-C. Monitoring HDL-C levels in patients with hyperuricemia is essential to prevent and slow the progression of aortic aneurysm.

Genetic effect of thyroid function-related diseases on acute respiratory distress syndrome: a Mendelian randomization study.

Previous studies have shown an association between acute respiratory distress syndrome (ARDS) and thyroid function. However, their causal relationship remains unspecified. Therefore, this study aims to explore the causal relationship between ARDS and thyroid function-related diseases with Mendelian Randomization (MR) analysis. ARDS dataset finn-b-J10_ARDS, finn-b-E4_THYROID dataset of disorders of the thyroid gland (DTG) and finn-b-E4_HYTHYNAS of hypothyroidism were acquired from public database. In univariate MR (UVMR), causal effects between DTG, hypothyroidism and ARDS were investigated using 5 types of algorithms, and reliability was validated by sensitivity analysis. Moreover, multivariate MR (MVMR), enrichment and interaction network analyses of genes corresponding to SNPs of DTG and hypothyroidism were carried out. Significant level was chosen as p<0.05. UVMR identified DTG and hypothyroidism (P < 0.05, OR > 1) as risk factors, and were causally related to ARDS. Reliability of UVMR results was confirmed through sensitivity analysis, and results were stable and reliable. However, DTG and hypothyroidism had no effect on ARDS in MVMR, possibly because these factors had independent effects on ARDS. Ultimately, 96 and 113 genes corresponding to SNPs of DTG and hypothyroidism were found closely related to immune-related pathways. UVMR and MVMR analysis revealed a causal connection between DTG and hypothyroidism as risk factors with ARDS, providing robust evidence for investigation into relationship of hypothyroidism on ARDS and between DTG and ARDS.

Risk Factors for Pelvic Organ Prolapse: Wide-Angled Mendelian Randomization Analysis.

We hypothesized that some metabolic factors, lifestyle factors, and socioeconomic factors may have a causal effect on pelvic organ prolapse (POP). We selected instruments from corresponding genome-wide association studies (GWAS), which identified independent single nucleotide polymorphisms strongly associated with 12 potential risk factors. Summary statistics for POP were derived from two GWAS datasets, serving for discovery and replication stage. The primary analysis involved the use of the inverse-variance weighting mendelian randomization (MR) method, with additional sensitivity MR analyses conducted. The univariable mendelian randomization (UVMR) analysis in both the discovery and replication stage provided evidence for significant causal effects between higher waist-to-hip ratio adjusted for body mass index (WHRadjBMI) levels, lower high-density lipoprotein cholesterol (HDL-C) levels, and lower educational attainment and higher POP risk, as well as a suggestive positive causal effect between triglycerides and POP. The multivariable mendelian randomization (MVMR)analysis showed that only HDL-C among the three blood lipid fractions could reduce the risk of POP. Mediation analysis indicated that HDL-C may partially mediate the effect of WHRadjBMI on POP risk, and the causal effect between educational attainment and POP may be mediated through WHRadjBMI and HDL-C. Our study's evidence supported a causal relationship between WHRadjBMI, triglycerides, HDL-C, educational attainment, and POP risk. This highlights that clinicians may guide the general female population to control obesity and blood lipid levels to reduce the risk of POP.

Independent Effects of Blood Pressure on Intraocular Pressure and Retinal Ganglion Cell Degeneration: A Mendelian Randomization Study.

To investigate the causal effect of elevated blood pressure on primary open-angle glaucoma (POAG) and POAG endophenotypes. Two-sample Mendelian randomization (MR) was performed to investigate the causal effect of elevated systolic blood pressure (SBP) (N = 757,601) and diastolic blood pressure (DBP) (N = 757,601) on intraocular pressure (IOP) (N = 139,555), macular retinal nerve fiber layer (mRNFL) thickness (N = 33,129), ganglion cell complex (GCC) thickness (N = 33,129), vertical cup-to-disc ratio (VCDR) (N = 111,724), and POAG liability (Ncases = 16,677, Ncontrols = 199,580). The primary analysis was conducted using the inverse-variance weighted approach. Sensitivity analyses were performed to investigate robustness to horizontal pleiotropy, winner's curse, and collider bias. Multivariable MR was performed to investigate whether any effect of blood pressure on retinal ganglion cell degeneration was mediated through increased IOP. Increased genetically predicted SBP and DBP associated with an increase in IOP (0.17 mm Hg [95% CI = 0.11 to 0.24] per 10 mm Hg higher SBP, P = 5.18 × 10-7, and 0.17 mm Hg [95% CI = 0.05 to 0.28 mm Hg] per 10 mm Hg higher DBP, P = 0.004). Increased genetically predicted SBP associated with a thinner GCC (0.04µm [95% CI = -0.07 to -0.01µm], P = 0.018) and a thinner mRNFL (0.04µm [95% CI = -0.07 to -0.01µm], P = 0.004), an effect that arises independently of IOP according to our mediation analysis. Neither SBP nor DBP associated with VCDR or POAG liability. These findings support a causal effect of elevated blood pressure on retinal ganglion cell degeneration that does not require intermediary changes in IOP. Targeted blood pressure control may help preserve vision by lowering IOP and, independently, by preventing retinal ganglion cell degeneration, including in individuals with a normal IOP.

Bi-directional two-sample Mendelian randomization identifies causal association of depression with temporomandibular disorders.

Depression and anxiety have been suggested to be associated with temporomandibular disorders (TMD) in observational studies. However, the causal association and the direction in the relationship between depression/anxiety and TMD remain unknown. This study investigated the potential causal relationship between depression/anxiety and TMD with two-sample bi-directional Mendelian randomization (MR). Summary statistics of depression (N = 500 199), anxiety disorder (N = 17 310) and TMD (N = 195 930) were sourced from large-scale genome-wide association studies (GWAS). The primary Mendelian randomization (MR) estimation employed the inverse-variance weighted meta-analysis (IVW). Additional MR sensitivity methods and multivariate MR (MVMR) were applied to address pleiotropy. IVW results indicated a causal effect of genetically predicted depression on TMD (OR = 1.887, 95% CI = 1.504-2.367, p < .001), which was supported by other sensitivity MR approaches. MVMR results suggested that the negative effect of depression on TMD persisted after conditioning on other potential confounders. The association of anxiety disorder with TMD was not supported by our findings. In the reverse direction, we did not find compelling evidence suggesting the causal effect of TMD on depression and anxiety disorder. The present study suggests a potential causal association between genetic liability for depression and the risk of TMD. Our MR findings align with prior epidemiological research, underscoring the significance of early detection and prevention of depression in the treatment of TMD.

Causal associations between systemic lupus erythematosus and primary biliary cholangitis: A bidirectional Mendelian randomization study

ObjectivesThe association between systemic lupus erythematosus (SLE) and primary biliary cholangitis (PBC) has been increasingly recognized. However, the existence of causal connections between SLE and PBC has yet to be established. In this study, we aimed to investigate the bidirectional causation between SLE and PBC utilizing Mendelian randomization (MR) analysis. MethodsWe acquired summary data from Genome-wide association studies (GWAS) for SLE and PBC from the IEU Open GWAS and FinnGen database. The inverse variance weighted (IVW) was employed as the key method to ascertain the causality between SLE and PBC. Subsequently, a range of sensitivity analyses were applied. We also performed a fixed-effects model meta-analysis to combine the MR results from different databases. Moreover, multivariable MR were conducted to clarify the roles of potential confounding factors. ResultsOur univariable MR investigation provided compelling evidence supporting a causal relationship between SLE and PBC in both directions. Specifically, the IVW method demonstrated a strong casual effect of SLE on PBC (odds ratio (OR) = 1.17, 95 % confidence interval (CI) = 1.09–1.25, p < 0.001). In addition, the results of reverse MR analysis revealed that genetically predicted PBC was associated with an increased risk of SLE (OR = 1.39, 95 % CI = 1.32–1.45, p < 0.001). The sensitivity analyses indicated the absence of horizontal pleiotropy and heterogeneity. Furthermore, the causality between SLE and PBC remained significant even after adjusting for common risk factors in the multivariable MR analysis. ConclusionsOur study provides statistical evidence of a potential causal relationship between SLE and PBC, but further research is needed to the explore of the underlying mechanisms of these disorders.

Causal Relationship Between Kidney Function and Cancer Risk: A Mendelian Randomization Study

Rationale & ObjectivePatients treated with kidney replacement therapy experience a 1.5 to 2-fold increased risk of cancer and cancer mortality compared to the general population. Whether this excess risk extends to people with earlier stages of chronic kidney disease is unclear. This study explored the potentially causal relationship between reduced kidney function and cancer. Study DesignTwo-sample Mendelian randomization (MR). Setting & ParticipantsGenome Wide Association Study (GWAS) summary statistics for estimated glomerular filtration rate (eGFR) (n=567,460) and urinary albuminuria (UACR) (n=127,865) from the CKDGen consortium and cancer outcomes from the UK Biobank (n=407,329). ExposureseGFR and UACR. OutcomesOverall cancer incidence, cancer-related mortality, and site-specific colorectal, lung, and urinary tract cancer incidence. Analytical ApproachUnivariable and multivariable MR were conducted for all outcomes using inverse-variance weighted methods. ResultsThe mean eGFR and median UACR were 91.4 mL/min/1.73m2 and 9.32 mg/g in the CKDGen and 90.4 mL/min/1.73m2 and 9.29 mg/g in the UK Biobank. There were 98,093 cases of cancer, 6,664 colorectal, 3584 lung, and 3,271 urinary tract. There were 15,850 cases of cancer-related death, The genetic instruments for eGFR and UACR comprised 34 and 38 variants, respectively. Genetically predicted kidney function (eGFR and UACR) was not associated with overall cancer risk or cancer death. No associations of genetically predicted eGFR and UACR with overall cancer incidence were observed; odds ratio (95%CI; p-value) of 0.88 (0.40-1.97; p=0.76) and 0.90 (0.78-1.04; p=0.16), respectively. An adjusted generalized additive model for eGFR and cancer demonstrated evidence of non-linearity. There was no evidence of a causal association between eGFR and cancer in a stratified MR. LimitationsTo avoid overlapping samples a smaller GWAS for UACR was used, reducing the strength of the instrument and potentially introducing population stratification. ConclusionsThese findings did not demonstrate a causal association of kidney function with overall cancer incidence or cancer-related death.