Multivariable Mendelian Randomization Research Articles

The role of the gluteofemoral adipose tissue in cerebrovascular disease risk: evidence from a mendelian randomization and mediation analysis.

To explore causal associations between BMI-independent body fat distribution profiles and cerebrovascular disease risk, and to investigate potential mediators underlying these associations. Leveraging data from genome wide association studies of BMI-independent gluteofemoral (GFAT), abdominal subcutaneous (ASAT), and visceral (VAT) adipose tissue volumes in UK Biobank, we selected variants associated with each trait, and performed univariable and multivariable mendelian randomization (MR) analyses on ischemic stroke and subtypes (large artery (LAS), cardioembolic (CES), small vessel (SVS)). We used coronary artery disease (CAD), carotid intima media thickness (cIMT), and an MRI-confirmed lacunar stroke as positive controls. For significant associations, we explored the mediatory role of four possible mediator categories in mediation MR analyses. Higher genetically proxied, BMI-independent GFAT volume was associated with decreased risk of ischemic stroke (FDR-p=0.0084), LAS (FDR-p=0.019), SVS (FDR-p<0.001), CAD (FDR-p<0.001), MRI-confirmed lacunar stroke (FDR-p=0.0053), and lower mean cIMT (FDR-p=0.0023), but not CES (FDR-p=0.749). Associations were largely consistent in pleiotropy- and sample structure-robust analyses. No association was observed between genetically proxied ASAT or VAT volumes and ischemic stroke/subtypes risk. In multivariable MR analyses, GFAT showed the most consistent independent association with ischemic stroke, LAS, and SVS. Common vascular risk factors were the predominant mediators in the GFAT-cerebrovascular disease axis, while adipose-tissue-specific adiponectin and leptin mediated a proportion of ischemic stroke and CAD risk. Genetically proxied, BMI-independent higher GFAT volume is associated with reduced cerebrovascular disease risk. Although this is largely mediated by common vascular risk factor modification, targeting adipose-tissue specific pathways may provide additional cardiovascular benefit.

Modifiable risk factors mediating the impact of educational inequality on heart failure: A Mendelian randomization study

BackgroundHeart failure (HF) is a rapidly growing global disease burden with high mortality rates. We aimed to utilize mendelian randomization (MR) analyses to investigate the association between educational attainment (EA) and HF, and to evaluate the contribution of modifiable risk factors as mediators. MethodsWe applied a two-sample MR approach based on the largest genome-wide association studies (GWAS) to investigate the causal relationship between EA and HF. Data collection was conducted in July 2023. We then conducted mediation analyses to explore whether body mass index (BMI), blood pressure, and type 2 diabetes mellitus (T2DM) mediate the effect of EA on HF, and utilized multivariable MR to estimate the proportion of mediation attributed to these factors. ResultsGenetically predicted 3.4 years of additional education was associated with a decrease in the risk of HF (OR 0.76 for each 3.4 years of schooling; 95% CI 0.72, 0.81). BMI, T2DM, systolic blood pressure, and diastolic blood pressure mediated 40.82% (95% CI: 28.86%, 52.77%), 18.00% (95% CI: 12.10%, 23.90%), 11.60% (95% CI: 7.63%, 15.56%), and 7.80% (95% CI: 4.63%, 10.96%) of the EA-HF association, respectively. All risk factors combined were estimated to mediate 63.81% (95% CI: 45.91%, 81.71%) of the effect of EA on HF. ConclusionHigher EA has a protective effect against the risk of HF, and potential mechanisms may include regulation of BMI, blood pressure, and blood glucose. Further research is needed to understand whether interventions targeting these factors could influence the association between EA and HF risk.

Polyunsaturated fatty acids and diabetic microvascular complications: a Mendelian randomization study.

Observational studies and clinical trials have implicated polyunsaturated fatty acids (PUFAs) in potentially safeguarding against diabetic microvascular complication. Nonetheless, the causal nature of these relationships remains ambiguous due to conflicting findings across studies. This research employs Mendelian randomization (MR) to assess the causal impact of PUFAs on diabetic microvascular complications. We identified instrumental variables for PUFAs, specifically omega-3 and omega-6 fatty acids, using the UK Biobank data. Outcome data regarding diabetic microvascular complications were sourced from the FinnGen Study. Our analysis covered microvascular outcomes in both type 1 and type 2 diabetes, namely diabetic neuropathy (DN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). An inverse MR analysis was conducted to examine the effect of diabetic microvascular complications on PUFAs. Sensitivity analyses were performed to validate the robustness of the results. Finally, a multivariable MR (MVMR) analysis was conducted to determine whether PUFAs have a direct influence on diabetic microvascular complications. The study indicates that elevated levels of genetically predicted omega-6 fatty acids substantially reduce the risk of DN in type 2 diabetes (odds ratio (OR): 0.62, 95% confidence interval (CI): 0.47-0.82, p = 0.001). A protective effect against DR in type 2 diabetes is also suggested (OR: 0.75, 95% CI: 0.62-0.92, p = 0.005). MVMR analysis confirmed the stability of these results after adjusting for potential confounding factors. No significant effects of omega-6 fatty acids were observed on DKD in type 2 diabetes or on any complications in type 1 diabetes. By contrast, omega-3 fatty acids showed no significant causal links with any of the diabetic microvascular complications assessed. Our MR analysis reveals a causal link between omega-6 fatty acids and certain diabetic microvascular complications in type 2 diabetes, potentially providing novel insights for further mechanistic and clinical investigations into diabetic microvascular complications.

Childhood Adiposity and Risk of Major Clinical Heart Diseases in Adulthood: A Mendelian Randomization Study.

The causal relationship between childhood adiposity and adult risk of heart diseases has not been clearly demonstrated. This study aims to ascertain whether genetically predicted childhood body mass index (BMI) and childhood obesity are causally associated with adult coronary heart disease, myocardial infarction, heart failure, atrial fibrillation, hypertrophic cardiomyopathy, and pulmonary heart disease. To investigate the causative relationships and underlying mechanisms between childhood adiposity and adult heart diseases, 3 main methods of Mendelian randomization were used: 2-sample Mendelian randomization, multivariable Mendelian randomization with controlling for several cardiometabolic risk variables, and mediation analysis. Every 1-SD rise in genetically predicted childhood body mass index was associated with 24% (odds ratio [OR], 1.24 [95% CI, 1.12-1.37]), 28% (OR, 1.28 [95% CI, 1.14-1.42]), 28% (OR, 1.28 [95% CI, 1.14-1.42]), and 27% (OR, 1.27 [95% CI, 1.04-1.49]) higher risk of coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation, respectively. Every 1-unit increase in log-odds in childhood obesity was associated with 11% (OR, 1.11 [95% CI, 1.06-1.16]), 14% (OR, 1.14 [95% CI, 1.04-1.23]), 10% (OR, 1.10 [95% CI, 1.03-1.18]), and 20% (OR, 1.20 [95% CI, 1.08-1.32]) higher risk of coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation, respectively. The link between childhood adiposity and adult heart diseases was found to be mediated by high-density lipoprotein cholesterol, triglyceride, hypertension, and type 2 diabetes. Our findings support the causal relationships between childhood adiposity and risk of adult coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation. Blood lipids, hypertension, and type 2 diabetes are factors that mediate the aforementioned associations.

A novel multivariable Mendelian randomization framework to disentangle highly correlated exposures with application to metabolomics

Mendelian randomization (MR) utilizes genome-wide association study (GWAS) summary data to infer causal relationships between exposures and outcomes, offering a valuable tool for identifying disease risk factors. Multivariable MR (MVMR) estimates the direct effects of multiple exposures on an outcome. This study tackles the issue of highly correlated exposures commonly observed in metabolomic data, a situation where existing MVMR methods often face reduced statistical power due to multicollinearity. We propose a robust extension of the MVMR framework that leverages constrained maximum likelihood (cML) and employs a Bayesian approach for identifying independent clusters of exposure signals. Applying our method to the UK Biobank metabolomic data for the largest Alzheimer disease (AD) cohort through a two-sample MR approach, we identified two independent signal clusters for AD: glutamine and lipids, with posterior inclusion probabilities (PIPs) of 95.0% and 81.5%, respectively. Our findings corroborate the hypothesized roles of glutamate and lipids in AD, providing quantitative support for their potential involvement.

Association between Kidney Stones and CKD: A Bidirectional Mendelian Randomization Study.

Kidney stones and CKD are common disorders with a substantial interaction. Although observational studies have suggested a potential for enhanced CKD risk after prior kidney stones, the exact relationship remains ambiguous. Shared comorbidities between two diseases were identified using unbiased screening. Genome-wide association study summary statistics were obtained from the UK Biobank (UKBB), FinnGen, and CKDGen, followed by genetic association analyses across various traits. Bidirectional Mendelian randomization (MR) analyses were performed to define causal links, complemented by multivariable MR that included the shared comorbidities including hypertension, diabetes, and obesity. Observational analyses were undertaken using cohorts from the Mayo Clinic and a UKBB subset. Despite identifying a total of 123 conditions as shared comorbidities, there was no significant genetic correlation between kidney stones and CKD. Unadjusted MR analysis revealed no significant association between kidney stones and CKD risk (UKBB [exposure]/FinnGen [outcome]: OR=0.97, 95% CI: 0.88∼1.06; FinnGen/UKBB: OR=1.17, 95% CI:0.98∼1.39). Kidney stones did significantly associate with a higher urinary albumin-creatinine ratio (UACR) (β=0.014, 95% CI: 0.002∼0.025), but this association disappeared in the multivariable MR model (β=0.009, 95% CI: -0.003∼0.020). Furthermore, in a cross-sectional analysis limited to the UKBB cohort, a robust regression model did not detect an independent association between kidney stones and UACR (β=0.16, 95% CI: -0.04∼0.35) or eGFR (β=0.10, 95% CI: -0.07∼0.28). Conversely, CKD associated with a diminished risk of kidney stones in multivariable MR models (UKBB/FinnGen: OR=0.77, 95% CI: 0.69∼0.87; FinnGen/UKBB: OR=0.73, 95% CI: 0.66∼0.81). Furthermore, in the Mayo Clinic cohort with available urinary biochemistries, lower eGFR was associated with lower urinary calcium excretion and urinary calcium oxalate/phosphate supersaturation. In this study, kidney stones were not independently associated with CKD. Conversely, CKD was associated with a lower risk of calcium kidney stones likely via changes in key urinary traits, including lower calcium excretion.

Multivariable Mendelian randomization with incomplete measurements on the exposure variables in the Hispanic Community Health Study/Study of Latinos

Multivariable Mendelian randomization allows simultaneous estimation of direct causal effects of multiple exposure variables on an outcome. When the exposure variables of interest are quantitative omic features, obtaining complete data can be economically and technically challenging: the measurement cost is high, and the measurement devices may have inherent detection limits. In this paper, we propose a valid and efficient method to handle unmeasured and undetectable values of the exposure variables in a one-sample multivariable Mendelian randomization analysis with individual-level data. We estimate the direct causal effects with maximum likelihood estimation and develop an expectation-maximization algorithm to compute the estimators. We show the advantages of the proposed method through simulation studies and provide an application to the Hispanic Community Health Study/Study of Latinos, which has a large amount of unmeasured exposure data.

Exploring the causal relationships between cholelithiasis, cholecystitis, cholecystectomy, and gastroesophageal reflux disease: A bidirectional two-sample mendelian randomization study.

Biliary disorders and gastroesophageal reflux disease (GERD) frequently coexist. However, precise linkages between these conditions remain to be clarified. Univariable Mendelian randomization (MR), Bayesian weighted MR (BWMR) along with multivariable MR approaches were conducted using genetic instruments to evaluate the causality involving biliary disorders and GERD. Furthermore, an investigation was conducted on the potential mediating roles of biliary disorders (or GERD), on the linkage involving body mass index (BMI) and GERD (or biliary disorders). Univariable MR analyses revealed significant causal effects of genetically predicted cholelithiasis (odds ratio (OR)=1.04, P=0.0001), cholecystitis (OR=1.06, P=0.0004), and cholecystectomy (OR=2.56, P=1.05×10-6) on GERD. These findings were replicated in the FinnGen cohort and were also confirmed by BWMR and multivariable MR analyses. Additionally, mediation analyses demonstrated that cholelithiasis and cholecystitis acted as partial mediators, linking BMI causally to GERD. Conversely, GERD exhibited causal effect on cholelithiasis (OR=1.52, P=9.17×10-30) and cholecystitis (OR=1.90, P=3.32×10-28), which remained significant after BWMR and multivariable MR analyses. Mediation analyses further revealed significant mediating effect of GERD on how BMI influenced cholelithiasis/cholecystitis. Our study elucidates the bidirectional causal linkages involving cholelithiasis, cholecystitis, cholecystectomy, and GERD. These results highlight the significance of GERD risk assessment in individuals suffering from biliary diseases and vice versa.

Effect of trace elements and nutrients on diabetes and its complications: a Mendelian randomization study.

Multiple clinical studies have observed a close relationship between serum trace elements and nutrients and diabetes and its complications, but it remains unclear whether there is a genetic causal effect between serum trace elements and nutrients and diabetes and its complications. This study aims to investigate the causal effects of serum trace elements and nutrients on diabetes and its complications using Mendelian randomization methods. The single nucleotide polymorphisms of serum trace elements and vitamins, as exposure factors, were sourced from the published UK Biobank database and public databases of genome-wide association studies. The genome-wide association study data of diabetes and its complications, as outcome events, were sourced from the FinnGen Biobank database. Mendelian randomization methods were employed to explore the causal relationships between 9 trace elements and 6 nutrients and diabetes and its complications. The causal relationships were inferred using inverse variance weighting, MR Egger, weighted median, simple model, and weighted model methods. Sensitivity analyses, including heterogeneity tests, horizontal pleiotropy tests, MR-PRESSO tests, and leave-one-out analysis, were conducted to evaluate the robustness of the study results. Finally, trace elements and nutrients with statistical significance in the IVW method and consistent Beta and OR directions in the five methods were selected as exposure factors with causal relationships with diabetes and its complications. This study also used multivariable Mendelian randomization methods to assess the combined effects of multiple exposure factors on the risk of diabetes and its complications. Mendelian randomization analysis revealed that selenium was linked to an elevated risk of T2D.Vitamin B6 was correlated with an increased risk of neurological complications in type 2 diabetes. Magnesium exhibited a negative causal relationship with the risk of T1D.Carotene was linked to a higher risk of renal complications in T1D.Vitamin B12 showed a negative causal relationship with renal complications in T1D.Carotene was connected to a higher risk of neurological complications in T1D.Potassium and vitamin B6 exhibited negative causal relationships with neurological complications in T1D.Vitamin E showed a negative causal relationship with peripheral circulation complications in T2D.Multivariable Mendelian randomization analysis suggested that vitamin B6 could independently influence neurological complications in both T1D and T2D, apart from other exposure factors. Vitamin B6 could also independently influence renal complications in T1D.Vitamin E could independently influence peripheral circulation complications in T1D, apart from other exposure factors. The findings from univariable and multivariable Mendelian randomization studies substantiate the causal relationships between trace elements and nutrients and different subtypes of diabetes and their complications. These findings hold significant clinical implications for developing targeted prevention and treatment strategies for diabetes and its complications.

The causal relationships of granulocytes and melanoma skin cancer: A univariable and multivariable Mendelian randomization study.

Increasing evidence has revealed that granulocyte has a critical role in tumorigenesis and progression. In this study, Mendelian randomization (MR) analysis was utilized for estimating the causal association between neutrophil percentage and melanoma skin cancer, eosinophil percentage and melanoma skin cancer, basophil percentage and melanoma skin cancer, respectively. The Genome-Wide Association Study (GWAS) ids for melanoma skin cancer, neutrophil percentage, eosinophil percentage and basophil percentage were derived from Integrative Epidemiology Unit (IEU) Open GWAS database. The univariable MR (UVMR) analysis was conducted to estimate the risk using MR-Egger, weighted median, inverse variance weighted (IVW). In addition, sensitivity analysis was conducted to assess the reliability of UVMR results. Finally, the multivariable MR (MVMR) analysis was performed to investigate causality between neutrophil percentage and eosinophil percentage in the presence of both and melanoma skin cancer. The UVMR indicated that neutrophil percentage and eosinophil percentage were significantly and causally related to melanoma skin cancer, with neutrophil percentage [p=0.025, odds ratio (OR)=1.002] as a risk factor and eosinophil percentage (p=7.04E-06, OR=0.997) as a protective factor. Moreover, MVMR analysis indicated eosinophil percentage remained the protective factor (p=0.003, OR=0.998), while the causality of neutrophil percentage and melanoma skin cancer became insignificant (p>0.05). The causal relationships of neutrophil percentage and melanoma skin cancer, eosinophil percentage and melanoma skin cancer were shown by this study, which provided a reference for subsequent research and treatment related to melanoma skin cancer.

PCSK9 Inhibitors and the Risk of Vitiligo: A Mendelian Randomization Study

Lipid-lowering agents have been suggested as a therapeutic option for vitiligo based on the potential pathogenic role of lipid metabolism abnormalities. We aimed to explore the impact of genetically proxied lipid-lowering agents on the risk of vitiligo and potentially associated mediators.Genome-wide association study summary statistics for European ancestry were extracted from the largest available meta-analysis for vitiligo, the Global Lipids Genetics Consortium for seven lipid profiles, and two large biobanks, UKB and deCODE, for 4,719 proteins. After identifying lipid-lowering agents with genetically proxied protective effects against vitiligo using lipid-lowering and protein-inhibition Mendelian randomization (MR) analyses, multivariable and two-step MR analyses were conducted to identify potential mediators between lipid-lowering agents and vitiligo.Lipid-lowering MR indicated a potential role of PCSK9 in reducing the vitiligo risk (OR[95%CI] = 0.71[0.52-0.95]), which was replicated in PCSK9-inhibition MR analyses across two separate biobanks (UKB: OR[95%CI]=0.82[0.71-0.96]; deCODE: OR[95%CI]=0.78[0.67-0.91]). Multivariable MR suggested that well-known lipid profiles do not mediate the relationship between PCSK9 and vitiligo, while two-step MR analyses identified five potential protein mediators (CCN5, CXCL12, FCRL1, LGMN, and FGF2).Hence, PCSK9 inhibitor may attenuate the vitiligo risk; PCSK9 and the potential protein mediators can serve as promising novel therapeutic targets for its effective treatment.

Novel Susceptibility Genes and Biomarkers for Obstructive Sleep Apnea: Insights from Genetic and Inflammatory Proteins.

Numerous observational studies link obstructive sleep apnea (OSA) to inflammatory proteins, yet the directionality of these associations remains ambiguous. Therefore, we aimed to clarify the potential associations of gene-predicted inflammatory proteins with OSA. Based on genome-wide association study data, we applied Mendelian randomization (MR) to explore potential connections between circulating inflammatory proteins and OSA, primarily using the inverse variance weighting method for robustness. Cochran's Q test, MR‒Egger intercept test, MR-PRESSO, and leave-one-out method were used to perform sensitivity tests for pleiotropy and heterogeneity. Replication analyses and meta-analyses were performed using other independent data. Steiger tests and multivariate MR assessed the independent effects of exposure factors, and the functional mapping and annotation (FUMA) platform was used to identify key genes to enhance the understanding of genetics. Our investigation revealed 21 circulating inflammatory proteins significantly associated with OSA-related phenotypes. Notably, IL-10RA, IL-18R1, TNFSF14, CCL23, ADA, and SLAMF1 had significant effects on multiple phenotypes. After FDR correction, IL-18R1, SLAMF1, IL-10RA, and IL-17C were identified as important candidates for OSA, and multivariate MR analysis strengthened the independent heritability of 20 inflammatory factors. The FUMA platform revealed seven overlapping genes: ROBO1, PRIM1, NACA, SHBG, HSD17B6, RBMS2, and WWOX. All reverse MR analyses and sensitivity analyses confirmed the robustness of these associations. Our results underscore crucial associations between inflammatory proteins and OSA pathogenesis, revealing new correlates and susceptibility genes. These findings advance biomarker identification for OSA risk and highlight the importance of genetic and inflammatory profiles in OSA management.

Association between cathepsins and skin cancers: A bidirectional two-sample Mendelian randomization study.

Several cathepsins have been identified as being involved in the development of cancer. Nevertheless, the connection between cathepsins and skin cancers remained highly elusive. A bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal association between cathepsins and skin malignancies. The genome-wide association studies (GWAS) data for cathepsins, malignant melanoma (MM), and basal cell carcinoma (BCC) were obtained from European research. The primary method employed was inverse variance weighted. In addition, MR-Egger, weighted median, weighted mode, and simple mode were also executed. Sensitivity analysis was performed using Cochran's Q test, MR-Egger, and MR-PRESSO. From univariable MR (UVMR), cathepsin H, and S were determined to have a causal relationship with BCC. Additionally, cathepsin H was identified as associated with MM. Multivariable MR (MVMR) showed that after correcting for risk factors of skin carcinoma, cathepsin H was detected to be protective against BCC, whereas cathepsin S has been observed as a risk factor for BCC. No substantial pleiotropy and heterogeneity were identified in the sensitivity analysis. This study was the first to establish a direct link between cathepsins and skin malignancies. Cathepsin H and S have the potential to serve as new biomarkers for BCC, offering valuable assistance in the prompt identification, treatment, and prevention of the disease. Nevertheless, additional clinical trials are required to validate our findings.

Gastroesophageal reflux disease increases the risk of rheumatoid arthritis: a bidirectional two-sample Mendelian randomization study

Rheumatoid arthritis (RA) is a common autoimmune disease, and some observational studies have indicated an association between Gastroesophageal Reflux Disease (GERD) and RA. However, the causal relationship between the two remains uncertain. We used Mendelian randomization (MR) to assess the causal relationship between GERD and RA. Two-sample Mendelian randomization analysis was performed using pooled data from large-scale genome-wide association studies. In addition, we performed multivariate MR analyses to exclude confounding factors between GERD and RA, including smoking quantity, drinking frequency, BMI, depression, and education attainment. The MR results for GERD on RA suggested a causal effect of the genetic susceptibility of GERD on RA (discovery dataset, IVW, odds ratio [OR] = 1.41, 95% confidence interval [CI] 1.22–1.63, p = 2.81 × 10−6; validation dataset, IVW, OR = 1.38, 95% CI 1.23–1.55, P = 1.76 × 10−8). Multivariate MR analysis also supports this result. But the results of the reverse MR analysis did not reveal compelling evidence that RA can increase the risk of developing GERD. Our bidirectional Two-Sample Mendelian randomization analysis and multivariate MR analysis provide support for the causal effect of GERD on RA. This discovery could offer new insights for the prevention and treatment of RA.

Causal associations between 45 dietary intake habits and urolithiasis: insights from genetic studies.

Different dietary habits can have varying effects on human health and metabolism, and these can be intervened and regulated. Kidney stones, as a disease caused by multiple factors, are largely attributed to diet and metabolism, but the potential causal relationship with dietary intake habits remains unclear. Therefore, this study aims to link the predicted dietary intake based on 45 genetic factors with urolithiasis and explore the potential causal relationship. We extracted complete genome-wide association studies (GWASs) data on 45 dietary intake traits from the UK Biobank study. Data on kidney stones were obtained from the FinnGen database. In both univariable and multivariable Mendelian randomization analyses, we used inverse variance weighted (IVW) as the primary method to calculate P values, odds ratios (ORs), and 95% confidence intervals (CIs). We examined result heterogeneity using Cochran's Q test. We also carefully investigated potential sources of horizontal pleiotropy using the Mendelian randomization (MR)-PRESSO and MR-Egger methods, and conducted linkage disequilibrium score regression (LDSC) analysis on the corrected P values. Through univariable analysis, we identified 11 dietary habits that potentially causally associate with kidney stones among the 45 examined traits, including 9 protective factors and 2 risk factors. Based on the corrected results with false discovery rate (FDR) and sensitivity analysis, we found one relatively robust evidence. We controlled for common stone risk factors, such as body mass index and smoking, as confounders in multivariable analysis, and no significant results were observed after controlling for these confounders. Based on the LDSC analysis, most of the evidence supports significant genetic correlations with urolithiasis among the 11 traits with potential causal associations. This study confirms the impact of certain dietary factors on the development of kidney stones. Our findings contribute to providing evidence for dietary adjustments in daily life or dietary guidance specifically targeting kidney stone patients.

Undetected Association Between Fatty Acids and Dementia with Lewy Bodies: A Bidirectional Two-Sample Mendelian Randomization Study.

Although observational studies indicated connections between fatty acids (FAs) and Alzheimer's disease and dementia, uncertainty persists regarding how these relationships extend to dementia with Lewy bodies (DLB). To explore the potential causal relationships between FAs and the development of DLB, thus clarifying these associations using genetic instruments to infer causality. We applied a two-sample Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) approach. Genetic data were obtained from a DLB cohort, comprising 2,591 cases and 4,027 controls of European descent. Eight FAs, including linoleic acid, docosahexaenoic acid, monounsaturated fatty acid, omega-3 fatty acid, omega-6 fatty acid, polyunsaturated fatty acid, saturated fatty acid, and total fatty acid, were procured from a comprehensive GWAS of metabolic biomarkers of UK Biobank, conducted by Nightingale Health in 2020 (met-d), involving 114,999 individuals. Our analysis included inverse-variance weighted, MR-Egger, weighted-median, simple mode, and weighted-mode MR estimates. Cochran's Q-statistics, MR-PRESSO, and MR-Egger intercept test were used to quantify the heterogeneity and horizontal pleiotropy of instrumental variables. Only linoleic acid showed a significant genetic association with the risk of developing DLB in the univariate MR. The odds ratio for linoleic acid was 1.337 with a 95% confidence interval of 1.019-1.756 (pIVW = 0.036). Results from the MVMR showed that no FAs were associated with the incidence of DLB. The results did not support the hypothesis that FAs could reduce the risk of developing DLB. However, elucidating the relationship between FAs and DLB risk holds potential implications for informing dietary recommendations and therapeutic approaches in DLB.

Exploring the impact of electrocardiographic parameters on the risk of common arrhythmias: a two-sample Mendelian randomization study.

Observational studies have shown that heart rate (HR), heart rate variability (HRV), P-wave terminal force, P-wave duration, T-wave amplitude and PR interval are associated with risk factors for atrial fibrillation (AF) or bradycardia. Arrhythmias are associated with many causes of hospitalization. However, observational studies are susceptible to confounding factors that have not yet been identified. The objective of this study was to clarify the causal relationships by Mendelian randomization analysis. We conducted a two-sample and multivariate Mendelian randomization (MVMR) analysis using genome-wide association study (GWAS) data from a European population to assess the total and direct causal effects of HR, three HRV traits, P-wave terminal force, P-wave duration, T-wave top amplitude in five-lead modes, and the PR interval on the risk of AF (N=191,205), bradycardia (N=463,010), and supraventricular tachycardia (SVT) (N=463,010). The results of the univariate MR analysis revealed the following significant causal effects: the higher the genetically predicted PR interval, the lower the risk of AF; the higher the HR and T-wave top amplitude (aVR leads and V3 + V4 + aVL leads), the lower the risk of bradycardia; and the higher HR and the lower PR interval, the higher the risk of SVT. The multivariate MR results indicated that the HRV_standard deviation of the normal-to-normal (SDNN) interval had an independent causal effect on the risk of AF [odds ratio (OR): 0.515; 95% confidence interval (CI): 0.278-0.954; P=0.03], and the T-wave top amplitude in the aVR leads (OR: 0.998; 95% CI: 0.996-0.999; P<0.001) and the HRV_SDNN (OR: 0.988; 95% CI: 0.976-1.000; P=0.045) had independent causal effects on the risk of bradycardia. The HRV_SDNN had an independent causal effect on AF, while the HRV_SDNN and T-wave top amplitude in the aVR leads had independent causal effects on bradycardia, which suggests that some of the electrocardiographic parameters have preventive effects on the incidence of AF and bradycardia.

Genetically Predicted Vascular Proteins and Risk of Intracranial Aneurysms: A Mendelian Randomization Study.

The relationship between vascular proteins (VPs) and intracranial aneurysms (IAs) has not been fully elucidated. We used Mendelian randomization (MR) analysis to explore the effect of VPs on IAs. Dataset of aneurysmal subarachnoid hemorrhage (aSAH) [5140 cases and 71,934 controls] and unruptured intracranial aneurysm (uIA) [2070 cases and 71,934 controls] were obtained from individuals of European ancestry. Univariate MR was used to explore the associations between 90 VPs and IAs. Then, we performed multivariate MR (MVMR) to further investigate the identified VP-to-IA estimates. Two-sample MR showed that TNFSF14 was inversely associated with aSAH (odds ratio [OR] = 0.831, 95% CI: 0.713-0.969, p = 0.018). IL-16 (OR = 1.218, 95% CI: 1.032-1.438, p = 0.020) and AgRP (OR = 1.394, 95% CI: 1.048-1.855, p = 0.023) were positively associated with aSAH. HBEGF (OR = 0.642, 95% CI: 0.461-0.894, p = 0.009), MCP-1 (OR = 1.537, 95% CI: 1.007-2.344, p = 0.046), and CX3CL1 (OR = 0.762, 95% CI: 0.581-0.999, 0.049 < p < 0.050) were associated with uIA risk. The MVMR showed that the TNFSF14-to-aSAH estimate remained statistically significant after adjustment for past tobacco smoking, alcohol consumption, systolic blood pressure and body mass index. Our study indicated that low serum TNFSF14 levels might be a potential risk factor for IA rupture. Five VPs (HBEGF, MCP-1, IL-6, CX3CL1, and AgRP) are associated with the risk of IAs (both uIA and aSAH).

The integrity of the corticospinal tract and corpus callosum, and the risk of ALS: univariable and multivariable Mendelian randomization

Studies suggest that amyotrophic lateral sclerosis (ALS) compromises the integrity of white matter fiber tracts, primarily affecting motor fibers. However, it remains uncertain whether the integrity of these fibers influences the risk of ALS. We performed bidirectional two-sample Mendelian randomization (MR) and multivariable MR analyses to evaluate the associative relationships between the integrity of fiber tracts [including the corticospinal tract (CST) and corpus callosum (CC)] and the risk of ALS. Genetic instrumental variables for specific fiber tracts were obtained from published genome-wide association studies (GWASs), including 33,292 European individuals from five diffusion magnetic resonance imaging (dMRI) datasets. Summary-level GWAS data for ALS were derived from 27,205 ALS patients and 110,881 controls. The MR results suggested that an increase in the first principal component (PC1) of fractional anisotropy (FA) in the genu of the CC (GCC) was correlated with an increased risk of ALS (PFDR = 0.001, odds ratio = 1.363, 95% confidence interval 1.178–1.577). Although other neuroimaging phenotypes [mean diffusivity in the CST, radial diffusivity (RD) in the CST, FA in the GCC, PC1 in the body of the CC (BCC), PC1 in the CST, and RD in the GCC] did not pass correction, they were also considered to have suggestive associations with the risk of ALS. No evidence revealed that ALS caused changes in the integrity of fiber tracts. In summary, the results of this study provide genetic support for the potential association between the integrity of specific fiber tracts and the risk of ALS. Greater fiber integrity in the GCC and BCC may be a risk factor for ALS, while greater fiber integrity in the CST may have a protective effect on ALS. This study provides insights into ALS development.

The role of hypertension in the relationship between leisure screen time, physical activity and migraine: a 2-sample Mendelian randomization study

BackgroundThe relationship between lifestyle and migraine is complex, as it remains uncertain which specific lifestyle factors play the most prominent role in the development of migraine, or which modifiable metabolic traits serve as mediators in establishing causality.MethodsIndependent genetic variants strongly associated with 20 lifestyle factors were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for migraine were obtained from the FinnGen consortium (18,477 cases and 287,837 controls) as a discovery set and the GWAS meta-analysis data (26,052 cases and 487,214 controls) as a replication set. Estimates derived from the two datasets were combined using fixed-effects meta-analysis. Two-step univariable MR (UVMR) and multivariable Mendelian randomization (MVMR) analyses were conducted to evaluate 19 potential mediators of association and determine the proportions of these mediators.ResultsThe combined effect of inverse variance weighted revealed that a one standard deviation (SD) increase in genetically predicted Leisure screen time (LST) was associated with a 27.7% increase (95% CI: 1.14–1.44) in migraine risk, while Moderate or/and vigorous physical activity (MVPA) was associated with a 26.9% decrease (95% CI: 0.61–0.87) in migraine risk. The results of the mediation analysis indicated that out of the 19 modifiable metabolic risk factors examined, hypertension explains 24.81% of the relationship between LST and the risk of experiencing migraine. Furthermore, hypertension and diastolic blood pressure (DBP) partially weaken the association between MVPA and migraines, mediating 4.86% and 4.66% respectively.ConclusionOur research findings indicated that both LST and MVPA in lifestyle have independent causal effects on migraine. Additionally, we have identified that hypertension and DBP play a mediating role in the causal pathway between these two factors and migraine.