A mendelian randomisation study of the causal effect of exercise intensity on the development of type 2 diabetes.

Objective: This study examines the causal effects of varying exercise intensities on type 2 diabetes mellitus (T2D) through Mendelian randomization (MR) analysis, using genetic variants as instrumental variables. Methods: A two-sample MR analysis was performed, employing Inverse Variance Weighted (IVW) as the primary method, supported by weighted median, MR-Egger regression, MR-PRESSO, and MR robustness-adjusted contour scores. Data were obtained from the International Exercise Genetics Database (IEGD) and the Global Diabetes Research Consortium (GRC), encompassing over 150,000 individuals for exercise intensity and around 200,000 T2D patients and controls. SNPs linked to exercise intensity were selected based on genome-wide significance (P < 5 × 10^-8) and linkage disequilibrium criteria (distance >10,000 kb, r^2 < 0.001). Results: The IVW analysis suggested that high-intensity exercise might reduce T2D risk, but the association was not statistically significant (OR = 0.667, 95% CI = 0.104-4.255, P = 0.667). The wide confidence interval indicates uncertainty in the effect estimate. Low-intensity exercise showed no significant effect on T2D risk (OR ∼ 1.0). Sensitivity analyses, including weighted median and MR-Egger regression, confirmed no significant association between high-intensity exercise and T2D risk. The MR-PRESSO analysis found no significant outliers, and the global test for pleiotropy was non-significant (P = 0.455). Cochran's Q test for heterogeneity in the IVW analysis was non-significant (Q = 12.45, P = 0.234), indicating consistency among SNP-derived estimates. Conclusion: High-intensity exercise potentially reduces T2D risk, but the association is not statistically significant. Further research is needed to understand the complex relationship between exercise intensity and T2D.

Association between waist circumference and chronic pain: insights from observational study and two-sample Mendelian randomization.

Background: Current research offers limited clarity on the correlation between waist circumference and chronic pain prevalence. Objective: This investigation seeks to elucidate the potential relationship between waist circumference and chronic pain and their causal association. Methods: An observational study was conducted, leveraging data from the National Health and Nutrition Examination Survey (NHANES) collected between 2001 and 2004. The multivariable logistic regression was used to assess the relationship between waist circumference and chronic pain. Furthermore, a meta-analysis of Mendelian Randomization (MR) was applied to explore a causal relationship between waist circumference and pain. Results: The observational study, post multivariable adjustment, indicated that an increase in waist circumference by 1 dm (decimeter) correlates with a 14% elevation in chronic pain risk (Odds Ratio [OR] = 1.14, 95% Confidence Interval [CI]: 1.04-1.24, p = 0.01). Moreover, the meta-analysis of MR demonstrated that an increased waist circumference was associated with a genetic predisposition to pain risk (OR = 1.14, 95%CI: 1.06-1.23, p = 0.0007). Conclusion: Observational analysis confirmed a significant relationship between increased waist circumference and the incidence of chronic pain, and results based on MR Study identified increased waist circumference as potentially causal for pain.

A mendelian randomization study investigating the causal relationships between 1400 serum metabolites and autoimmune diseases.

Objective: This study aims to explore the causal relationships between 1400 serum metabolites (SMs) and five autoimmune diseases (Myasthenia gravis [MG], Multiple sclerosis [MS], Systemic lupus erythematosus [SLE], Type 1 diabetes mellitus [T1DM], and Ulcerative colitis [UC]) through Mendelian randomization analysis. Method: Data on MG, MS, SLE, T1DM, and UC were obtained from the IEU OpenGWAS Project database, while information on 1400 SMs was extracted from GWAS summary statistics provided by Chen et al. Causal relationships were assessed using the inverse variance weighted (IVW), MR-Egger, Weighted Median (WME), and Simple median (SME) methods. The robustness of instrumental variables was verified through computation of the F-statistic. Heterogeneity was evaluated using Cochran's Q test and the leave-one-out (LOO) method. Horizontal pleiotropy was assessed using MR-Egger regression and MR-PRESSO. Result: Following correction of the IVW P values using the False Discovery Rate (FDR) method, it was found that increased levels of 5-methyluridine (ribothymidine) (OR = 1.191, 95%CI 1.086-1.307, FDR-P = 0.000) and 2'-deoxyuridine (OR = 1.337, 95%CI 1.127-1.586, FDR-P = 0.001) were found to be correlated with a higher risk of MS. Conversely, the ratio of S-adenosylhomocysteine (SAH) to 5-methyluridine (ribothymidine) (OR = 0.771, 95%CI 0.649-0.916, FDR-P = 0.007) was linked to a decreased risk of MS. Levels of 1,2-dilinoleoyl-GPE (18:2/18:2) (OR = 0.877, 95%CI 0.791-0.974, FDR-P = 0.003) appear to be a protective factor for T1DM. No notable correlations between SMs and MG, SLE, or UC. The study detected no heterogeneity or horizontal pleiotropy. Conclusion: Levels of 5-methyluridine (ribothymidine), 2'-deoxyuridine, and the ratio of S-adenosylhomocysteine (SAH) to 5-methyluridine (ribothymidine) can serve as predictors for MS. Similarly, 1,2-dilinoleoyl-GPE (18:2/18:2) levels can be used to predict T1DM. However, no significant causal relationships were found between SMs and MG, SLE, or UC. This observation holds significant clinical implications for crafting tailored preventive and therapeutic approaches for ADs.

Causal effects of gut microbiota on risk of interstitial cystitis: a two-sample Mendelian randomization study.

Background: The correlation between gut microbiota and interstitial cystitis has garnered significant attention in previous studies. Nevertheless, the causal relationship between them remains to be clarified. Methods: Genetic variation serves as a tool in Mendelian randomization analyses, facilitating the inference of causal relationships between exposure factors and disease outcomes. In this study, summary statistics derived from a comprehensive genome-wide association study conducted by the MiBioGen consortium were utilized as exposure factors, while interstitial cystitis data sourced from the GWAS Catalog served as the disease outcome. Then, a two-sample Mendelian randomization analysis was performed by applying inverse variance-weighted, MR-Egger, Weighted Median, Simple Mode, and Weighted Mode. In addition, heterogeneity and horizontal pleiotropy were excluded by sensitivity analysis. Results: IVW results confirmed that genus Haemophilus (OR = 2.20, 95% CI: 1.16-4.15, p = 0.015), genus Butyricimonas (OR = 2.26, 95% CI: 1.15-4.45, p = 0.018), genus Bacteroides (OR = 4.27, 95% CI: 1.36-13.4, p = 0.013) and Coprococcus1 (OR = 3.39, 95% CI: 1.28-8.99, p = 0.014) had a risk effect on interstitial cystitis. Sensitivity analysis did not find outlier SNPs. Conclusion: Our analysis has identified a causal relationship between specific genera and interstitial cystitis. However, further validation through randomized controlled trials is essential to substantiate these findings.

Association between gut microbiota and postpartum depression: A bidirectional Mendelian randomization study.

BACKGROUNDS: Empirical investigations have shown an association between gut microbiota and postpartum depression (PPD); nevertheless, the precise cause-and-effect relationship between these two variables remains ambiguous. This research aimed to examine the possible reciprocal causal relationship between the gut microbiota and PPD. METHODS: In this work, we used Mendelian randomization (MR) to analyze the relationship between the gut microbiota (n = 18,340) and PPD (n = 67,205). We obtained the relevant SNPs from publicly accessible genome-wide association studies (GWAS). The SNP estimations were combined by the inverse-variance weighted (IVW) method, including sensitivity analyses such as weighted median, MR Egger, and MR Pleiotropy Residual Sum and Outlier (PRESSO). RESULTS: We have identified strong correlations between six bacterial characteristics and the likelihood of developing PPD. Our research revealed that the genus Ruminococcaceae UCG010, the family Veillonellaceae, and the class Clostridia had a beneficial effect on preventing PPD. The class Alphaproteobacteria, genus Slackia, and order NB1n were found to have a significant negative impact on PPD. The sensitivity studies conducted on these bacterial features consistently confirmed these finding. LIMITATIONS: It is crucial to acknowledge that our study was conducted just within a European society, which may restrict its applicability to other groups. CONCLUSIONS: The findings from our MR investigation indicate a potential causal relationship between certain kinds of gut bacteria and PPD. Additional investigation is required to elucidate the influence of gut microbiota on the advancement of PPD.

Exploring the Causal Relationship Between Migraine and Insomnia Through Bidirectional Two-Sample Mendelian Randomization: A Bidirectional Causal Relationship.

Introduction: The intricate relationship between migraine and insomnia has been a subject of great interest due to its complex mechanisms. Despite extensive research, understanding the causal link between these conditions remains a challenge. Material and Methods: This study employs a bidirectional Mendelian randomization approach to investigate the causal relationship between migraine and insomnia. Risk loci for both conditions were derived from large-scale Genome-Wide Association Studies (GWAS). The primary method of Mendelian Randomization utilized in this study is the Inverse Variance Weighted (IVW) method. Results: Our findings indicate a bidirectional causal relationship between migraine and insomnia. In the discovery set, migraine had a significant effect on insomnia (OR=1.02, 95% CI=1.02 (1.01-1.03), PIVW=5.30E-04). However, this effect was not confirmed in the validation set (OR=1.03, 95% CI=1.03 (0.87-1.21), PIVW=0.77). Insomnia also had a significant effect on migraine (OR=1.02, 95% CI=1.02 (0.01-1.03), PIVW=2.67E-08), and this effect was validated in the validation set (OR=2.30, 95% CI=2.30 (1.60-3.30), PIVW=5.78E-06). Conclusion: This study provides meaningful insights into the bidirectional causality between migraine and insomnia, highlighting a complex interplay between these conditions. While our findings advance the understanding of the relationship between migraine and insomnia, they also open up new avenues for further research. The results underscore the need for considering both conditions in clinical and therapeutic strategies.

Genetic Causality between Type 1 Diabetes and Arrhythmia Identified by a Two-sample Mendelian Randomization Study.

BACKGROUND: Clinical studies have shown that cardiovascular diseases in patients with type 1 diabetes (T1D) are often atypical or asymptomatic. The link between T1D and arrhythmia remains unclear. To infer causality between T1D and arrhythmia at the genetic level, we conducted a Mendelian randomization study through the genetic tools of T1D. METHODS: In this study, we used genetic variables and summary statistics from genome-wide association studies of T1D and arrhythmia. Single nucleotide polymorphisms were selected based on the assumptions of instrumental variables. The inverse variance-weighted method was used as the primary analysis to summarize the causal effects between exposure and outcome. The weighted median and weighted mode methods were used as secondary methods. We tested for horizontal pleiotropy using the MR-Egger method and detected heterogeneity using the Q-test. A leave-one-out sensitivity analysis was performed. Scatter plots, forest plots, and funnel plots were used to visualize the results of the MR analysis. RESULTS: In this study, we selected 28 T1D-related SNPs as instrumental variables. The IVW [odds ratio (OR) = 0.98, 95 % confidence interval (CI) = 0.97-1.00, P = 0.008], weighted median (OR = 0.98, 95 % CI = 0.96 - 0.99, P = 0.009), and weighted mode (OR = 0.98, 95 % CI = 0.96-0.99, P = 0.018) analysis methods suggested a causal effect of T1D on arrhythmia. The MR-Egger method indicated no horizontal pleiotropy (P = 0.649), and the Q-test showed no heterogeneity (IVW, P = 0.653). CONCLUSIONS: Our MR analysis revealed a causal association between T1D and the development of arrhythmia, indicating that patients with T1D had a higher risk of arrhythmia.

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

Purpose: To investigate the causal relationship between gut microbiota (GM) and chalazion through Mendelian randomization (MR) analysis. Methods: GM-related genome-wide association studies (GWAS) were obtained from the International Consortium MiBioGen. Genetic data for chalazion were sourced from the MRC Integrative Epidemiology Unit (IEU) Open GWAS database. Five MR methods, including inverse variance weighted (IVW), were employed to estimate causal relationships. Cochran's Q test was used to detect heterogeneity, the MR-Egger intercept test and MR-PRESSO regression were utilized to detect horizontal pleiotropy, and the leave-one-out method was employed to validate data stability. Results: We identified 1,509 single nucleotide polymorphisms (SNPs) across 119 genera as instrumental variables (IVs) (p < 1 × 10-5). According to the inverse variance weighted (IVW) estimate, the Family XIII AD3011 group (OR = 1.0018, 95% CI 1.0002-1.0035, p = 0.030) and Catenibacterium (OR = 1.0013, 95% CI 1.0002-1.0025, p = 0.022) were potentially associated with increased risk of chalazion. Conversely, Veillonella (OR = 0.9986, 95% CI 0.9974-0.9999, p = 0.036) appeared to provide protection against chalazion. There was no evidence of heterogeneity or pleiotropy. Conclusion: This study uncovered the causal relationship between GM and chalazion, pinpointing Catenibacterium and Family XIII AD3011 group as potential risk contributors, while highlighting Veillonella as a protective factor. In-depth investigation into the potential mechanisms of specific bacteria in chalazion was essential for providing novel therapeutic and preventive strategies in the future.

Investigating the causal relationship between thyroid dysfunction diseases and osteoporosis: a two-sample Mendelian randomization analysis.

The prevalence of thyroid dysfunction diseases (TDFDs) and osteoporosis (OP) is high. Previous studies have indicated a potential association between TDFDs and OP, yet the causal direction remains unclear. This study aimed to investigate the potential causal relationship between TDFDs and the risk of developing OP and related fractures. We obtained pooled data from genome-wide association studies (GWASs) conducted on TDFDs and OP in European populations and identified single-nucleotide polymorphisms (SNPs) with genome-wide significance levels associated with exposure to TDFDs as instrumental variables. Inverse variance weighted (IVW) was employed as the primary method for Mendelian randomization (MR) analysis, supplemented by MR‒Egger, weighted median, simple mode and weighted mode methods. Sensitivity analyses were conducted to evaluate the robustness of the findings. The IVW method demonstrated an increased risk of OP in patients with TDFDs, including hyperthyroidism and hypothyroidism (TDFDs: OR = 1.11; 95% CI 1.09, 1.13; hypothyroidism: OR = 1.14; 95% CI 1.10, 1.17; hyperthyroidism: OR = 1.09; 95% CI 1.06, 1.12). These findings were supported by supplementary analysis, which revealed a positive correlation between TDFDs and the risk of OP. Multiple sensitivity analyses confirmed the absence of horizontal pleiotropy in the study, thus indicating the robustness of our results. The causal relationship between TDFDs and increased risk of OP implies the need for early bone mineral density (BMD) screening and proactive prevention and treatment strategies for individuals with TDFDs.

Rheumatoid arthritis and the risk of chronic kidney diseases: a Mendelian randomization study.

Background: The extra-articular lesions of rheumatoid arthritis (RA) are reported to involve multiple organs and systems throughout the body, including the heart, kidneys, liver, and lungs. This study assessed the potential causal relationship between RA and the risk of chronic kidney diseases (CKDs) using the Mendelian randomization (MR) analysis. Method: Independent genetic instruments related to RA and CKD or CKD subtypes at the genome-wide significant level were chosen from the publicly shared summary-level data of genome-wide association studies (GWAS). Then, we obtained some single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs), which are associated with RA in individuals of European origin, and had genome-wide statistical significance (p5 × 10-8). The inverse-variance weighted (IVW) method was the main analysis method in MR analysis. The other methods, such as weighted median, MR-Egger, simple mode, and weighted mode were used as supplementary sensitivity analyses. Furthermore, the levels of pleiotropy and heterogeneity were assessed using Cochran's Q test and leave-one-out analysis. Furthermore, the relevant datasets were obtained from the Open GWAS database. Results: Using the IVW method, the main method in MR analysis, the results showed that genetically determined RA was associated with higher risks of CKD [odds ratio (OR): 1.22, 95% confidence interval (CI) 1.13-1.31; p < 0.001], glomerulonephritis (OR: 1.23, 95% CI 1.15-1.31; p < 0.000), amyloidosis (OR = 1.43, 95% CI 1.10-1.88, p < 0.001), and renal failure (OR = 1.18, 95% CI 1.00-1.38, p < 0.001). Then, using multiple MR methods, it was confirmed that the associations persisted in sensitivity analyses, and no pleiotropy was detected. Conclusion: The findings revealed a causal relationship between RA and CKD, including glomerulonephritis, amyloidosis, and renal failure. Therefore, RA patients should pay more attention to monitoring their kidney function, thus providing the opportunity for earlier intervention and lower the risk of progression to CKDs.

Dried fruit intake can lower the risk of ulcerative colitis: evidence from a Mendelian randomization study.

BACKGROUND AND OBJECTIVES: This study aims to examine the causal relationship between dietary factors and ulcerative colitis (UC). METHODS AND STUDY DESIGN: The analysis utilized data from genome-wide association studies (GWAS). Dried fruit, vegetables, processed meat, fresh fruit, and cereal intake were examined as exposure factors. UC was considered the outcome. Two-sample Mendelian randomization (TSMR) analysis was performed using methods. Heterogeneity and horizontal pleiotropy assessments were conducted to ensure the robustness of our findings. Additionally, we applied False Discovery Rate (FDR) corrections for multiple tests. RESULTS: The analysis revealed a significant inverse causal relationship between dried fruit intake and UC risk (odds ratio [OR]: 0.488, 95% confidence interval [CI]: 0.261 to 0.915, p = 0.025). No significant association was observed between vegetable intake (OR: 1.742, 95% CI: 0.561 to 5.415, p = 0.337), processed meat intake (OR: 1.136, 95% CI: 0.552 to 2.339, p = 0.729), fresh fruit intake (OR: 0.977, 95% CI: 0.465 to 2.054, p = 0.952), cereal intake (OR: 1.195, 95% CI: 0.669 to 2.134, p = 0.547). The low heterogeneity observed across analyses and the confirmation of stability through leave-one-out analysis reinforce the reliability of these results. Moreover, after adjusting for multiple tests, none of the dietary factors reached a p-value below the conventional significance threshold of 0.05. CONCLUSIONS: This study provides evidence of a potential association between dried fruit intake and a reduced risk of UC. Further MR studies incorporating larger GWAS datasets are needed to confirm these findings.

Gut microbiota and risk of coronary heart disease: a two-sample Mendelian randomization study.

Background: The relationship between gut microbiota composition and coronary heart disease (CHD) has been recently reported in several observational studies. However, the causal effect of gut microbiota on coronary heart disease is uncharted. Objective: This study attempted to investigate the effect of gut microbiota on coronary heart disease by Mendelian randomization (MR) analysis. Methods: Through the two-sample MR method, single-nucleotide polymorphisms relevant to gut microbiota were selected as instrument variables to evaluate the causal association between gut microbiota and the risk of CHD. Results: According to the selection criteria of the inverse variance-weighted average method, Class Actinobacteria, Class Lentisphaeria, Family Clostridiales vadinBB60group, Genus Clostridium innocuum group, Genus Bifidobacterium, Genus Butyricicoccus, Genus Oxalobacter, Genus Turicibacter, and Order Victivallales, presented a suggestive association with coronary heart disease. Conclusion: This two-sample Mendelian randomization study found that gut microbiota was causally associated with coronary heart disease. Further randomized controlled trials are needed to clarify the protective effect of probiotics on coronary heart disease and their specific protective mechanisms.

Comparison of instrumental variable methods with continuous exposure and binary outcome: A simulation study.

BACKGROUND: Instrumental variable (IV) methods are widely employed to estimate causal effects when concerns regarding unmeasured confounders. Although comparisons among several IV methods for binary outcomes exist, comprehensive evaluations are insufficient. Therefore, in this study, we aimed to conduct a simulation with some settings for a detailed comparison of these methods, focusing on scenarios where IVs are valid and under effect homogeneity with different instrument strengths. METHODS: We compared six IV methods under 32 simulation scenarios: two-stage least squares (2SLS), two-stage predictor substitutions (2SPS), two-stage residual inclusions (2SRI), limited information maximum likelihood (LIML), inverse-variance weighted methods with a linear outcome model (IVWLI), and inverse-variance weighted methods with a non-linear model (IVWLL). By comparing these methods, we examined three key estimates: the parameter estimates of the exposure variable, the causal risk ratio, and the causal risk differences. RESULTS: Based on the results, six IV methods could be classified into three groups: 2SLS and IVWLI, 2SRI and 2SPS, and LIML and IVWLL. The first pair showed a clear bias owing to outcome model misspecification. The second pair showed a relatively good performance when strong IVs are available; however, the estimates suffered from a significant bias when only weak IVs are used. The third pair produced relatively conservative results, although they were less affected by weak IV issues. CONCLUSIONS: The findings indicate that no panacea is available for the bias associated with IV methods. We suggest using multiple IV methods: one for primary analysis and another for sensitivity analysis.

Eosinophils and risk of ulcerative colitis in European population: Evidence from Mendelian randomization study.

BACKGROUND: Observational studies have indicated that peripheral blood eosinophil count is elevated in individuals diagnosed with ulcerative colitis (UC) and correlates with the disease activity of UC. However, this conclusion contradicts with findings from other studies. Therefore, we employed Mendelian randomization (MR) method to assess the genetic link between eosinophil count and UC. METHOD: This MR study utilized summary data from genome-wide association studies (GWAS) on eosinophil count and UC. The main approach used for conducting MR analysis was the inverse variance weighted (IVW) method. Meta-analysis of the IVW results was performed alongside multiple sensitivity analyses to confirm the robustness of the MR analysis results. RESULTS: The IVW method unveiled a causal relationship between eosinophil count and UC (OR = 1.18, 95% CI: 1.04-1.33, p = .01) in the discovery cohort. This finding was further corroborated by the replication cohorts (OR = 1.16, 95% CI: 1.04-1.29, p = .01; OR = 1.12, 95% CI: 1.01-1.24, p = .03). The meta-analysis indicated that the overall odds ratio (OR) for all studies was 1.15 (common effect model, 95% CI: 1.08-1.23, p < .01). Sensitivity analysis suggested the absence of heterogeneity and horizontal pleiotropy in all MR analyses. CONCLUSION: Based on bidirectional two-sample MR analysis, there is an indication that elevated eosinophil count may increase the risk of UC. However, potential confounding factors cannot be ruled out, and further research is necessary to explore how eosinophils contribute to the onset and progression of UC.

A Mendelian Randomisation Analysis Reveals No Relationship Between Periodontitis and Coronary Atherosclerosis.

OBJECTIVES: Growing evidence appears to intimate a profound connection between periodontitis and coronary atherosclerosis (CA), yet the existence of a causal relationship remains unclear. Through the implementation of Mendelian randomization analysis, we further evaluated the potential causal link between chronic/acute periodontitis (CP/AP) and CA. METHODS: Utilizing genome-wide association study (GWAS) summary statistics, we incorporated periodontitis data derived from European samples (n1 = 198,441; n2 = 195,762) and CA data from 61,194 cases. We conducted a 2 sample, bidirectional Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW) method as the main analytical approach. Supplementary analyses were executed through MR Egger, Weighted median (WM), IVW, Simple mode, and Weighted mode approaches. RESULTS: The IVW analysis revealed no significant causal relationship between CA and periodontitis (CA-CP: OR = 2.110, 95% CI = 0.208-21.317, P = .527; CA-AP: OR = 0.414, 95% CI = 0.051-3.384, P = .644). Similarly, the bidirectional analysis did not identify impact of periodontitis on CA (OR = 1.000, 95% CI = 0.999-1.001, P = .953). The supplementary analyses corroborated these findings. CONCLUSIONS: While studies highlighting a correlation between periodontitis and CA, our comprehensive analysis does not corroborate a causal association between periodontitis and CA. Further research is needed to elucidate other potential shared mechanisms and causal evidence between periodontitis and CA.

C-reactive protein and cognitive impairment: A bidirectional Mendelian randomization study.

OBJECTIVES: While C-reactive protein (CRP) has been solidly linked as a risk factor for cognitive impairment, observational research alone cannot definitively demonstrate a causal relationship. This study therefore sought to determine whether there was an association between CRP and the development of cognitive impairment. METHODS: This study employed bidirectional Mendelian randomization (MR) to investigate the genetic association between CRP and cognitive impairment. genome-wide association studies (GWAS) summary statistics for both were sourced from IEU Open GWAS or prior reports. Cognitive GWAS's used were on tests designed to assess cognitive performance, fluid intelligence, prospective memory, and reaction time. The MR analysis applied several methods, including inverse variance-weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode approaches, then use of MR sensitivity analyses to interrogate findings. RESULTS: Forward MR analysis showed that genetically proxied CRP was associated with prospective memory (P = 0.009), whereas there is little evidence to support an association between CRP and other cognitive tests. Reverse MR analysis indicated a potential association between genetic proxy cognitive performance (P = 0.002) and fluid intelligence score (P = 0.019) with CRP levels. For genetically proxied CRP on prospective memory, the level of pleiotropy (P > 0.05) and no genetic variant heterogeneity (P > 0.05) made bias unlikely, and leave-one-out tests also confirmed robust associations. CONCLUSIONS: The effect of genetically proxied CRP on prospective memory, with little evidence on other cognitive tests. The reverse MR shows some evidence of genetically proxied cognition (cognitive performance and fluid intelligence) on CRP levels.

The causal association between body fat distribution and risk of abdominal wall hernia: a two-sample Mendelian randomization study.

PURPOSE: Obesity and a high body mass index (BMI) are considered as risk factors for abdominal wall hernia (AWH). However, anthropometric measures of body fat distribution (BFD) seem to be better indicators in the hernia field. This Mendelian randomization analysis aimed to generate more robust evidence for the impact of waist circumstance (WC), body, trunk, arm, and leg fat percentages (BFP, TFP, AFP, LFP) on AWH. METHODS: A univariable MR design was employed and the summary statistics allowing for assessment were obtained from the genome-wide association studies (GWASs). An inverse variance weighted (IVW) method was applied as the primary analysis, and the odds ratio value was used to evaluate the causal relationship between BFD and AWH. RESULTS: None of the MR-Egger regression intercepts deviated from null, indicating no evidence of horizontal pleiotropy (p > 0.05). The Cochran Q test showed heterogeneity between the genetic IVs for WC (p = 0.005; p = 0.005), TFP (p < 0.001; p < 0.001), AFP-L (p = 0.016; p = 0.015), LFP-R (p = 0.012; p = 0.009), and LFP-L (p < 0.001; p < 0.001). Taking the IVW random-effects model as gold standard, each standard deviation increment in genetically determined WC, BFP, TFP, AFP-R, AFP-L, LFP-R, and LFP-L raised the risk of AWH by 70.9%, 70.7%, 56.5%, 69.7%, 78.3%, 87.7%, and 72.5%, respectively. CONCLUSIONS: This study proves the causal relationship between AWH and BFD, attracting more attention from BMI to BFD. It provides evidence-based medical evidence that healthy figure management can prevent AWH.

Vitamin D levels and five cardiovascular diseases: A Mendelian randomization study.

Cardiovascular disease is the leading cause of death worldwide, whilst vitamin D levels have been found to be associated with cardiovascular disease. To investigate the causal relationship between vitamin D levels and five cardiovascular diseases, a genome-wide association study (GWAS) was carried out using data on vitamin D levels (sample size = 79366), angina pectoris (18168 cases and 187840 controls), coronary heart disease (21012 cases and 197780 controls), lacunar stroke (6030 cases and 248929 controls), heart attack (10693 cases and 451187 controls), and hypertension (55917 cases and 162837 controls), with a Mendelian randomization (MR) analysis being subsequently performed. Six single nucleotide polymorphisms were used as instrumental variables (IVs). In addition, sensitivity analysis was performed to verify the reliability of the MR results here. The results showed a causal relationship between vitamin D levels and angina pectoris (OR = 0.51, 95 % CI: 0.28-0.93, P = 0.03), coronary heart disease (OR = 0.53, 95 % CI: 0.34-0.81, P = 0.004), and lacunar stroke (OR = 0.41, 95 % CI: 0.20-0.86, P = 0.02), but no causal relationship with heart attacks (OR = 1.00, 95 % CI: 0.99-1.01, P = 0.76) or hypertension (OR = 0.99, 95 % CI: 0.73-1.34, P = 0.94). Additionally, our IVs data showed no heterogeneity or pleiotropy, whilst the results of the MR analysis were reliable. This study contributes to the prevention and treatment of these five cardiovascular diseases.

Genetic Association of Allergic Rhinitis with Sleep and Neuropsychological Disorders: A Mendelian Randomization Study.

BACKGROUND: The genetic association of allergic rhinitis (AR) with other physiological systems throughout the human body remains unknown. OBJECTIVE: The aim of this Mendelian randomization (MR) study was to explore the association of this respiratory disorder with multiple common sleep and neuropsychological disorders at the genetic level. METHODS: Summary data for total AR and pollen AR were collected from the most updated FinnGen genome-wide association studies involving more than 340 000 European subjects. Summary data for 12 sleep and neuropsychological disorders (including snoring) were included from UK Biobank studies involving 63 392 to 462 933 European subjects. Three MR methods, including inverse-variance weighting (IVW), weighted median and MR-Egger, were used to determine the relationships between the exposures and outcomes. Several sensitivity analyses, including Cochran's Q, MR-Egger intercept, MR-PRESSO, "leave-one-out" test and funnel plot, were used to detect heterogeneity and horizontal pleiotropy. RESULTS: IVW revealed that total and pollen AR were associated with an increased risk of snoring (odds ratio (OR) = 1.011, 95% confidence interval (CI) = 1.004∼1.019, P = .003; OR = 1.006, 95% CI = 1.001∼1.011, P = .014). Two other MR methods supported the results from the IVW analysis. No heterogeneity or horizontal pleiotropy was confirmed by sensitivity analyses. In addition, IVW did not reveal any association between AR and other included disorders. CONCLUSION: AR (specifically AR caused by pollen) might be an independent risk factor for snoring at the genetic level, which should be verified in the future.

Identification of heel bone mineral density as a risk factor of Alzheimer's disease by analyzing large-scale genome-wide association studies datasets.

Introduction: Both low bone mineral density (BMD) and Alzheimer's disease (AD) commonly co_occur in the older adult. Until now, the association between AD and BMD has been widely reported by observational studies. However, Mendelian randomization (MR) studies did not support the causal association between BMD and AD. We think that the lack of significant causal association between AD and BMD identified by recent MR studies may be caused by small number of potential instrumental variables. Methods: We conduct a MR study to evaluate the causal effect of heel BMD on the risk of AD using 1,362 genome-wide significant and independent (p < 5.00E-08) heel BMD genetic variants as the potential instrumental variables, which are identified by a large-scale genome wide association study (GWAS) of heel BMD in 394,929 UK Biobank individuals. Using these 1,362 genome-wide significant and independent heel BMD genetic variants, we extracted their corresponding AD GWAS summary results in IGAP AD GWAS dataset (n = 63,926) and FinnGen AD GWAS dataset (n = 377,277). Five methods including inverse-variance weighted meta-analysis (IVW), weighted median, MR-Egger, MR-PRESSO, and MRlap were selected to perform the MR analysis. 951 of these 1,362 genetic variants are available in AD GWAS dataset. Results: We observed statistically significant causal effect of heel BMD on the risk of AD using IVW in IGAP AD GWAS dataset (OR = 1.048, 95%CI: 1.002-1.095, p = 0.04) and FinnGen AD GWAS dataset (OR = 1.053, 95% CI:1.011-1.098, p = 0.011). Importantly, meta-analysis of IVW estimates from IGAP and FinnGen further supported the causal effect of heel BMD on the risk of AD (OR = 1.051, 95% CI: 1.02-1.083, p = 0.0013). Discussion: Collectively, our current MR study supports heel BMD to be a risk factor of AD by analyzing the large-scale heel BMD and AD GWAS datasets. The potential mechanisms underlying the association between heel BMD and AD should be further evaluated in future.