MR Pleiotropy Residual Sum And Outlier Research Articles

Dissecting Causal Relationships Between Dietary Habits and Diverse Subtypes of Stroke: Mendelian Randomization Study

Background: Understanding the causal relations between dietary habits and stroke is crucial for prioritizing public health interventions and developing effective health strategies. This study utilized Mendelian randomization (MR) analysis to examine the causal associations between 20 dietary habits and various stroke subtypes, aiming to identify potential mediators and evaluate the proportions of mediation. Methods: A two-sample MR analysis was conducted to examine the causal relationships between dietary habits and stroke incidence. Mediation analysis, two-step MR (TSMR), and multivariable MR (MVMR) were employed to identify potential mediators. Genetic data pertaining to dietary habits and stroke were obtained from extensive genome-wide association study (GWAS) consortia. The inverse variance-weighted (IVW) method served as the primary analytical approach, with the additional scrutiny of significant correlations conducted through the Egger regression, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), and weighted median techniques. Results: Our analyses indicated that genetically predicted intakes of dried fruits, cheese, cereal, oily fish, and hot drink temperatures were protective against stroke, whereas higher intakes of lamb/mutton, poultry, and added salt significantly elevated stroke risk. Specifically, dried fruit consumption demonstrated a protective effect against total stroke (β = −0.009, p = 0.013), ischemic stroke (β = −0.475, p = 0.003), and small-vessel ischemic stroke (β = −0.682, p = 0.033) through reductions in BMI levels, accounting for mediated proportions of 3.2%, 17.1%, and 8.5%, respectively. Furthermore, cheese intake provided a protective effect against ischemic stroke (β = −0.275, p = 0.003) by decreasing BMI and increasing HDL-C levels, with mediated proportions of 30.5% and 6.5%. Together, BMI and HDL-C accounted for 34.9% of the beneficial effect of cheese intake on reducing the risk of ischemic stroke. In contrast, an increased salt intake exhibited a positive association with large-artery ischemic stroke (β = 0.432, p = 0.033) through BMI elevation, with a mediated proportion of 10.9%. Conclusions: Our findings provide compelling evidence supporting causal relationships between dietary habits and stroke subtypes, while identifying mediators and evaluating the proportions of mediation. Adhering to a low-calorie, nutrient-dense diet enriched with dried fruits, cheese, and cereal, along with reduced salt and poultry consumption, could potentially mitigate stroke risk.

Impulsivity and epilepsy: a bidirectional mendelian randomization study

BackgroundPrevious studies have found that patients with epilepsy are more likely to suffer impulsivity. However, the causal relationship between impulsivity and epilepsy is unknown. In this study, we conduct a bidirectional Mendelian randomization (MR) study to explore the causal relationship between impulsivity and epilepsy with recurrent seizure.MethodsData of the genome-wide association studies (GWAS) on 14 impulsivity traits and epilepsy were obtained from the GWAS catalog and UK Biobank. Inverse-variance weighted (IVW) and weighted median (WM) methods were utilized for MR estimates. IVW, MR-Egger regression, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods were used to assess heterogeneity and pleiotropy.ResultsSingle-nucleotide polymorphisms (SNPs) related to the lack of perseverance were associated with a decreased risk of epilepsy with recurrent seizures according to the results of IVW (odd ratio [OR] = 0.93, 95% confident interval [CI] = 0.90–0.97, P = 0.001) and WM (OR = 0.93, 95%CI = 0.87–0.98, P = 0.007). Meanwhile, heterogeneity was not observed with a Cochran Q-derived P value of 0.819 for MR egger and a P value of 0.808 for IVW. Pleiotropy was not found according to the MR-PRESSO (P = 0.273). The other 13 impulsivity traits had no causal effect on epilepsy with recurrent seizures. Meanwhile, SNPs related with epilepsy with recurrent seizures had no causal effect on the 14 impulsivity traits.ConclusionsThis MR study suggests that lack of perseverance may be a protective factor against epilepsy with recurrent seizures. However, epilepsy with recurrent seizures does not affect impulsivity.

The Association between Non-Alcohol Liver Fatty Disease and Coronary Artery Calcification: A Two-Sample Mendelian Randomization Study.

Although prior observational studies have suggested that patients with non-alcohol fatty liver disease (NAFLD) may have a higher risk of coronary artery calcification (CAC), these findings remain controversial. This study aimed to explore the causal association between NAFLD and CAC at genetic level by two-sample Mendelian randomization (MR) analysis. Utilizing summary-level data from multiple large-scale genome-wide association studies (GWAS) in European populations, a two-sample MR analysis was initially conducted to explore the potential causal association between NAFLD and CAC. The results of the MR analysis were pooled through random-effect meta-analysis. The inverse variance weighting (IVW) method served as the primary approach for MR analysis. Additionally, the weighted median, MR-Egger and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods was applied for sensitivity analysis. Summary-level data on liver fatty content was utilized for validation analysis, while summary-level data on cirrhosis served as positive control, further ensuring the validity and robustness of our findings. Reverse MR analysis was performed to assess the association between CAC and NAFLD, employing instrument variables derived from CAC. The MR analysis indicated that genetically predicted NAFLD had no effects on the risk of CAC (Beta: 0.01, 95% CI: -0.02 to 0.03, P = 0.74). Likewise, the reverse MR analysis found no significant genetic association between CAC and NAFLD (OR: 1.00, 95% CI: 0.96 to 1.06, P = 0.88). Validation analysis yielded consistent results, showing no significant association between fatty liver content and CAC. Our two-sample MR analysis did not support that there is a causal association between NAFLD and CAC at genetic level. The association between NAFLD and CAC reported in some previous observational studies may rely on NAFLD complicated with metabolic disorders, rather than being directly linked to the hepatic steatosis.

A Mendelian randomization study of the association between serum uric acid and osteoporosis risk.

The relationship between serum uric acid (SUA) and osteoporosis (OP) has yielded conflicting results in observational studies. This Mendelian randomization (MR) study aims to elucidate the causal association between SUA and OP. A two-sample MR analysis was conducted using summary-level data from genome-wide association studies (GWAS). Two sets of polygenic instruments strongly associated (p < 5 × 10-8) with SUA were extracted from the CKDGen consortium and UK biobank. Polygenic instruments associated with OP (p < 5 × 10-8) were derived from FinnGen biobank and UK biobank. Inverse variance weighting (IVW) was employed as the primary analysis method. Additionally, we utilized MR-Egger, weighted median, the simple mode method, and the weighted mode as complementary analyses. Cochran's Q statistics were used to assess heterogeneity, with MR-Egger intercept testing and MR pleiotropy residual sum and outlier (MR-PRESSO) to examine horizontal pleiotropy. Sensitivity analysis was performed using the leave-one-out method. The IVW analysis conducted across four groups confirms no significant causal relationship between SUA concentration and OP: UKB-UKB (OR: 1.001, 95% CI: 0.999-1.003, p=0.464), CKD-UKB (OR: 1.001, 95% CI: 0.999-1.003, p=0.349), UKB-Fin (OR: 0.934, 95% CI: 0.747-1.168, p=0.549), CKD-Fin (OR: 1.041, 95%CI: 0.934-1.161, p=0.470). Furthermore, additional four MR analyses corroborated these findings. Upon excluding all outliers identified by the MR-PRESSO test, no significant directional pleiotropy was observed, except for some data heterogeneity noted in the UKB-UKB group (Q=50.65, P=0.002). Additionally, a leave-one-out analysis indicated that no single SNP exerted undue influence on the results. This MR analysis provides convincing genetic evidence that there is no causal association between SUA and OP, SUA is unlikely to increase or reduce the risk of OP.

Causality between diabetes and membranous nephropathy: Mendelian randomization.

Membranous nephropathy (MN) has not yet been fully elucidated regarding its relationship with Type I and II Diabetes. This study aims to evaluate the causal effect of multiple types of diabetes and MN by summarizing the evidence from the Mendelian randomization (MR) study. The statistical data for MN was obtained from a GWAS study encompassing 7979 individuals. Regarding diabetes, fasting glucose, fasting insulin, and HbA1C data, we accessed the UK-Biobank, within family GWAS consortium, MAGIC, FinnGen database, MRC-IEU, and Neale Lab, which provided sample sizes ranging from 17,724 to 298,957. As a primary method in this MR analysis, we employed the Inverse Variance Weighted (IVW), Weighted Median, Weighted mode, MR-Egger, Mendelian randomization pleiotropy residual sum, and outlier (MR-PRESSO) and Leave-one-out sensitivity test. Reverse MR analysis was utilized to investigate whether MN affects Diabetes. Meta-analysis was applied to combine study-specific estimates. It has been determined that type 2 diabetes, gestational diabetes, type 1 diabetes with or without complications, maternal diabetes, and insulin use pose a risk to MN. Based on the genetic prediction, fasting insulin, fasting blood glucose, and HbA1c levels were not associated with the risk of MN. No heterogeneity, horizontal pleiotropy, or reverse causal relationships were found. The meta-analysis results further validated the accuracy. The MR analysis revealed the association between MN and various subtypes of diabetes. This study has provided a deeper understanding of the pathogenic mechanisms connecting MN and diabetes.

Association Between Serum Galectin-3 and Parkinson's Disease: A Two-Sample Mendelian Randomization Study.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder with poor prognosis. Observational studies have demonstrated a significant correlation between serum galectin-3 and PD, suggesting a potential role of galectin-3 as a biomarker for PD. However, it is still unclear whether galectin-3 contributes to the risk of the disease. A two-sample Mendelian randomization (MR) approach was used in this study. Genetic instruments for serum galectin-3 level were selected from a genome-wide association study (GWAS), including 30,931 European individuals. Summary-level statistics for PD were derived from another published GWAS, including 33,674 cases and 449,056 controls. Primary analysis was conducted using the inverse-variance weighting (IVW) method. Weighted median, MR-Egger, simple mode, weighted mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods were used as complementary analyses. To detect heterogeneity, Cochran's Q statistic and leave-one-out analysis were used. For testing potential horizontal pleiotropy, the MR-Egger intercept test and MR-PRESSO global test were conducted. MR analysis using IVW model (OR 1.112, 95% CI 1.025-1.206, p = 0.010), weighted median (OR 1.135, 95% CI 1.037-1.242, p = 0.006), weighted mode (OR 1.142, 95% CI 1.038-1.257, p = 0.030), and MR-PRESSO (OR 1.112, 95% CI 1.046-1.182, p = 0.012) presented a consistent result, indicating that increased serum galectin-3 was associated with a higher risk of PD. No heterogeneity or horizontal pleiotropy was detected in the analyses. The study shows a suggestive association between galectin-3 and PD. Increasing serum galectin-3 was associated with an increase in PD risk. Galectin-3 may play an important role in the causal pathway to PD.

Inflammatory cytokines and their potential role in kidney stone disease: a Mendelian randomization study.

Previous studies have reported a complex relationship between inflammatory cytokines and kidney stone disease (KSD). The purpose of this paper is to investigate the potential causal impact of inflammatory cytokines on KSD by Mendelian randomization (MR) analysis. In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between inflammatory cytokines and kidney stone disease. Utilizing GWAS summary data of inflammatory cytokines and KSD, we performed the first two-sample MR analysis. Genetic variants in GWASs related to inflammatory cytokines were employed as instrumental variables (IVs). The data on cytokines were derived from 14,824 participants and analyzed by utilizing the Olink Target-96 Inflammation Panel. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Reverse MR analysis, Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results. 91 cytokines were enrolled in the MR analysis after strict quality control of IV. The IVW analysis revealed 2 cytokines as risk factors for KSD: Cystatin D (OR 1.06, 95% CI 1.01-1.11), Fibroblast growth factor 5 (OR 1.06, 95% CI 1.00-1.12), suggesting they are positively associated with the occurrence of kidney stones. We also found 3 protective associations between cytokines and KSD: Artemin (OR 0.86, 95% CI 0.78-0.96), T-cell surface glycoprotein CD6 isoform (OR 0.92, 95% CI 0.88-0.98), STAM-binding protein (OR 0.83, 95% CI 0.69-0.99). There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our MR Egger's intercept test, Cochrane Q-test, and MR-PRESSO, which were all > 0.05. Our study explored a variety of inflammatory cytokines related to KSD through MR analysis, which validated several previous findings and provided some new potential biomarkers for KSD. However, the findings require further investigation to validate their exact functions in the pathogenesis and evolution of KSD.

Causal Relationship Between Autism Spectrum Disorder and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization Study.

Patients with autism spectrum disorder (ASD) are often accompanied by inflammatory bowel disease (IBD) in observational research; however, the potential causal link between the two conditions remains unknown. In this study, we used a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal relationship between ASD and IBD and its main subtypes, Crohn's disease (CD), and ulcerative colitis (UC). Independent genetic instruments from a genome-wide association study (GWAS) for IBD (25,042 cases and 34,915 controls) were used to investigate the association of IBD with ASD data obtained from the PGC and the iPSYCH consortia (N = 46,351). The primary analysis employed the random effects inverse variance weighting (IVW) method. Horizontal pleiotropy was detected using the MR Egger regression and the MR-pleiotropy residual sum and outlier (MR-PRESSO) analysis while heterogeneity was detected using Cochran's Q. The IVW method indicated a positive causal relationship of IBD with ASD (odds ratio (OR) = 1.028, 95% confidence interval (CI) = 1.001-1.056, p = 0.042). In subtype analyses, CD was positively related to ASD (OR = 1.036; 95% CI = 1.004-1.069; p = 0.02); however, UC showed no relationship (OR = 1.021; 95% CI = 0.999-1.044; p = 0.065). In contrast, no evidence of a causal relationship between ASD and IBD or its subtypes (p > 0.05) was found. Our findings provided evidence in support of potential causal associations between IBD/CD and ASD.

Association of dietary intake with pneumothorax: A Mendelian randomization study

BackgroundAn association between dietary habits and lung disease has been demonstrated in previous studies. Employing Mendelian randomization, we aimed to explore how different dietary intakes relate to pneumothorax, shedding light on the interplay among gut flora, the lung-gut axis, and pneumothorax. MethodsEmploying both two-sample and multi-sample Mendelian randomization (MR) analyses, we investigated 24 dietary intake variables to establish a strong association with pneumothorax. Causal inferences were drawn using the inverse variance weighted (IVW) method. To fortify our findings, we employed a diverse array of methodologies, including Weighted Median Estimator (WME), Weighted Mode, Simple Mode, Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO), MR-Egger regression, and LASSO. ResultsOur analysis identified genetic variants reliably predicting dietary intakes, meeting stringent criteria (p < 5 × 10−8) and demonstrating independence (r2 < 0.001). Causal-effect estimates derived from the IVW model unveiled a statistically significant association, indicating a causal correlation between pneumothorax and three dietary intakes. Specifically, heightened consumption of fresh fruit (OR = 0.196, 95%CI: 0.063–0.606, p = 0.004) and dried fruit (OR = 0.323, 95%CI: 0.114–0.911, p = 0.032) correlated with reduced pneumothorax risk, while increased processed meat intake (OR = 2.705, 95%CI: 1.026–7.128, p = 0.044) showed a positive correlation. ConclusionIn summary, our MR analysis yields robust evidence supporting a causal correlation between dietary elements and pneumothorax. This study significantly advances our comprehension of pneumothorax risk factors, protective agents, and the intricate mechanisms of the lung-gut axis.

Thyroid Dysfunction and Alopecia Areata: A Genetic Prediction Causality Analysis Study.

Observational studies have suggested a correlation between alopecia areata (AA) and thyroid dysfunction (TD). However, the causal relationship between AA and TD remains uncertain. The purpose of this study is to investigate the causal relationship between these two conditions. Understanding the potential causal relationship between AA and TD is valuable for elucidating the pathogenesis of AA and for designing innovative methods to prevent and treat AA and its related complications. All data for this two-sample Mendelian randomization (MR) study were sourced from public databases. This study selected hypothyroidism, Hashimoto's thyroiditis, hyperthyroidism, subacute thyroiditis, and Graves' disease as exposure factors, with AA as the outcome variable. Data for hypothyroidism, Hashimoto's thyroiditis, hyperthyroidism, subacute thyroiditis, Graves' disease, and AA were obtained from related genome-wide association studies (GWAS). Various MR analysis methods such as inverse variance weighted (IVW), MR-Egger, and weighted median were utilized. Additionally, Cochrane's Q test was used to detect heterogeneity in MR results, and the MR-Egger intercept test and MR pleiotropy residual sum and outlier (MR-PRESSO) test were used to detect horizontal pleiotropy. A leave-one-out analysis was conducted to investigate the sensitivity of this association. We found statistically significant genetic predictions of AA with hypothyroidism, Hashimoto's thyroiditis, and subacute thyroiditis (IVW OR=1.4009815, 95% confidence interval [CI]: 1.1210399-1.750829; p=0.003030698, OR=1.396101, 95% CI: 1.030134-1.89208; p=0.03144273, OR=0.732702, 95% CI: 0.604812-0.887634; p=0.001483368). Furthermore, tests for pleiotropy showed no evidence of pleiotropy, enhancing the credibility of the study results. Finally, the leave-one-out test demonstrated the stability and robustness of this association. This study provides new evidence of a potential genetic link between thyroid issues and AA. By employing the two-sample MR method to eliminate confounding factors and reverse causation, unbiased results were obtained, confirming a causal relationship between hypothyroidism, Hashimoto's thyroiditis, subacute thyroiditis, and AA. This lays the foundation for further mechanistic studies and potential clinical applications. Future research should further explore the specific biological mechanisms between TD and the onset of AA.

Systemic Immune Factors and Risk of Allergic Contact Dermatitis: A Bidirectional Mendelian Randomization Study.

Skin inflammation and immune regulation have been suggested to be associated with allergic contact dermatitis (ACD) progression, but whether the system's immune regulation is a cause or a potential mechanism is still unknown. This study aims to assess the upstream and downstream of systemic immune factors on ACD within a bidirectional Mendelian-randomization design. A bidirectional two-sample MR analysis was employed to implement the results from genome-wide association studies for 52 system immune factors and ACD. Genetic associations with systemic immune factors and ACD were obtained from the IEU Open GWAS project database. The inverse-variance weighted (IVW) method was adopted as the primary MR analysis, MR-Egger, weighted median, MR-pleiotropy residual sum, and outlier (MR-PRESSO) was also used as the sensitivity analyses. Only Tumor necrosis factor ligand superfamily member 11 (TNFS11) from among 52 systemic immune factors was associated with a protective effect of ACD. However, ACD was associated with a decrease in Interleukin-9 (IL9) and an increase in C-X-C motif chemokine 1 (GROα), Tumor necrosis factor ligand superfamily member 10 (TRAIL), C4, and complement factor B of the assessed systemic immune factors. This study identified TNFS11 as the upstream regulator and IL9, GROα, TRAIL, C4, and complement factor B as the downstream regulator of ACD, providing opportunities for new therapeutic exploitation of ACD. Nonetheless, these associations of systemic immune factors need to be verified in vivo.

Causal links between immune cells and asthma: Insights from a Mendelian Randomization analysis

Objectives Recent studies suggest immunophenotypes may play a role in asthma, but their causal relationship has not been thoroughly examined. Methods We used single nucleotide polymorphism (SNP)-derived instrumental variables. Summary data from 731 immune cell profiles and asthma cases were analyzed from genome-wide association studies (GWAS) of European populations. Mendelian Randomization (MR) analyses included inverse variance weighted (IVW), weighted median, and MR–Egger methods. Pleiotropy was assessed using the MR-Egger intercept and MR pleiotropy residual sum and outlier (MR-PRESSO) tests. Reverse MR analysis explored bidirectional causation between asthma and immunophenotypes. All statistical analyses were conducted using R software. Results MR analysis identified 108 immune signatures potentially contributing to asthma. Two immunophenotypes were significantly associated with asthma risk: CD4+ secreting Treg cells in allergic asthma (ORIVW = 1.078; 95% CI: 1.036–1.122; PIVW = 0.0002) and IgD + CD38− %lymphocyte cells in non-allergic asthma (ORIVW = 1.123; 95% CI: 1.057–1.194; PIVW = 0.0002). Conclusions This study highlights the causal associations between specific immunophenotypes and asthma risk, providing new insights into asthma pathogenesis.

Causal link between childhood obesity and adult osteoporosis: An investigation through Mendelian randomization.

The intricate link between childhood obesity and adult osteoporosis has been a subject of numerous clinical inquiries, yet the genetic underpinnings of this association remain enigmatic. Our research aims to unravel the association between adult osteoporosis and childhood obesity using genome-wide association study data for Mendelian randomization (MR) analysis. Utilizing a pool of single-nucleotide polymorphism data associated with childhood obesity obtained from a previous genome-wide association study report involving a study population of 13,848 people in Europe, alongside data of adult osteoporosis sourced from Neale Lab (5266 cases and 331,893 controls). Various methods for MR were used in our research, including weighted mode, simple mode, weighted median, MR-Egger, and the inverse-variance weighted (IVW). We also used Cochran Q test of IVW to assess for heterogeneity, MR-Egger intercept and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis for pleiotropy, and leave-one-out analysis for the result stability. The instrumental variables associated with 11 single-nucleotide polymorphisms were selected. MR analyses unveiled a noteworthy link between genetically forecasted childhood obesity and the onset of adult osteoporosis based on the odds ratio, 95% confidence interval, and P-value from the results of IVW, MR-Egger, weighted median: simple mode, and weighted mode analyses. No significant heterogeneity was found by the assessment using MR-Egger and IVW. Similarly, there was no indication of pleiotropy based on the MR-PRESSO and MR-Egger analyses. Leave-one-out analysis confirmed the stability of the results. Our research suggests that childhood obesity, as predicted by genetic factors, may pose a significant risk for the development of osteoporosis in adulthood.

The causal effects of inflammatory and autoimmune skin diseases on thyroid diseases: evidence from Mendelian randomization study.

To clarify the controversy between inflammatory or autoimmune skin diseases and thyroid diseases, we performed two-sample Mendelian randomization (MR) analyses. Genetic data on factors associated with atopic dermatitis (AD, n=40,835), seborrheic dermatitis (SD, n=339,277), acne (n=363,927), rosacea (n=299,421), urticaria (n=374,758), psoriasis (n=373,338), psoriasis vulgaris (n=369,830), systemic lupus erythematosus (SLE, n=14,267), vitiligo (n=353,348), alopecia areata (AA, n=361,822), pemphigus (n=375,929), bullous pemphigoid (BP, n=376,274), systemic sclerosis (SSc, n=376,864), localized scleroderma (LS, n=353,449), hypothyroidism (n=314,995 or n=337,159), and hyperthyroidism (n=281,683 or n=337,159) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates of inflammatory or autoimmune skin diseases on the risk of thyroid diseases, complemented by MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). AD, SLE, SD, and psoriasis vulgaris were associated with an increased risk of hypothyroidism, whereas BP was associated with a lower risk of hypothyroidism (all with p < 0.05). The multivariable MR analyses showed that AD (OR = 1.053; 95%CI: 1.015-1.092; p = 0.006), SLE (OR = 1.093; 95%CI: 1.059-1.127; p < 0.001), and SD (OR = 1.006; 95%CI: 1.002-1.010; p = 0.006) independently and predominately contributed to the genetic causal effect on hypothyroidism after adjusting for smoking. The results showed no causal effects of inflammatory or autoimmune skin diseases on hyperthyroidism. The findings showed a causal effect of AD, SLE, SD on hypothyroidism, but further investigations should be conducted to explore the pathogenic mechanisms underlying these relationships.

Causal relationship between dietary intake and IgA nephropathy: a Mendelian randomization study.

Previous studies have reported that dietary intake is associated with immunoglobulin A nephropathy (IgAN). However, the causal relationship remains unknown. Based on publicly available genome-wide association study (GWAS) data, we conducted a two-sample Mendelian randomization (MR) analysis to assess the causal association between 26 dietary exposures and IgAN. Five methods, including inverse variance weighting (IVW), MR-Egger regression, weighted median, simple mode, and weighted mode, were applied in the MR analysis. To identify the presence of horizontal pleiotropy, we used the MR-Egger intercept test and MR pleiotropy residual sum and outlier (MR-PRESSO) global test. Cochran's Q statistics were used to assess instrument heterogeneity. We conducted sensitivity analysis using the leave-one-out method. Finally, the results indicated alcohol intake frequency (odds ratio [OR] (95% confidence interval [CI]) = 1.267 (1.100-1.460), p = 0.0010295) was a risk factor of IgAN, while cheese intake (OR (95% CI) = 0.626 (0.492-0.798), p = 0.0001559), cereal intake (OR (95% CI) = 0.652 (0.439-0.967), p = 0.0334126), and sushi intake (OR (95% CI) = 0.145 (0.021-0.997), p = 0.0497) were protective factors of IgAN. No causal relationship was found between IgAN and the rest of the dietary exposures. Our study provided genetic evidence that alcohol intake frequency was associated with an increased risk of IgAN, while cheese, cereal, and sushi intake were associated with a decreased risk of IgAN. Further investigation is required to confirm these results.

Abstract P192: The Impact of Sleep Apnea on Preeclampsia or Eclampsia: The Mediation Role of Large High-Density Lipoprotein Components

Introduction: Sleep apnea is increasingly recognized as a significant risk factor for preeclampsia/eclampsia (PE). Research increasingly shows that large high-density lipoprotein (L-HDL) may influence the PE development. This study aimed to investigate the association between sleep apnea and PE and the proportion of this association that is mediated through different L-HDL components. Hypothesis: Modifications in the L-HDL components induced by sleep apnea significantly contribute to the pathogenesis of PE. Methods: A two-sample Mendelian randomization (MR) was conducted using genetic variants associated with relative sleep apnea from the FinnGen study and different L-HDL components from UK Biobank. The single-nucleotide polymorphisms (SNPs) were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. Then the multivariable MR analysis was performed to estimate the effect of the mediators on the risk of PE with adjustment for sleep apnea. The MR-Egger and MR pleiotropy residual sum and outlier (MR-PRESSO) were mainly used for sensitivity analyses. In mediation analyses, the direct effect of different L-HDL components estimated in multivariable MR was compared with the total effect estimated in the main univariable MR analysis. Results: This study found that sleep apnea significantly affects the risk of PE, as well as various L-HDL components, including large high-density lipoprotein cholesterol (L-HDL-C), large high-density lipoprotein cholesteryl ester (L-HDL-CE), large high-density lipoprotein concentration (L-HDL concentration), cholesterol to total lipids ratio in large high-density lipoprotein (C/TL-L-HDL), cholesteryl esters to total lipids ratio in large high-density lipoprotein (CE/TL-L-HDL), and phospholipids to total lipids ratio in large high-density lipoprotein (P/TL-L-HDL). In multivariable MR analysis, these components were also significantly associated with the risk of PE. Additionally, mediation analysis identified P/TL-L-HDL as the only significant mediator between sleep apnea and PE (mediation effect = 0.0224; 95% CI=0.0005, 0.0443; p-value=0.0455). Conclusion: This study establishes a causal link between sleep apnea and an increased risk of preeclampsia/eclampsia, mediated by P/TL-L-HDL. Key Words: Sleep apnea; Preeclampsia; Eclampsia; Large HDL; Mendelian randomization; Mediation analysis

Causal associations between insulin and Lp(a) levels in Caucasian population: a Mendelian randomization study

BackgroundNumerous observational studies have demonstrated that circulating lipoprotein(a) [Lp(a)] might be inversely related to the risk of type 2 diabetes (T2D). However, recent Mendelian randomization (MR) studies do not consistently support this association. The results of in vitro research suggest that high insulin concentrations can suppress Lp(a) levels by affecting apolipoprotein(a) [apo(a)] synthesis. This study aimed to identify the relationship between genetically predicted insulin concentrations and Lp(a) levels, which may partly explain the associations between low Lp(a) levels and increased risk of T2D.MethodsIndependent genetic variants strongly associated with fasting insulin levels were identified from meta-analyses of genome-wide association studies in European populations (GWASs) (N = 151,013). Summary level data for Lp(a) in the population of European ancestry were acquired from a GWAS in the UK Biobank (N = 361,194). The inverse-variance weighted (IVW) method approach was applied to perform two-sample summary-level MR. Robust methods for sensitivity analysis were utilized, such as MR‒Egger, the weighted median (WME) method, MR pleiotropy residual sum and outlier (MR-PRESSO), leave-one-out analysis, and MR Steiger.ResultsGenetically predicted fasting insulin levels were negatively associated with Lp(a) levels (β = − 0.15, SE = 0.05, P = 0.003). The sensitivity analysis revealed that WME (β = − 0.26, SE = 0.07, P = 0.0002), but not MR‒Egger (β = − 0.22, SE = 0.13, P = 0.11), supported a causal relationship between genetically predisposed insulin levels and Lp(a).ConclusionOur MR study provides robust evidence supporting the association between genetically predicted increased insulin concentrations and decreased concentrations of Lp(a). These findings suggest that hyperinsulinaemia, which typically accompanies T2D, can partially explain the inverse relationship between low Lp(a) concentrations and an increased risk of T2D.

Genetic Susceptibility of Thrombin Measurement Levels and the Risk of Colon Adenocarcinoma: A Mendelian Randomization Study.

Aims/Background: This investigation sought to establish a possible correlation between thrombin measurement levels and the risk of developing colon adenocarcinoma (COAD). Methods: Thrombin measurement levels were sourced from a study by Pietzner M (2020, PMID: 33328453) and integrated into the IEU database. Data on COAD were obtained from the FinnGen database (2021, C3_COLON_ADENO). Various analytical methods were used to assess the relationship, including inverse variance weighting (IVW), mendelian randomization-Egger (MR-Egger) regression, as well as weighted median and mode techniques. Sensitivity analyses were performed, including Cochran's Q test, MR-Egger intercept test, mendelian randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), along with leave-one-out analysis, to ensure the robustness of the results. Results: The IVW analysis indicated a significant inverse association between elevated thrombin levels and the risk of COAD (odds ratio (OR) = 0.76, 95% CI = 0.66-0.88, p = 0.0003). These findings were supported by the weighted median analysis (OR = 0.78, 95% CI = 0.68-0.90, p = 0.0006) and the weighted mode analysis (OR = 0.78, 95% CI = 0.68-0.88, p = 0.0017). Conclusion: This research identified an inverse causal relationship between thrombin measurement levels and the incidence of COAD, suggesting that higher thrombin levels are associated with a reduced risk of developing COAD.

COVID-19, vaccination and migraine: Causal association or epiphenomenon?

Diverse studies have revealed discrepant evidence concerning the causal association between Corona Virus Disease 2019 (COVID-19) and COVID-19 vaccination in relation to migraines. Investigating the correlation between the former two factors and migraines can facilitate policymakers in the precise formulation of comprehensive post-pandemic interventions while urging the populace to adopt a judicious perspective on COVID-19 vaccination. We undertook a Mendelian randomization (MR) study. The primary assessment of the causal relationship between the three different COVID-19 exposures and migraine was conducted using the standard inverse variance weighted (IVW) approach. In the supplementary analysis, we also employed two methodologies: the weighted median estimator (WME) and the MR-Egger regression. Ultimately, the reliability and stability of the outcomes were assessed via Cochran's Q test, the leave-one-out method, the MR-Egger intercept test, and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. The results indicate an absence of correlation between genetically predicted COVID-19 (①Very severe respiratory confirmed COVID-19: odds ratio [OR], 1.0000881; 95%CI, 0.999748-1.000428; p = 0.6118; ②Hospitalized COVID-19: OR, 1.000024; 95%CI, 0.9994893-1.000559; p = 0.931;③SARS-CoV-2 infection: OR, 1.000358; 95%CI, 0.999023-1.001695; p = 0.5993) and the risk of migraine. Furthermore, the MR-Egger regression and WME also yielded no evidence of COVID-19 elevating the risk of migraine occurrence. Sensitivity analysis affirmed the robustness and consistency of all outcomes. The results of this study do not offer genetic evidence to substantiate a causal relationship between COVID-19 and migraines. Thus, the deduction drawn from COVID-19 genetic data is that COVID-19 vaccination is unlikely to exert an impact on the occurrence of migraines, though this conclusion warrants further investigation.

Causal effect of cerebral small vessel disease on unexplained dizziness: A Mendelian randomization study

BackgroundPrevious cohort studies have suggested an association between cerebral small vessel disease (cSVD) and “unexplained dizziness”. The causality of this link remains uncertain, but it would be of significant clinical importance, considering the substantial number of patients presenting with unexplained dizziness is large. We aimed to investigate the causal effect of cSVD-related phenotypes on unexplained dizziness using a Mendelian randomization approach. MethodsGenetic instruments for each cSVD-related phenotype - white matter hyperintensity (WMH) volume, lacunar stroke (LS), perivascular spaces (PVS), and cerebral microbleeds (CMBs) - as well as unexplained dizziness were identified through large-scale genome-wide association studies. We conducted 2-sample Mendelian randomization analyses. The random-effects inverse-variance weighted (IVW) method was chosen for the primary analysis. For sensitivity analyses, we employed the weighted-median, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis methods were implemented for the sensitivity analyses. ResultsWe successfully identified a significant causal effect of WMH volume on unexplained dizziness (odds ratio [95% CI], 1.12 [1.01–1.23]). However, we were unable to detect any significant causal effects of the other cSVD-related phenotypes on unexplained dizziness, with odds ratios [95% CI] of 1.03 [0.98–1.09] for LS, 0.75 [0.55–1.02] for white matter PVS, 1.02 [0.68–1.52] for basal ganglia PVS, 0.80 [0.43–1.51] for hippocampal PVS, 0.95 [0.90–1.00] for lobar CMBs, and 0.97 [0.92–1.01] for mixed CMBs respectively. The results from the sensitivity analyses were generally consistent with those of the primary analyses. ConclusionsThis MR study supports a causal relationship between WMH, a phenotype associated with cSVD, and the risk of unexplained dizziness, but does not support such a relationship between other cSVD-related phenotypes and unexplained dizziness. These findings require further validation through randomized controlled trials, larger cohort studies, and MR studies based on more extensive GWASs.