2-sample Mendelian Randomization Analysis Research Articles

Large Databases Can Answer Difficult Questions: Commentary on an article by Ming-Xiang Zou, MD, PhD, et al.: "Is Type 2 Diabetes Mellitus Associated with Spinal Degenerative Disorders? Evidence from Observational and 2-Sample Mendelian Randomization Analyses".

Large Databases Can Answer Difficult Questions: Commentary on an article by Ming-Xiang Zou, MD, PhD, et al.: "Is Type 2 Diabetes Mellitus Associated with Spinal Degenerative Disorders? Evidence from Observational and 2-Sample Mendelian Randomization Analyses".

Is Type 2 Diabetes Mellitus Associated with Spinal Degenerative Disorders?: Evidence from Observational and 2-Sample Mendelian Randomization Analyses.

Type 2 diabetes mellitus (T2DM) and spinal degenerative disorders (SDD) are common diseases that frequently coexist. However, both traditional observational studies and recent Mendelian randomization (MR) studies have demonstrated conflicting evidence on the association between T2DM and SDD. This comparative study explored and compared the association between T2DM and SDD using observational and MR analyses. For observational analyses, cross-sectional studies (44,972 participants with T2DM and 403,095 participants without T2DM), case-control studies (38,234 participants with SDD and 409,833 participants without SDD), and prospective studies (35,550 participants with T2DM and 392,046 participants without T2DM with follow-up information until 2022) were performed to test the relationship between T2DM and SDD using individual-level data from the U.K. Biobank from 2006 to 2022. For MR analyses, the associations between single-nucleotide polymorphisms with SDD susceptibility obtained using participant data from the U.K. Biobank, which had 407,938 participants from 2006 to 2022, and the FinnGen Consortium, which had 227,388 participants from 2017 to 2022, and genetic predisposition to T2DM obtained using summary statistics from a pooled genome-wide association study involving 1,407,282 individuals were examined. The onset and severity of T2DM are not available in the databases being used. Participants with T2DM were more likely to have SDD than their counterparts. Logistic regression analysis identified T2DM as an independent risk factor for SDD, which was confirmed by the Cox proportional hazard model results. However, using single-nucleotide polymorphisms as instruments, the MR analyses demonstrated no causal relationship between T2DM and SDD. The lack of such an association was robust in the sensitivity analysis, and no pleiotropy was seen. Our results suggest that the association between T2DM and SDD may be method-dependent. Researchers and clinicians should be cautious in interpreting the association, especially the causal association, between T2DM and SDD. Our findings provide fresh insights into the association between T2DM and SDD by various analysis methods and guide future research and clinical efforts in the effective prevention and management of T2DM and SDD. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Effect of the Blood Pressure and Antihypertensive Drugs on Cerebral Small Vessel Disease: A Mendelian Randomization Study.

Previous studies yielded conflicting results about the influence of blood pressure (BP) and antihypertensive treatment on cerebral small vessel disease. Here, we conducted a Mendelian randomization study to investigate the effect of BP and antihypertensive drugs on cerebral small vessel disease. We extracted single-nucleotide polymorphisms for systolic BP and diastolic BP from a genome-wide association study (N=757 601) and screened single-nucleotide polymorphisms associated with calcium channel blockers, thiazides, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers from public resources as instrumental variables. Then, we chose the genome-wide association study of white matter hyperintensity (WMH; N=18 381), cerebral microbleed (3556 cases, 22 306 controls), white matter perivascular space (9317 cases, 29 281 controls), basal ganglia perivascular space (BGPVS; 8950 cases, 29 953 controls), hippocampal perivascular space (HIPPVS; 9163 cases, 29 708 controls), and lacunar stroke (6030 cases, 248 929 controls) as outcome data sets. Subsequently, we conducted a 2-sample Mendelian randomization analysis. We found that elevated systolic BP significantly increases the risk of BGPVS (odds ratio [OR], 1.05 [95% CI, 1.04-1.07]; P=1.72×10-12), HIPPVS (OR, 1.04 [95% CI, 1.02-1.05]; P=2.71×10-7), and lacunar stroke (OR, 1.41 [95% CI, 1.30-1.54]; P=4.97×10-15). There was suggestive evidence indicating that elevated systolic BP is associated with higher WMH volume (β=0.061 [95% CI, 0.018-0.105]; P=5.58×10-3) and leads to an increased risk of cerebral microbleed (OR, 1.16 [95% CI, 1.04-1.29]; P=7.17×10-3). Elevated diastolic BP was significantly associated with higher WMH volume (β=0.087 [95% CI, 0.049-0.124]; P=5.23×10-6) and significantly increased the risk of BGPVS (OR, 1.05 [95% CI, 1.04-1.06]; P=1.20×10-16), HIPPVS (OR, 1.03 [95% CI, 1.02-1.04]; P=2.96×10-6), and lacunar stroke (OR, 1.31 [95% CI, 1.21-1.41]; P=2.67×10-12). The use of calcium channel blocker to lower BP was significantly associated with lower WMH volume (β=-0.287 [95% CI, -0.408 to -0.165]; P=4.05×10-6) and significantly reduced the risk of BGPVS (OR, 0.85 [95% CI, 0.81-0.89]; P=8.41×10-19) and HIPPVS (OR, 0.88 [95% CI, 0.85-0.92]; P=6.72×10-9). Our findings contribute to a better understanding of the pathogenesis of cerebral small vessel disease. Additionally, the utilization of calcium channel blockers to decrease BP can effectively reduce the likelihood of WMH, BGPVS, and HIPPVS. These findings offer valuable insights for the management and prevention of cerebral small vessel disease.

Causal effects of BMI, waist circumference, and body fat percentage on the risk of bladder cancer: A Mendelian randomization study.

The causal role of body mass index (BMI) in bladder cancer (BC) by Mendelian randomization (MR) has not yet been reported. We evaluated the causal associations between the measures of obesity (BMI, waist circumference, and body fat percentage) and BC. We conducted a 2-sample MR analysis to assess the genetic effect of measures of obesity on BC. The BMI dataset (GWAS ID: ukb-b-2303) comprised 454,884 Europeans, and we identified 9,851,867 single nucleotide polymorphisms (SNPs). The waist circumference data (GWAS ID: ukb-b-9405) included 462,166 Europeans and 9,851,867 SNPs. The body fat percentage dataset (GWAS ID: ukb-a-264) contained data from 331,117 Europeans and 10,894,596 SNPs. For the outcome data, the GWAS ID was finn-b-C3_BLADDER, consisting of 1115 cases and 217,677 controls, with 16,380,466 SNPs. The inverse-variance weighted (IVW) model was used as the primary MR analysis. Cochran Q-statistic was used to identify heterogeneity between the SNPs. The MR-Egger and MR-PRESSO methods were employed to assess directional pleiotropy and outlier SNPs. We detected a decisive causal link between BMI and BC by the IVW analysis (odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.08-1.85, P = .011). The IVW analyses revealed a significant correlation between BC and waist circumference (OR = 1.55, 95% CI: 1.08-2.12, P = .016). However, the IVW method (OR = 1.49, 95% CI: 0.99-2.00, P = .05) did not report any statistical significance between body fat percentage and BC. We did not observe heterogeneity and directional pleiotropy in the 3 pairs of MR studies. The 2-sample MR analysis revealed a conceivable causal association between obesity (BMI, waist circumference) and BC.

Exploring Putative Causal Associations between Diet and Periodontal Disease Susceptibility.

Dietary factors may play an important role in periodontal health. However, current evidence from observational studies remains inconclusive. This study aimed to investigate the causal relationships between dietary exposures and periodontal disease risks using Mendelian randomization analysis. Large-scale genome-wide association study summary statistics for 20 dietary factors were obtained from the MRC-IEU consortium. Multivariable and univariable 2-sample Mendelian randomization analyses were performed to assess the causal effects of each dietary exposure on 6 periodontal outcomes, including gingivitis and periodontitis. Genetically predicted higher dried fruit intake was significantly associated with reduced risks of acute gingivitis (odds ratio [OR]: 0.02; 95% confidence interval [CI]: 0.00-0.42; P = 0.01) and bleeding gums (OR: 0.96; 95% CI: 0.93-0.99; P = 0.01). Higher fresh fruit and water intake showed protective effects against chronic gingivitis (OR: 0.18; 95% CI: 0.04-0.91; P = 0.04 and OR: 0.15; 95% CI: 0.04-0.53; P = 0.00) and bleeding gums (OR: 0.95; 95% CI: 0.92-0.981; P = 0.00 and OR: 0.98; 95% CI: 0.96-0.99; P = 0.02). Alcohol intake frequency and processed meat intake were risk factors for bleeding gums (OR: 1.01; 95% CI: 1.00-1.02; P = 0.01 and OR: 1.05; 95% CI: 1.01-1.08; P = 0.00) and painful gums (OR: 1.01; 95% CI: 1.00-1.01; P = 0.00 and OR: 1.02; 95% CI: 1.01-1.03; P = 0.00). Most of the causal relationships between genetic predisposition to the specified dietary factors and periodontal diseases remained statistically significant (P < 0.05) after adjusting for genetic risks associated with dentures, smoking, and type 2 diabetes in multivariable Mendelian randomization models. The findings suggest potential protective effects of higher fruit and water intake against gingivitis and other periodontal problems, while alcohol and processed meat intake may increase the risks of periodontal disease. Our study provides preliminary causal evidence on the effects of diet on periodontal health and could inform prevention strategies targeting dietary habits to improve oral health. This study suggests that fruit and water intake may protect against periodontal disease, while alcohol and processed meats increase risk, informing dietary guidelines to improve oral health.

A causal analysis of the relationship between exposure to sunlight and colorectal cancer risk: A Mendelian randomization study.

Several observational studies have found that exposure to sunlight reduces the risk of colorectal cancer (CRC). However, sun exposure remains ambiguous in its relationship to CRC. We carried out a Mendelian randomization (MR) study to explore the potential associations between them. We examined the exposure to sunlight summary statistics of the UK Biobank Consortium using a 2-sample MR analysis. Using data from the FinnGen consortium, we derived summary statistics for CRC. We conducted our analysis with various methods, incorporating inverse variance weighted (IVW) along with 4 other approaches. A Cochran Q statistic was used to measure the heterogeneity of instrumental variables (IVs). We screened 133 single nucleotide polymorphisms (SNPs) (time spent outdoors in summer), 41 SNPs (time spent outdoors in winter), and 35 SNPs (frequency of solarium/sunlamp use) representing sunlight exposure for MR analysis. All selected SNPs had an F-statistic >20, indicating that IVs did not weakly bias the results. The summer outdoor activity trait exhibited significant heterogeneity (Cochran Q statistic = 183.795, P = .002 < 0.05), but we found no horizontal polymorphisms or significant heterogeneity for the other exposure traits. According to IVW estimates, no causal association exists between time spent outdoors in summer and CRC (Odds Ratio, OR = 0.735, 95% confidence interval, CI = 0.494-1.017, P = .128 > 0.017). No causal relationship existed between time spent outdoors in winter and CRC, as indicated by Bonferroni-corrected adjusted p-values. The OR was 0.877 with a 95% CI of 0.334-2.299, and the P value was .789, more significant than the significance threshold of 0.017. The solarium/sunlamp use frequency was not associated with CRC (OR = 1.567, 95%CI = 0.243-10.119, P = .637 > .017). Also, an IVW with random effects was applied to determine the causal relationship between summer outdoor time and CRC. No causal association between summer outdoor time and CRC was found (OR = 0.735, 95% CI = 0.494-1.017, P = .128 > .017). Additionally, 4 additional analyses yielded similar results. The findings of our study suggest that exposure to sunlight may reduce CRC risk, but the causal relationship remains unsolved. There is no evidence to suggest that exposure to sunlight prevents CRC. Randomized, controlled trials are needed to determine whether sunlight exposure protects against CRC.

Associations of Proteomics With Hypertension and Systolic Blood Pressure: KORA S4/F4/FF4 and KORA Age1/Age2 Cohort Studies.

Hypertension, a complex condition, is primarily defined based on blood pressure readings without involving its pathophysiological mechanisms. We aimed to identify biomarkers through a proteomic approach, thereby enhancing the future definition of hypertension with insights into its molecular mechanisms. The discovery analysis included 1560 participants, aged 55 to 74 years at baseline, from the KORA (Cooperative Health Research in the Region of Augsburg) S4/F4/FF4 cohort study, with 3332 observations over a median of 13.4 years of follow-up. Generalized estimating equations were used to estimate the associations of 233 plasma proteins with hypertension and systolic blood pressure (SBP). For validation, proteins significantly associated with hypertension or SBP in the discovery analysis were validated in the KORA Age1/Age2 cohort study (1024 participants, 1810 observations). A 2-sample Mendelian randomization analysis was conducted to infer causalities of validated proteins with SBP. Discovery analysis identified 49 proteins associated with hypertension and 99 associated with SBP. Validation in the KORA Age1/Age2 study replicated 7 proteins associated with hypertension and 23 associated with SBP. Three proteins, NT-proBNP (N-terminal pro-B-type natriuretic peptide), KIM1 (kidney injury molecule 1), and OPG (osteoprotegerin), consistently showed positive associations with both outcomes. Five proteins demonstrated potential causal associations with SBP in Mendelian randomization analysis, including NT-proBNP and OPG. We identified and validated 7 hypertension-associated and 23 SBP-associated proteins across 2 cohort studies. KIM1, NT-proBNP, and OPG demonstrated robust associations, and OPG was identified for the first time as associated with blood pressure. For NT-proBNP (protective) and OPG, causal associations with SBP were suggested.

Thyroid function effect on cardiac structure, cardiac function, and disease risk: Evidence of causal associations in European ancestry

BackgroundThyroid hormones play a crucial role in cardiovascular physiology. Subclinical thyroid dysfunction has been associated with adverse cardiovascular outcomes, but evidence is mixed regarding causality. ObjectiveThe purpose of this study was to investigate the potential causal relationships of thyroid-stimulating hormone (TSH), free thyroxine, hypothyroidism, and hyperthyroidism with cardiovascular outcomes, including atrial fibrillation (AF), coronary artery disease, myocardial infarction, heart failure, and ischemic stroke, as well as their effect on cardiac structure and function assessed by cardiac magnetic resonance imaging. MethodsA comprehensive 2-sample Mendelian randomization analysis was performed using summary data from large-scale meta-analyses of European ancestry individuals. ResultsGenetically determined lower TSH levels (odds ratio 0.928; 95% confidence interval 0.884–0.974; P = .003) and genetic risk of hyperthyroidism (odds ratio 1.049; 95% confidence interval 1.016–1.083; P = .003) were associated with increased AF risk. These associations remained significant even after adjusting for cardiovascular risk factors. Colocalization and multivariable Mendelian randomization revealed height as a key mediator between TSH/hyperthyroidism and AF. These findings were further corroborated in the independent FinnGen cohort. However, no clear evidence was found for relationships between thyroid function and other cardiovascular outcomes and cardiac structure and function. ConclusionOur study shows that reduced TSH levels and hyperthyroidism heighten AF risk, with height serving as an important mediator in these associations. The primary focus of thyroid management in cardiovascular health should be on preventing and treating arrhythmias, particularly AF. Our research highlights the importance of routine screening and timely treatment of thyroid dysfunction to optimize the prevention and management of arrhythmias.

Interplay Between Plasma Glycine and Branched-Chain Amino Acids Contributes to the Development of Hypertension and Coronary Heart Disease.

Higher levels of plasma glycine are linked to a reduced risk, while increased levels of total branched-chain amino acids (tBCAAs) are associated with a higher risk of essential hypertension and coronary heart disease (CHD). As these metabolic components are interconnected, analyzing the tBCAAs/glycine ratio may help to understand their interplay in the pathogenesis of cardiovascular disease. The Cox regression approach was combined with the development of novel genetic tools for assessments of associations between plasma metabolomic data (glycine, tBCAAs, and tBCAAs/glycine ratio) from the UK Biobank and the development of hypertension and CHD. Genome-wide association study was performed on 186 523 White UK Biobank participants to identify new independent genetic instruments for the 2-sample Mendelian randomization analyses. P-gain statistic >10 identified instruments associated with tBCAAs/glycine ratio significantly stronger compared with individual amino acids. Outcomes of genome-wide association study on hypertension and CHD were derived from the UK Biobank (nonoverlapping sample), FinnGen, and CARDIoGRAMplusC4D. The tBCAAs/glycine ratio was prospectively associated with a higher risk of developing hypertension and CHD (hazard ratio quintile Q5 versus Q1, 1.196 [95% CI, 1.109-1.289] and 1.226 [95% CI, 1.160-1.296], respectively). Mendelian randomization analysis demonstrated that tBCAAs/glycine ratio (P-gain >10) was a risk factor for hypertension (meta-analyzed inverse-variance weighted causal estimate 0.45 log odds ratio/SD (95% CI, 0.26-0.64) and CHD (0.48 [95% CI, 0.29-0.67]) with an absolute effect significantly larger compared with the effect of glycine (-0.06 [95% CI, -0.1 to -0.03] and -0.08 [95% CI, -0.11 to -0.05], respectively) or tBCAAs (0.22 [95% CI, 0.09-0.34] and 0.12 [95% CI, 0.01-0.24], respectively). The total BCAAs/glycine ratio is a key element of the metabolic signature contributing to hypertension and CHD, which may reflect biological pathways shared by glycine and tBCAAs.

Genetic causal association between varicella-zoster virus infection and psychiatric disorders: A 2-sample Mendelian randomization study

BackgroundPsychiatric disorders, such as schizophrenia (SCZ), major depressive (MDD), and bipolar disorder (BD) have a profound impact on millions of individuals worldwide. The critical step toward developing effective preventive and treatment strategies lies in comprehending the causal mechanisms behind these diseases and identifying modifiable risk factors associated with them. MethodsIn this study, we conducted a 2-sample Mendelian randomization analysis to explore the potential links between chickenpox(varicella-zoster virus infection) and three major psychiatric disorders(SCZ, MDD, BD). ResultsIn our MR study, among the three major psychiatric disorders, chickenpox was shown to be causally related to BD, indicating that infection with chickenpox may increase the risk of developing BD (IVW: OR = 1.064, 95% CI =1.025–1.104, P=0.001; RAPS: OR=1.066, 95% CI=1.024–1.110, P=0.002), while there was no causal relationship between SCZ and MDD. Similar estimated causal effects were observed consistently across the various MR models. The robustness of the identified causal relationship between chickenpox and BD holds true regardless of the statistical methods employed, as confirmed by extensive sensitivity analyses that address violations in model assumptions. The MR–Egger regression test failed to reveal any signs of directional pleiotropy (intercept = −0.042, standard error (SE) = 0.029, p = 0.236). Similarly, the MR-PRESSO analysis revealed no evidence of directional pleiotropy or outliers among the chickenpox-related instrumental variables (global test p = 0.653). Furthermore, a leave-one-out sensitivity analysis yielded consistent results, further underscoring the credibility and stability of the causal relationship. ConclusionsOur findings provide compelling evidence of a causal effect of chickenpox on the risk of BD. To gain a more comprehensive understanding of this association and its underlying mechanisms, additional research is needed. Such investigations are pivotal in identifying effective interventions for promoting BD prevention.

Irritable Bowel Syndrome Is Associated With Brain Health by Neuroimaging, Behavioral, Biochemical, and Genetic Analyses

BackgroundIrritable bowel syndrome (IBS) interacts with psychopathology in a complex way; however, little is known about the underlying brain, biochemical, and genetic mechanisms. MethodsTo clarify the phenotypic and genetic associations between IBS and brain health, we performed a comprehensive retrospective cohort study on a large population. Our study included 171,104 participants from the UK Biobank who underwent a thorough assessment of IBS, with the majority also providing neuroimaging, behavioral, biochemical, and genetic information. Multistage linked analyses were conducted, including phenome-wide association analysis, polygenic risk score calculation, and 2-sample Mendelian randomization analysis. ResultsThe phenome-wide association analysis showed that IBS was linked to brain health problems, including anxiety and depression, and poor cognitive performance. Significantly lower brain volumes associated with more severe IBS were found in key areas related to emotional regulation and higher-order cognition, including the medial orbitofrontal cortex/ventromedial prefrontal cortex, anterior insula, anterior and mid-cingulate cortices, dorsolateral prefrontal cortex, and hippocampus. Higher triglycerides, lower high-intensity lipoprotein, and lower platelets were also related (p < 1 × 10−10) to more severe IBS. Finally, Mendelian randomization analyses demonstrated potential causal relationships between IBS and brain health and indicated possible mediating effects of dyslipidemia and inflammation. ConclusionsFor the first time, this study provides a comprehensive understanding of the relationship between IBS and brain health phenotypes, integrating perspectives from neuroimaging, behavioral performance, biochemical factors, and genetics, which is of great significance for clinical applications to potentially address brain health impairments in patients with IBS.

Pulmonary function and atherosclerosis in the general population: causal associations and clinical implications

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50–64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis.

Genetic analyses identify brain imaging-derived phenotypes associated with the risk of amyotrophic lateral sclerosis.

Brain imaging-derived phenotypes have been suggested to be associated with amyotrophic lateral sclerosis in observational studies, but whether these associations are causal remains unclear. We aimed to assess the potential bidirectional causal associations between imaging-derived phenotypes and amyotrophic lateral sclerosis using bidirectional 2-sample Mendelian randomization analyses. Summary statistics for 469 imaging-derived phenotypes (33,224 individuals) and amyotrophic lateral sclerosis (20,806 cases and 59,804 controls) were obtained from 2 large-scale genome-wide association studies of European ancestry. We used the inverse-variance weighted Mendelian randomization method in the main analysis to assess the bidirectional associations between imaging-derived phenotypes and amyotrophic lateral sclerosis, followed by several sensitivity analyses for robustness validation. In the forward Mendelian randomization analyses, we found that genetically determined high orientation dispersion index in the right cerebral peduncle was associated with the increased risk of amyotrophic lateral sclerosis (odds ratio = 1.30, 95% confidence interval = 1.16-1.45, P = 2.26 × 10-6). In addition, the reverse Mendelian randomization analysis indicated that amyotrophic lateral sclerosis had no effect on 469 imaging-derived phenotypes. Mendelian randomization-Egger regression analysis showed no directional pleiotropy for the association between high orientation dispersion index in the right cerebral peduncle and amyotrophic lateral sclerosis, and sensitivity analyses with different Mendelian randomization models further confirmed these findings. The present systematic bidirectional Mendelian randomization analysis showed that high orientation dispersion index in the right cerebral peduncle might be the potential causal mediator of amyotrophic lateral sclerosis, which may provide predictive guidance for the prevention of amyotrophic lateral sclerosis. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment

BackgroundThrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient’s prognosis. ObjectivesTo investigate the association between genetically determined natural hemostatic factors’ levels and increased risk of HT after r-tPA treatment. MethodsUsing data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. ResultsLocal correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10−11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10−10; rs1421067 (CHD9), P = 1.81 × 10−14; and rs34780449, near ROBO1 gene, P = 1.64 × 10−8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10−14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [−0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05). ConclusionWe identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.

Relationship between inflammatory bowel disease and erectile dysfunction: a 2-sample Mendelian randomization study.

Observational studies have indicated a high prevalence of erectile dysfunction (ED) among patients with inflammatory bowel disease (IBD), but a definitive causal relationship remains unestablished. The primary aim of this study was to assess the potential causal relationship between IBD and ED using Mendelian randomization (MR) analysis. We obtained statistical data for 2 subtypes of IBD, ulcerative colitis (UC) and Crohn's disease (CD), as well as for ED, from publicly available genome-wide association studies (GWASs). Subsequently, a 2-sample MR analysis was conducted using these datasets. The primary MR analysis utilized the inverse variance-weighted (IVW) method, complemented by secondary analyses employing MR-Egger and weighted median methods. Furthermore, we assessed heterogeneity using Cochran's Q test and evaluated pleiotropy with the MR-Egger intercept test. To identify potential influential single nucleotide polymorphisms, we employed a leave-one-out analysis. Additionally, outliers were identified using the MR-PRESSO method. The study outcomes encompassed results from 3 MR analyses, namely IVW, MR-Egger, and weighted median, along with sensitivity analyses involving Cochran's Q test, the MR-Egger intercept test, leave-one-out analysis, and the MR-PRESSO method. There was no causal effect of UC and CD on ED in the MR analysis (IVW P > .05). Results of complementary methods were consistent with those of the IVW method. The results of sensitivity analyses supported our conclusion, and no directional pleiotropy was found. Genetically, despite the absence of a causal link between IBD and ED according to MR analysis, we must emphasize the elevated ED prevalence among IBD patients in observational studies, with particular consideration for the influence of negative emotions on erectile function. This study is the inaugural application of a 2-sample MR analysis using extensive GWAS datasets to evaluate the causal relationship between IBD and ED, effectively mitigating biases stemming from confounding factors and reverse causality often present in observational studies. Nevertheless, it is imperative to exercise caution when drawing conclusions due to inherent limitations in GWAS data, encompassing factors like samples overlap, gender categorization, population ancestry, and the persistent ambiguity surrounding the precise functionality of specific single nucleotide polymorphisms. MR analysis did not provide genetic-level evidence supporting a direct causal relationship between IBD (UC and CD) and ED.

Causal relationship between dried fruit intake and meniscal injuries: Two-sample Mendelian randomization.

To investigate the causal relationship between dried fruit intake and meniscal injuries using Mendelian randomization (MR). Data were pooled from large-scale genome wide association studies (GWAS), and genetic loci independently associated with dry fruit intake and meniscal injuries in populations of European origin were selected as instrumental variables. Three MR analyses, inverse variance weighting (IVW), weighted median (WME) and MR-Egger, were used to investigate the causal relationship between dried fruit intake and meniscal injuries. The results were tested for robustness by heterogeneity and multiplicity tests, and sensitivity analyses were performed using the "leave-one-out" method. The IVW results showed an OR (95 % CI) of 0.47 (0.28-0.78), P = .003, indicating a causal relationship between dried fruit intake and meniscus injury. And no heterogeneity and multiplicity were found by the test and sensitivity analysis also showed robust results. The present study used a 2-sample MR analysis, and by analyzing and exploring the genetic data, the study showed that too little intake of dry fruits is a risk factor for meniscal injuries.

Causal relationship between obesity and meniscal injuries: Two-sample Mendelian randomization.

To investigate the causal relationship between obesity and meniscal injuries using Mendelian randomization (MR). Genetic loci independently associated with obesity and meniscal injuries in people of European origin were selected as instrumental variables using pooled data from genome-wide association studies. Three MR analyses, MR-Egger, weighted median and inverse variance weighting, were used to investigate the causal relationship between obesity and meniscal injuries. The results were tested for robustness by heterogeneity and multiplicity tests, and sensitivity analyses were performed using the "leave-one-out" method. The inverse variance weighting results showed an OR (95% CI) of 1.13 (1.04-1.22), P = .003, indicating a causal relationship between obesity and the occurrence of meniscal injuries. And no heterogeneity and multiplicity were found by the test and sensitivity analysis also showed robust results. In this study, genetic data were analyzed and explored using 2-sample MR analysis, and the results showed that obesity is a risk factor for meniscal injuries.

Assessment of the relationship between telomere length and atherosclerosis: A Mendelian randomization study.

To evaluate the causal relationship between genetically determined telomere length (TL) and atherosclerosis (AS). We performed a 2-sample Mendelian randomization (MR) study to assess the potential causal relationship between TL and AS (coronary AS, cerebral AS, peripheral atherosclerosis (PAD), and AS, excluding cerebral, coronary, and PAD). The TL phenotype contained 472,174 participants, and the 4 subtypes of AS had 361,194, 218,792, 168,832, and 213,140 participants, all of European ancestries. The single nucleotide polymorphisms (SNPs) of TL strongly associated with the 4 atherosclerotic subtypes included in this study were 101, 92, 91, and 92, respectively. The odds ratios (ORs) and 95% confidence interval (CI) between TL and coronary AS calculated using inverse variance weighted (IVW) were 0.993 (0.988, 0.997), and the results were statistically significant (P < .05). The results between TL and cerebral AS, PAD, and AS (excluding cerebral, coronary, and PAD) were not statistically significant (P > .05). "Egger-intercept test" showed that there was no horizontal pleiotropy (P > .05); "leave-one-out analysis" sensitivity analysis showed that the results were stable and there were no instrumental variables with strong effects on the results; "MR- pleiotropy residual sum and outlier (PRESSO) test" showed 1 outlier for coronary AS and no outliers for the remaining subgroups. The results of the 2-sample MR analysis showed a causal association between TL and coronary AS but not with cerebral AS, PAD, and AS (excluding cerebral, coronary, and PAD). This may elucidate the observation that various vascular regions can be affected by AS but highlights the propensity of coronary arteries to be more susceptible to AS development.

Smoking and the risk of atopic dermatitis: A two-sample mendelian randomization study.

Atopic dermatitis (AD) is considered to be one of the most common chronic diseases. It has been shown that smoking is associated with atopic dermatitis, but previous studies were mainly observational, which may be biased. The present study conducted a 2-sample mendelian randomization (MR) study to investigate the causal relationship. The present study obtained data on "ever smoked" and "atopic dermatitis" from published large-scale genome-wide association studies. The data were obtained from the UK Biobank and BioBank Japan. Three methods were used to perform a 2-sample MR analysis and also performed sensitivity analysis. The odds ratio and 95% confidence interval (CI) between smoking and AD calculated by MR-Egger regression, weighted median, and random-effects inverse variance weighting method were 1.096 (95% CI.756-1.587) and 1.159 (95% CI 1.040-1.292), respectively, 1.137 (95% CI .975-1.325). The inverse variance weighting method showed statistical significance between the 2 and a causal relationship between smoking and AD. In conclusion, the results of our MR analysis suggest that smoking is likely to affect the incidence of AD.

The causal relationship between hypothyroidism and frozen shoulder: A two-sample Mendelian randomization.

To investigate the causal relationship between hypothyroidism and frozen shoulder using a Mendelian randomization (MR) approach. Pooled data from a large-scale genome-wide association study (GWAS) were used. Genetic loci that were independent of each other and associated with hypothyroidism and frozen shoulder in populations of European ancestry were selected as instrumental variables. Inverse variance weighting (IVW) was used as the primary analysis method. Weighted median (WME) and MR-Egger were used as complementary analysis methods to assess causal effects. To explore the causal relationship between hypothyroidism and frozen shoulder. Sensitivity test analysis was performed using heterogeneity test, multiple validity test, and leave-one-out analysis to explore the robustness of the results. IVW results showed an OR (95% CI) of 1.07 (1.01-1.14), P = .024, indicating that hypothyroidism is a risk factor for a frozen shoulder. And no pleiotropy was found by the test, and sensitivity analysis also showed robust results. This study used 2-sample MR analysis to analyze and explore the genetic data, and the results showed a higher prevalence of frozen shoulder in patients with hypothyroidism, suggesting that active control of hypothyroidism may reduce the occurrence of frozen shoulder.