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Jianhong Li,1 Yingna Liang2 1Department of Radiology, Foshan Hospital of Traditional Chinese Medicine, Foshan, People’s Republic of China; 2Department of Gynaecology and Obstetrics, Guangzhou Baiyun First People’s Hospital (Baiyun District Maternal and Child Health Hospital), Guangzhou, Guangdong Province, People’s Republic of ChinaCorrespondence: Yingna Liang, Department of Gynaecology and Obstetrics, Guangzhou Baiyun First People’s Hospital (Baiyun District Maternal and Child Health Hospital), Guangzhou, Guangdong Province, People’s Republic of China, Email liangyn123@126.comObjective: In this study, it was intended to explore the causal association between mean platelet volume (MPV) and risk of deep vein thrombosis (DVT) using a two-sample Mendelian randomization (MR) analysis and a retrospective study.Methods: This study applied two-sample MR analysis to estimate the causal association between MPV and risk of DVT. Twenty-one single nucleotide polymorphisms (SNPs) were selected as genetic variants from two independent consortiums cohorts (p-value < 5× 10− 8, linkage disequilibrium r2< 0.1). Inverse variance weighted (IVW), MR-egger method and weighted median were performed. A retrospective study was also conducted to verify the associations identified from the MR study.Results: The MR analysis demonstrated that genetically predicted higher MPV was associated with significantly lower risk of DVT (OR 0.982, 95% CI = 0.967– 0.998, P = 0.023), with the consistent result in weighted median and MR-Egger. There was no directional horizontal pleiotropy in the method of MR-Egger regression (intercept=2.9e-04, P = 0.194). There was no single SNP was found to strongly drive the combined causal effect in the leave-one-out sensitivity analysis. Additionally, the similar result was observed in the retrospective study.Conclusion: This study suggested that MPV was negatively associated with the risk of DVT. More basic researches are needed in the future to explore its specific mechanism.Keywords: mean platelet volume, deep vein thrombosis, Mendelian randomization, causal association

Sleep has attracted extensive attention due to its significance in health. However, its association with erectile dysfunction (ED) is insufficiently investigated. To investigate the potential causal links between sleep traits (insomnia, sleep duration, and chronotype) and ED, this study was performed. The single-nucleotide polymorphisms (SNPs) associated with insomnia, sleep duration, and chronotype were retrieved from previous genome-wide association studies (GWAS). A conventional two-sample Mendelian randomization (MR) was used to estimate the causal links between sleep traits and ED. The summary statistics of ED were from individuals of European ancestry (6175 cases vs 217 630 controls). As shown by the random effect inverse-variance-weighting (IVW) estimator, genetically predicted insomnia was causally associated with a 1.15-fold risk of ED (95% confidence interval: 1.07–1.23, P < 0.001). Sleep duration and morningness were not causally associated with ED, as indicated by the IVW (all P > 0.05). These findings were consistent with the results of sensitivity analyses. Based on genetic data, this study provides causal evidence that genetically predicted insomnia increases the risk of ED, whereas sleep duration and chronotype do not.

Abstract Objectives Heart failure (HF) has been implicated in osteoporosis. However, causality remains unestablished. Here, we sought to assess causal associations of genetic liability to HF with osteoporosis using Mendelian randomization (MR) analyses. Methods Independent single nucleotide polymorphisms associated with HF at genome-wide significance were derived from a large genome-wide association study (GWAS) (including up to 977,323 individuals). We obtained summary statistics for forearm (FA) bone mineral density (BMD) (n = 8,143), femoral neck (FN) BMD (n = 32,735), lumbar spine (LS) BMD (n = 28,498), heel (HE) BMD (n = 426,824), and fracture (n = 1,214,434) from other GWAS meta-analyses. Inverse variance weighted (IVW) and several supplementary methods were performed to calculate the MR estimates. Results Genetically determined HF has no causal effect on FA-BMD (odds ratio (OR) 1.17; 95% confidence interval (CI) 0.82, 1.66; P = 0.389), FN-BMD (OR 1.01; 95% CI 0.85, 1.19; P = 0.936), LS-BMD (OR 0.96; 95% CI 0.80, 1.17; P = 0.705), HE-BMD (OR 1.01; 95% CI 0.90, 1.13; P = 0.884), and fracture risk (OR 1.00; 95% CI 0.92, 1.10; P = 0.927). Complementary analyses returned broadly consistent results. Conclusion This MR study provides genetic evidence that HF may not lead to an increased risk of reduced BMDs or fracture.

Abstract Background Epidemiological evidence relating obesity to peptic ulcer disease (PUD) has been mixed. Here we sought to determine the causality in the association of obesity with PUD risk using the Mendelian randomization (MR) approach. Methods This study was based on summary-level data for body mass index (BMI), waist-to-hip ratio (WHR), and PUD derived from large genome-wide association studies (GWASs). Single nucleotide polymorphisms significantly associated with BMI and WHR (P

Background: Previous epidemiological studies have reported controversial results on the relationship between smoking and Alzheimer's disease (AD). Therefore, we sought to assess the association using Mendelian randomization (MR) analysis. Methods: We used single nucleotide polymorphisms (SNPs) associated with smoking quantity (cigarettes per day, CPD) from genome-wide association studies (GWAS) of Japanese population as instrumental variables, then we performed two-sample MR analysis to investigate the association between smoking and AD in a Chinese cohort (1,000 AD cases and 500 controls) and a Japanese cohort (3,962 AD cases and 4,074 controls), respectively. Results: Genetically higher smoking quantity showed no statistical causal association with AD risk (the inverse variance weighted (IVW) estimate in the Chinese cohort: odds ratio (OR) = 0.510, 95% confidence interval (CI) = 0.149-1.744, p = 0.284; IVW estimate in the Japanese cohort: OR = 1.170, 95% confidence interval CI = 0.790-1.734, p = 0.434). Conclusion: This MR study, for the first time in Chinese and Japanese populations, found no significant association between smoking and AD. [ABSTRACT FROM AUTHOR]

Background: Retinal vein occlusion (RVO) is a common retinal vascular disease that can cause severe visual impairment. Many observational studies have shown that type 2 diabetes (T2DM) is associated with RVO, but it remains unknown if the association is causal. The present study aimed to perform Mendelian randomization (MR) analyses to evaluate the causal contribution of genetically predicted T2DM to RVO. Methods: We obtained summary-level data from a genome-wide association study meta-analysis including 48,286 cases and 250,671 controls for T2DM and from a genome wide association study of 372 cases and 182,573 controls in the FinnGen project for RVO. To verify the robustness of the results, an independent validation dataset for T2DM (12,931 cases and 57,196 controls) was used. In addition to the main MR analysis using the inverse variance weighted (fixed effect) approach, sensitivity analyses and multivariable MR adjusting for common risk factors of RVO were conducted. Results: Genetically predicted T2DM was found to be causally associated with RVO risk (odds ratio (OR)=2.823, 95% confidence interval (CI): 2.072-3.847, P=4.868×10-11). This association was supported by sensitivity analyses using the weighted median (OR=2.415, 95% CI: 1.411-4.132, P=1.294×10-3), weighted mode (OR=2.370, 95% CI: 1.321-4.252, P=5.159×10-3), maximum likelihood (OR=2.871, 95% CI: 2.100-3.924, P=3.719×10-11), MR-PRESSO (OR=2.823, 95% CI: 2.135-3.733, P=5.150×10-10), and MR-Egger (OR=2.441, 95% CI: 1.149-5.184, P=2.335×10-2) methods. In addition, this association persisted in multivariable MR after accounting for common RVO risk factors (OR=1.748, 95% CI: 1.238-2.467, P=1.490×10-3). The MR analyses using the validation dataset obtained consistent results. Conclusion: This study indicates that genetically predicted T2DM may have a causal contribution to RVO. Future studies are required to elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Context: Whether diabetes diagnosed at different age groups is causally associated with cardiovascular diseases (CVDs) is unknown. Objective: We conducted 2-sample Mendelian randomization analyses to investigate the causal associations of diabetes by age at diagnosis with 5 type-specific CVDs and 11 cardiometabolic traits. Methods: We selected 208 single nucleotide polymorphisms (SNPs) for diabetes and 3, 21, 57, and 14 SNPs for diabetes diagnosed at <50, 50-60, 60-70, and >70 years, respectively, based on the genome-wide association study (GWASs) (24 986 cases/187 130 controls) in the UK Biobank, and extracted genetic associations with stroke, myocardial infarction, heart failure, atrial fibrillation, and CVD mortality, as well as blood pressures, adiposity measurements, and lipids and apolipoproteins from corresponding European-descent GWASs. The inverse variance-weighted method was used as the main analysis with several sensitivity analyses. Results: Diabetes diagnosed at all 4 age groups was causally associated with increased risks of stroke (5-8%) and myocardial infarction (8-10%), higher systolic blood pressure (0.56-0.94 mmHg) and waist to hip ratio (0.003-0.004), and lower body mass index (0.31-0.42 kg/m² ), waist circumference (0.68-0.99 cm), and hip circumference (0.57-0.80 cm). Diabetes diagnosed at specific age groups was causally associated with increased risks of heart failure (4%) and CVD mortality (8%), higher diastolic blood pressure (0.20 mmHg) and triglycerides (0.06 SD), and lower high-density lipoprotein cholesterol (0.02 mmol/L). The effect sizes of genetically determined diabetes on CVD subtypes and cardiometabolic traits were comparable and the corresponding 95% confidence intervals largely overlapped across the 4 age groups. Conclusion: Our findings provide novel evidence that genetically determined diabetes subgroups by age at diagnosis have similar causal effects on CVD and cardiometabolic risks. [ABSTRACT FROM AUTHOR]

Background: Previous epidemiological and other studies have shown an association between major depressive disorder (MDD) and migraine. However, the causal relationship between them remains unclear. Therefore, this study aimed to investigate the causal relationship between MDD and migraine using a bidirectional, two-sample Mendelian randomization (MR) approach. Methods: Data on MDD and migraine, including subtypes with aura migraine (MA) and without aura migraine (MO), were gathered from a publicly available genomewide association study (GWAS). Single nucleotide polymorphisms (SNPs) utilized as instrumental variables (IVs) were then screened by adjusting the intensity of the connection and removing linkage disequilibrium. To explore causal effects, inverse variance weighting (IVW) was used as the primary analysis method, with weighted median, MR-Egger, simple mode, and weighted mode used as supplementary analytic methods. Furthermore, heterogeneity and pleiotropy tests were carried out. Cochran's Q-test with IVW and MR-Egger was used to assess heterogeneity. Pleiotropy testing was carried out using the MR-Egger intercept and MR-PRESSO analysis methods. A leave-one-out analysis was also used to evaluate the stability of the findings. Finally, we used migraine (MA and MO) levels to deduce reverse causality with MDD risk. Results: Random effects IVW results were (MDD-Migraine: odds ratio (OR), 1.606, 95% confidence interval (CI), 1.324-1.949, p = 1.52E-06; MDD-MA: OR, 1.400, 95%CI, 1.067-1.8378, p = 0.015; MDD-MO: OR, 1.814, 95%CI, 1.277-2.578, p = 0.0008), indicating a causal relationship between MDD levels and increased risk of migraine (including MA and MO). In the inverse MR analysis, the findings were all negative, while in sensitivity analyses, the results were robust except for the study of MA with MDD. Conclusion: Our study confirms a causal relationship between MDD levels and increased risk of migraine, MA, and MO. There was little evidence in the reverse MR analysis to suggest a causal genetic relationship between migraine (MA and MO) and MDD risk levels. [ABSTRACT FROM AUTHOR]

Several studies have shown that rheumatologic patients can benefit from metformin, but it remains unclear whether metformin treatment is causally associated with the risk of rheumatoid arthritis (RA). A two-sample Mendelian randomization (MR) study was conducted to investigate the causal relationship between metformin treatment and the incidence of rheumatoid arthritis. The genome-wide significant (p < 5 × 10−8) single-nucleotide polymorphisms (SNPs) associated with metformin use were selected as instrumental variables (IVs). Summary statistics on RA were extracted from a large genome-wide association study (GWAS) meta-analysis. The inverse variance-weighted (IVW) method was used as the determinant of the causal effects of metformin treatment on RA. Cochran's Q was used to detect heterogeneity. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test and MR-Egger regression were used to detect horizontal pleiotropy. A total of 34 SNPs significantly associated with metformin treatment were obtained. Thirty-two SNPs were selected as IVs after removing two SNPs for being palindromic with intermediate allele frequencies (rs11658063 and rs4930011). The IVW results showed a negative causal association between metformin treatment and RA (OR = 0.0232, 95% CI 1.6046 × 10−3 − 0.3368; p = 0.006). Meanwhile, no heterogeneity or pleiotropy was detected, indicating that the results were reliable. This study indicated a negative causality between metformin treatment and RA, indicating that the treatment of metformin can prevent the pathogenesis of RA. [ABSTRACT FROM AUTHOR]

In contemporary literature, little attention has been paid to the association between coronavirus disease‐2019 (COVID‐19) and cancer risk. We performed the Mendelian randomization (MR) to investigate the causal associations between the three types of COVID‐19 exposures (critically ill COVID‐19, hospitalized COVID‐19, and respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection) and 33 different types of cancers of the European population. The results of the inverse‐variance‐weighted model indicated that genetic liabilities to critically ill COVID‐19 had suggestive causal associations with the increased risk for HER2‐positive breast cancer (odds ratio [OR] = 1.0924; p‐value = 0.0116), esophageal cancer (OR = 1.0004; p‐value = 0.0226), colorectal cancer (OR = 1.0010; p‐value = 0.0242), stomach cancer (OR = 1.2394; p‐value = 0.0331), and colon cancer (OR = 1.0006; p‐value = 0.0453). The genetic liabilities to hospitalized COVID‐19 had suggestive causal associations with the increased risk for HER2‐positive breast cancer (OR = 1.1096; p‐value = 0.0458), esophageal cancer (OR = 1.0005; p‐value = 0.0440) as well as stomach cancer (OR = 1.3043; p‐value = 0.0476). The genetic liabilities to SARS‐CoV‐2 infection had suggestive causal associations with the increased risk for stomach cancer (OR = 2.8563; p‐value = 0.0019) but with the decreasing risk for head and neck cancer (OR = 0.9986, p‐value = 0.0426). The causal associations of the above combinations were robust through the test of heterogeneity and pleiotropy. Together, our study indicated that COVID‐19 had causal effects on cancer risk. [ABSTRACT FROM AUTHOR]

Previous studies have shown conflicting results about the impact of moderate to vigorous physical activity on the risk of venous thromboembolism (VTE). Using Mendelian randomization, we assessed whether moderate to vigorous physical activity causally affects VTE from genetic level. Genetic instruments associated with moderate to vigorous physical activity at the genome-wide significance level (P < 5×10− 8) were selected from the UK Biobank. Summary-level data for VTE were obtained from the FinnGen consortium. Univariable and multivariable Mendelian randomization analyses were conducted. Genetically predicted moderate to vigorous physical activity had no effect on VTE [odds ratio (OR) = 1.08; 95% confidence interval (CI) 0.66–1.78; P = 0.75] under a multiplicative random-effects inverse-variance weighted model. MR-Egger (OR = 0.20; 95% CI 0.01–4.70; P = 0.33), weighted median (OR = 1.08; 95% CI 0.52–2.25; P = 0.84), simple mode (OR = 2.53; 95% CI 0.59–10.92; P = 0.23), weighted mode (OR = 2.21; 95% CI 0.50–9.74; P = 0.31), and multivariable Mendelian randomization (OR = 0.74; 95% CI 0.46–1.19; P = 0.22) also yielded no significant association. The overall estimate was not influenced by individual single nucleotide polymorphism. No evidence of heterogeneity or horizontal pleiotropy was observed. Therefore, moderate to vigorous physical activity had no causal association with VTE in the general population. [ABSTRACT FROM AUTHOR]

Background and Aims: There are currently no clear conclusions about whether major depression (MD) and bipolar disorder (BD) increase the risk of erectile dysfunction (ED). In our study, we used a Mendelian randomization (MR) analysis to discover the causal associations between MD, BD and ED. Methods: We got single-nucleotide polymorphisms (SNPs) related to MD, BD and ED from the MRC IEU Open genome-wide association study (GWAS) datasets. After a series of selection, SNPs left were selected as instrumental variables (IVs) of MD and BD for the following MR test to evaluate the relationship of genetically predicted MD or BD with the incidence of ED. Among them, we used the random-effects inverse-variance weighted (IVW) method as the main analysis. Finally, sensitivity analyses were further performed using Cochran's Q test, funnel plots, MR-Egger regression, Leave-one-out method and MR- pleiotropy residual sum and outlier (PRESSO). Results: Genetically-predicted MD was causally related to the incidence of ED in the IVW methods (odds ratio (OR), 1.53; 95% confidence interval (CI), 1.19–1.96; p = 0.001), while no causal impact of BD on the risk of ED (OR = 0.95, 95% CI 0.87–1.04; p = 0.306). The results of sensitivity analyses supported our conclusion, and no directional pleiotropy were found. Conclusion: The findings of this research found evidence of a causal relationship between MD and ED. However, we did not find a causal relationship between BD and ED in European populations. [ABSTRACT FROM AUTHOR]

• The first bidirectional two-sample MR study to assess the causal association between IDA and COPD. • We found evidence of a causal relationship between IDA and COPD risk. • Mendelian randomization analysis has the advantage of providing a more reliable causality analysis, which is not available in general observational studies. Observational studies have found an association between iron deficiency anemia (IDA) and chronic obstructive pulmonary disease (COPD) risk. However, whether IDA plays a role in COPD development remains unclear. This study was performed to explore the causal association between IDA and COPD. We obtained summary statistics for IDA from 6087 cases and 211,115 controls of European ancestry in an open genome-wide association study (GWAS) to select strongly associated single nucleotide polymorphisms that could serve as instrumental variables for IDA (P < 5 × 10–8). Additional summary statistics for COPD were obtained from 6915 COPD cases and 186,723 controls of European ancestry from a publicly available GWAS. A bidirectional Mendelian randomization analysis was performed using inverse variance weighting as the primary method of analysis. The reliability of the results was verified by heterogeneity and sensitivity analysis. IDA increased the risk of COPD, with an odds ratio (OR) of 1.15 (95% confidence interval (CI: 1.04–1.25, p = 0.002). There was no evidence of a causal effect of COPD on IDA risk, with an OR of 0.99 (95% CI: 0.87–1.13, p = 0.91). The sensitivity analysis showed no evidence of heterogeneity or horizontal pleiotropy. We found that IDA increases the risk of COPD. Additionally, there was no evidence that COPD increases the risk of IDA. Therefore, IDA should be considered in future COPD risk studies and reintroduced as a potential therapeutic target. The relationship between COPD and IDA risk requires further study using indirect mechanisms. [ABSTRACT FROM AUTHOR]

Brain structure is related to its ability to resist external pathogens. Furthermore, there are several abnormal anatomical brain events and central system symptoms associated with COVID‐19. This study, which was conducted based on genetic variables, aimed to identify the causal association between brain structure and COVID‐19 phenotypes. We performed a two‐sample bidirectional Mendelian randomization analysis using genetic variables obtained from large genome‐wide association studies as instruments to identify the potential causal effects of various brain imaging‐derived phenotypes (BIDPs) traits on susceptibility, hospitalisation, and severity of COVID‐19. We explored the genetic correlations of 1325 BIDPs with the susceptibility, hospitalisation, and severity of COVID‐19 using Linkage Disequilibrium Score Regression. We observed a causal relationship between increased cortical thickness of the left inferior temporal area and an increased risk of increased COVID‐19 infection (p = 4.29 × 10‐4) and hospitalisation (p = 3.67 × 10‐3). Moreover, the larger total surface area of the whole brain was negatively correlated with the risk of hospitalisation for COVID‐19. Furthermore, there was a significant causal association between increased cerebrospinal fluid volume and decreased severity of COVID‐19 (p = 3.74 × 10‐3). In a conclusion, we provide new insights into the causal association between BIDPs and COVID‐19 phenotypes, which may help elucidate the aetiology of COVID‐19. [ABSTRACT FROM AUTHOR]

Clinical trials often collect intermediate or surrogate endpoints other than their true endpoint of interest. It is important that the treatment effect on the surrogate endpoint accurately predicts the treatment effect on the true endpoint. There are settings in which the proposed surrogate endpoint is positively correlated with the true endpoint, but the treatment has opposite effects on the surrogate and true endpoints, a phenomenon labeled "surrogate paradox". Covariate information may be useful in predicting an individual's risk of surrogate paradox. In this work, we propose methods for incorporating covariates into measures of assessing the risk of surrogate paradox using the meta-analytic causal association framework. The measures calculate the probability that a treatment will have opposite effects on the surrogate and true endpoints and determine the size of a positive treatment effect on the surrogate endpoint that would reduce the risk of a negative treatment effect on the true endpoint as a function of covariates, allowing the effects of covariates on the surrogate and true endpoint to vary across trials. [ABSTRACT FROM AUTHOR]

Abstract Background The causal association between educational attainment (EA) and stroke remains unclear. Hence, a novel multivariable Mendelian randomization (MVMR) approach was applied to solve this issue. Methods The single nucleotide polymorphisms (SNPs) from a recent genome-wide association study (GWAS) on years of schooling served as instruments. Univariable mendelian randomization (MR) and MVMR analyses were performed to detect the relationship between genetically predicted EA and the stroke risk. In the MVMR, cigarette consumption, alcohol consumption, body mass index (BMI), intelligence, and hypertension were adjusted. The summary statistics for stroke from the MEGASTROKE consortium included 446,696 participants (40,585 cases of stroke and 34,217 cases of ischemic stroke), most of whom were of European descent. Results In the univariable MR, genetically predicated EA could decrease the risks of total stroke (OR = 0.66, 95% CI 0.61–0.72, P = 2.70 × 10–23), ischemic stroke (OR = 0.67, 95% CI 0.61–0.73, P = 2.58 × 10–18), large artery atherosclerosis (OR = 0.51, 95% CI 0.40–0.64, P = 1.80 × 10–8), small vessel stroke (OR = 0.60, 95% CI 0.49–0.73, P = 5.59 × 10–7), and cardioembolic stroke (OR = 0.81, 95% CI 0.68–0.96, P = 1.46 × 10–2) using the inverse-variance weighted (IVW) estimator. Higher EA might be negatively correlated with the odds of total stroke (OR = 0.62, 95% CI 0.50–0.77, P = 1.44 × 10–5), ischemic stroke (OR = 0.63, 95% CI 0.50–0.80, P = 1.41 × 10–4), and cardioembolic stroke (OR = 0.59, 95% CI 0.39–0.90, P = 0.01), but was not significant in large artery atherosclerosis (OR = 0.65, 95% CI 0.37–1.15, P = 0.14) and small vessel stroke (OR = 0.68, 95% CI 0.41–1.13, P = 0.14) after controlling other exposures. Conclusions We found that genetically predicated higher EA decreased the risks of total stroke, ischemic stroke, and cardioembolic stroke, independent of smoking, alcohol consumption, BMI, intelligence, and hypertension.

IntroductionOver the past few years, multiple observational studies have speculated a potential association between inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), and osteoporosis. However, no consensus has been reached regarding their interdependence and pathogenesis. Herein, we sought to further explore the causal associations between them.MethodsWe validated the association between IBD and reduced bone mineral density in humans based on genome-wide association studies (GWAS) data. To investigate the causal relationship between IBD and osteoporosis, we performed a two-sample Mendelian randomization study using training and validation sets. Genetic variation data for IBD, CD, UC, and osteoporosis were derived from published genome-wide association studies in individuals of European ancestry. After a series of robust quality control steps, we included eligible instrumental variables (SNPs) significantly associated with exposure (IBD/CD/UC). We adopted five algorithms, including MR Egger, Weighted median, Inverse variance weighted, Simple mode, and Weighted mode, to infer the causal association between IBD and osteoporosis. In addition, we evaluated the robustness of Mendelian randomization analysis by heterogeneity test, pleiotropy test, leave-one-out sensitivity test, and multivariate Mendelian randomization.ResultsGenetically predicted CD was positively associated with osteoporosis risk, with ORs of 1.060 (95% CIs 1.016, 1.106; p = 0.007) and 1.044 (95% CIs 1.002, 1.088; p = 0.039) for CD in the training and validation sets, respectively. However, Mendelian randomization analysis did not reveal a significant causal relationship between UC and osteoporosis (p > 0.05). Furthermore, we found that overall IBD was associated with osteoporosis prediction, with ORs of 1.050 (95% CIs 0.999, 1.103; p = 0.055) and 1.063 (95% CIs 1.019, 1.109; p = 0.005) in the training and validation sets, respectively.ConclusionWe demonstrated the causal association between CD and osteoporosis, complementing the framework for genetic variants that predispose to autoimmune disease.

BackgroundPrevious epidemiological and other studies have shown an association between ischemic stroke (IS) and frozen shoulder (FS). However, the causal relationship between them remains unclear. Therefore, the present study aimed to investigate the causal relationship between IS and FS using a two-sample Mendelian randomization method.MethodsOur research was divided into two stages: discovery and replication. The data were extracted from publicly available genome-wide association studies (GWAS). We selected a large sample of IS (n = 440, 328) and its subtypes (large-artery atherosclerotic stroke (LAS), cardioembolic stroke (CES), and stroke caused by small-vessel disease (SVS) and lacunar stroke (n = 254, 959) as exposure data. Additionally, we selected a large sample of FS as outcome data (n = 451, 099). Inverse variance weighting (IVW) was applied as the primary analysis method. The weighted median, MR-Egger, simple model, and weighted model were used as complementary analysis methods to assess causal effects. Moreover, heterogeneity was analyzed using Cochran's Q-test with IVW and MR-Egger. The MR-Egger intercept and MR-PRESSO analysis methods were used for pleiotropy testing. The stability of the results was also assessed using a leave-one-out analysis.ResultsIn the discovery stage, the IVW approach revealed an odds ratio (OR) of 1.207 with a 95% confidence interval (CI) of 1.027–1.417 and a P-value of 0.022. This suggests a causal association between IS levels and an increased risk of FS. In the subtype studies of IS, the findings were negative. However, during the replication stage, a significant causal link was found between selected lacunar strokes and FS with an OR of 1.252, a 95% CI of 1.105–1.419, and a P-value of 0.0004. All studies had no pleiotropy or heterogeneity, and the findings were robust.ConclusionsOur study confirmed the causal relationship between any IS level and increased risk of FS. Furthermore, the same results were obtained in the replication stage with lacunar stroke as an exposure factor. However, there was no direct causal relationship between the subtypes of IS and FS. Our study provides theoretical support for shoulder care for patients with IS.

BackgroundObservational studies have reported inconsistent associations between micronutrient levels and the risk of coronary artery disease (CAD) in diabetic patients. We aim to explore the causal association between genetically predicted concentrations of micronutrients (phosphorus, magnesium, selenium, iron, zinc, and copper) and CAD in patients with diabetes.MethodsSingle nucleotide polymorphisms (SNPs) connected to serum micronutrient levels were extracted from the corresponding published genome-wide association studies (GWASs). Summary-level statistics for CAD in diabetic patients were obtained from a GWAS of 15,666 patients with diabetes. The primary analysis was carried out with the inverse variance weighted approach, and sensitivity analyses using other statistical methods were further employed to assess the robustness of the results.ResultsGenetically predicted selenium level was causally associated with a higher risk of CAD in diabetic patients (odds ratio [OR]: 1.25; 95% confidence interval [CI]: 1.10–1.42; p = 5.01 × 10−4). While, genetically predicted iron concentrations in patients with diabetes were inversely associated with the risk of CAD (OR: 0.82; 95% CI: 0.75–0.90; p = 2.16 × 10−5). The association pattern kept robust in most sensitivity analyses. Nominally significant associations were observed for magnesium and copper with the risk of CAD in patients with diabetes. No consistent evidence was found for the causal associations between phosphorus and zinc levels, and the risk of CAD in patients with diabetes.ConclusionWe provide consistent evidence for the causal effect of increased selenium and decreased iron levels on CAD in patients with diabetes, highlighting the necessity of micronutrient monitoring and application in these patients.

BackgroundPrevious studies have suggested that dietary salt intake affects atrial fibrillation (AF); however, the causal association between them still remains unclear. Thus, we conducted this Mendelian randomization (MR) study to explore the correlation between them.MethodsGenetic instruments for dietary salt intake were from a genome-wide association study (GWAS), which included 462,630 European individuals. Summary-level data for AF were obtained from another published GWAS (22,068 cases and 116,926 controls). The inverse-variance weighting (IVW) method was performed as the primary MR analysis. Multiple MR methods, including Robust Adjusted Profile Score (MR-RAPS), maximum likelihood estimation, and Mendelian randomization pleiotropy residual sum and outlier test (MR-PRESSO) were conducted as complementary analyses. The MR-Egger regression intercept and MR-PRESSO global test were conducted to test potential horizontal pleiotropy. The IVW (Q) method and MR-Egger were performed to detect heterogeneity.ResultsOur results suggested that high dietary salt intake was significantly correlated with increased risk of AF [IVW: odds ratio (OR), 1.36; 95% confidence interval (CI), 1.04–1.77; p = 2.25E-02]. The maximum likelihood estimation (OR, 1.37; 95% CI, 1.05–1.78; p = 2.09E-02), MR-RAPS (OR, 1.37; 95% CI, 1.03–1.81; p = 2.79E-02), and MR-PRESSO method (OR, 1.36; 95% CI, 1.05–1.76; p = 2.37E-02) also showed that dietary salt intake was significantly correlated with the risk of AF.ConclusionThe findings of this study provide robust evidence supporting the correlation between dietary salt intake and the risk of AF. Future studies are required to further clarify this relationship and translate the findings into clinical and public health practice.

Background and aimsThe association between sleep traits and coronary artery disease (CAD) in patients with diabetes has been reported in previous observational studies. However, whether these potential relationships are causal remains unclear. We aim to assess the causal relationship between sleep traits and CAD in diabetic.MethodsGenetic instrumental variables associated with five sleep-related traits (insomnia, sleep duration, ease of getting up, morningness and snoring) were extracted from corresponding genome-wide association studies (GWAS). The associations of genetic variants with CAD were based on 15,666 individuals with diabetes (3,968 CAD cases and 11,696 controls). The primary analysis was derived using the inverse variance weighting method. Further sensitivity analysis was conducted to confirm the robustness and consistency of the main results.ResultsGenetic liability to insomnia was significantly related to the increased risk of CAD in individuals with diabetes [odds ratio (OR): 1.163; 95% CI: 1.072–1.254; p = 0.001]. Suggestive evidence was found for the borderline associations between both sleep duration (OR: 0.629; 95% CI: 0.380–1.042, p = 0.072) and snoring (OR: 1.010, 95% CI: 1.000–1.020, p = 0.050) with CAD risk. However, no consistent evidence was found for the association between ease of getting up and morningness with the risk of CAD in diabetic. Similar results can be verified in most sensitivity analyses.ConclusionsWe provide consistent evidence for the causal effect of insomnia on the increased risk of CAD in individuals with diabetes. The management of sleep health should be emphasized to prevent CAD in diabetic patients.

Background: Rheumatoid arthritis (RA) increases the risk of depression. However, studies on the effects of RA on the dose of depression medications are limited. Therefore, in this study, we used two-sample Mendelian randomization (MR) to explore whether RA increases the dose of depression medications and gain a more comprehensive understanding of the relationship between RA and depression. Methods: Two-sample MR was used to evaluate the causal effect of RA on the dose of depression medications. The aggregated data on RA originated from extensive genome-wide association studies (GWASs) of European descent (14,361 cases and 42,923 controls). The summary GWAS data for the dose of depression medications were derived from the FinnGen consortium (58,842 cases and 59,827 controls). Random effects inverse-variance weighted (IVW), MR-Egger regression, weighted median, and fixed effects IVW methods were used for the MR analysis. Random effects IVW was the primary method. The heterogeneity of the MR results was detected using the IVW Cochran's Q test. The pleiotropy of the MR results was detected using MR-Egger regression and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. Finally, a leave-one-out analysis was performed to determine whether the MR results were affected by a specific single-nucleotide polymorphism (SNP). Results: The primary method, random effects IVW, revealed that genetically predicted RA had a positive causal association with the dose of depression medications (Beta, 0.035; 95% confidence interval (CI), 0.007–0.064; p = 0.015). The IVW Cochran's Q test results revealed no heterogeneity in the MR analysis (p > 0.05). The MR-Egger regression and MR-PRESSO tests revealed that there was no pleiotropy in our MR analysis. The leave-one-out analysis confirmed that a single SNP did not affect the MR results, indicating the study's robustness. Conclusion: Using MR techniques, we discovered that having RA increases the dose of depression medications; however, the exact mechanisms and pathways still need to be further explored. [ABSTRACT FROM AUTHOR]

Background: Migraine is a disabling neurological disorder with the pathophysiology yet to be understood. The microstructural alteration in brain white matter (WM) has been suggested to be related to migraine in recent studies, but these evidence are observational essentially and cannot infer a causal relationship. The present study aims to reveal the causal relationship between migraine and microstructural WM using genetic data and Mendelian randomization (MR). Methods: We collected the Genome-wide association study (GWAS) summary statistics of migraine (48,975 cases / 550,381 controls) and 360 WM imaging-derived phenotypes (IDPs) (31,356 samples) that were used to measure microstructural WM. Based on instrumental variables (IVs) selected from the GWAS summary statistics, we conducted bidirectional two-sample MR analyses to infer bidirectional causal associations between migraine and microstructural WM. In forward MR analysis, we inferred the causal effect of microstructural WM on migraine by reporting the odds ratio (OR) that quantified the risk change of migraine for per 1 standard deviation (SD) increase of IDPs. In reverse MR analysis, we inferred the causal effect of migraine on microstructural WM by reporting the β value that represented SDs of changes in IDPs were caused by migraine. Results: Three WM IDPs showed significant causal associations (p < 3.29 × 10− 4, Bonferroni correction) with migraine and were proved to be reliable via sensitivity analysis. The mode of anisotropy (MO) of left inferior fronto-occipital fasciculus (OR = 1.76, p = 6.46 × 10− 5) and orientation dispersion index (OD) of right posterior thalamic radiation (OR = 0.78, p = 1.86 × 10− 4) exerted significant causal effects on migraine. Migraine exerted a significant causal effect on the OD of left superior cerebellar peduncle (β = − 0.09, p = 2.78 × 10− 4). Conclusions: Our findings provided genetic evidence for the causal relationships between migraine and microstructural WM, bringing new insights into brain structure for the development and experience of migraine. [ABSTRACT FROM AUTHOR]

The causality between the urinary sodium–potassium ratio and upper urinary calculi has not been clarified and easily affected by confounders. We performed two-sample and multivariable Mendelian randomization (MR) analysis to evaluate the potential causal role of the urinary sodium–potassium ratio in upper urinary calculi. Data of the urinary sodium–potassium ratio (N = 326,938), upper urinary calculi (N = 337,199), and confounding factors including BMI (N = 336,107), ever-smoke (N = 461,066), hypertension (N = 218,754), diabetes (N = 218,792), and alcohol intake frequency (N = 462,346) were obtained from the IEU OpenGWAS Project database. The inverse-variance weighted (IVW), weighted median, and MR-Egger methods were used to estimate MR effects. The MR-Egger intercept test, Cochran's Q test, MR-PRESSO, leave-one-out method, and funnel plot were used for sensitivity analysis. A causal relationship was found between the urinary sodium–potassium ratio and upper urinary calculi (OR = 1.008, 95% CI = 1.002–1.013, P = 0.011). FinnGen data supported this conclusion (OR = 2.864, 95% CI = 1.235–6.641, P = 0.014). The multivariable Mendelian randomization analysis result showed that after adjusting for the effects of five confounders, the urinary sodium–potassium ratio was still positively correlated with upper urinary calculi (OR = 1.005, 95% CI = 1.001–1.009, P = 0.012). This study demonstrated a positive causal association between the urinary sodium–potassium ratio and upper urinary calculi using MR analysis. Timely identification of changes in urine composition and dietary regulation of sodium and potassium intake could greatly reduce the incidence of future urinary calculi. [ABSTRACT FROM AUTHOR]

Objective: To explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR). Methods: Publicly available genome-wide association study (GWAS) summary data were used for MR analysis with four iron status-related indicators (ferritin, iron, total iron binding capacity, and transferrin saturation) as exposures and three different types of OP (OP, OP with pathological fracture, and postmenopausal OP with pathological fracture) as outcomes. The inversevariance weighted (IVW) method was used to analyze the genetic causal association between the four indicators of iron status and OP. The heterogeneity of MR results was determined using IVW and MR-Egger methods. The pleiotropy of MR results was determined using MR-Egger regression. A leave-one-SNP-out test was performed to determine whether the MR results were affected by a single nucleotide polymorphism (SNP). The weighted median method was conducted to further validate our results. Results: Based on IVW, MR-Egger and weighted median models, we found no causal association between iron status (ferritin, iron, total iron binding capacity, or transferrin saturation) and OP (Pbeta > 0.05 in all models). IVW and MR-Egger analysis of OP with pathological fracture and iron status indicators showed no potential genetic causal association (Pbeta> 0.05 in the two analyses). The results of the weighted median were consistent with those of IVW (Pbeta> 0.05 in all analyses). There was no potential genetic causal association between iron status and postmenopausal OP with pathological fracture based on serum iron (Pbeta>0.05 in all models). No heterogeneity or horizontal pleiotropy was found in any of the analyses. None of the leave-one-out tests in the analyses found any SNP that could affect the results of MR. Conclusion: Our results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded. [ABSTRACT FROM AUTHOR]

Objectives: Heart failure (HF) has been implicated in osteoporosis. However, causality remains unestablished. Here, we sought to assess causal associations of genetic liability to HF with osteoporosis using Mendelian randomization (MR) analyses. Methods: Independent single nucleotide polymorphisms associated with HF at genome-wide significance were derived from a large genome-wide association study (GWAS) (including up to 977,323 individuals). We obtained summary statistics for forearm (FA) bone mineral density (BMD) (n = 8,143), femoral neck (FN) BMD (n = 32,735), lumbar spine (LS) BMD (n = 28,498), heel (HE) BMD (n = 426,824), and fracture (n = 1,214,434) from other GWAS meta-analyses. Inverse variance weighted (IVW) and several supplementary methods were performed to calculate the MR estimates. Results: Genetically determined HF has no causal effect on FA-BMD (odds ratio (OR) 1.17; 95% confidence interval (CI) 0.82, 1.66; P = 0.389), FN-BMD (OR 1.01; 95% CI 0.85, 1.19; P = 0.936), LS-BMD (OR 0.96; 95% CI 0.80, 1.17; P = 0.705), HE-BMD (OR 1.01; 95% CI 0.90, 1.13; P = 0.884), and fracture risk (OR 1.00; 95% CI 0.92, 1.10; P = 0.927). Complementary analyses returned broadly consistent results. Conclusion: This MR study provides genetic evidence that HF may not lead to an increased risk of reduced BMDs or fracture. [ABSTRACT FROM AUTHOR]

Background: Epidemiological evidence suggests an association between rheumatoid arthritis (RA) and myocardial infarction (MI). However, causality remains uncertain. Therefore, this study aimed to explore the causal association between RA and MI. Methods: Using publicly available genome-wide association study summary datasets, bidirectional two-sample Mendelian randomization (TSMR) was performed using inverse-variance weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode methods. Results: The MR results for the causal effect of RA on MI (IVW, odds ratio [OR] = 1.041, 95% confidence interval [CI]: 1.007–1.076,P= 0.017; weighted median, OR = 1.027, 95% CI: 1.006–1.049, P = 0.012) supported a causal association between genetic susceptibility to RA and an increased risk of MI. MR results for the causal effect of MI on RA (IVW, OR = 1.012, 95% CI: 0.807–1.268, P = 0.921; weighted median, OR = 1.069, 95% CI: 0.855–1.338, P = 0.556) indicated that there was no causal association between genetic susceptibility to MI and an increased risk of RA. Conclusion: Bidirectional TSMR analysis supports a causal association between genetic susceptibility to RA and an increased risk of MI but does not support a causal association between genetic susceptibility to MI and an increased risk of RA. [ABSTRACT FROM AUTHOR]

Background: Multiple risk factors of stroke have been identified in previous studies; however, the causal role of snoring in the onset of stroke is less investigated. To clarify the causal association of snoring on stroke and its subtypes, this study is performed. Methods: The single nucleotide polymorphisms in relation to snoring were retrieved from the UK biobank cohort with 408,317 participants. The data for stroke and its subtypes of European ancestry (67,162 cases and 453,702 controls) were obtained fromtheMEGASTROKE consortium. In single-variable Mendelian randomization (SVMR) and multivariable MR (MVMR) analyses, inverse variance weighting was used as the primary estimate, complemented with sensitivity analyses more robust to pleiotropy. Results: Genetically predicted snoring increased the risk of stroke (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.19-6.08, P = 0.016) and ischemic stroke (IS) (OR = 2.82, 95% CI = 1.23-6.44, P = 0.013), but not large artery stroke (LAS) (OR = 3.02, 95% CI = 0.31-29.44, P = 0.339), cardioembolic stroke (CES) (OR = 1.51, 95% CI = 0.58-3.92, P = 0.395). We provide novel genetic evidence that snoring increases the risk of stroke and IS, but not LAS, CES, and SVS. Conclusion: Our findings provide novel genetic evidence that snoring increases the risk of stroke and IS, but not LAS, CES, and SVS. [ABSTRACT FROM AUTHOR]

Abstract Background Despite accumulating epidemiological studies support that diabetes increases the risk of Alzheimer’s disease (AD), the causal associations between diabetes and AD remain inconclusive. The present study aimed to explore: i) whether diabetes is causally related to the increased risk of AD; ii) and if so, which diabetes-related physiological parameter is associated with AD; iii) why diabetes drugs can be used as candidates for the treatment of AD. Two-sample Mendelian randomization (2SMR) was employed to perform the analysis. Results Firstly, the 2SMR analysis provided a suggestive association between genetically predicted type 1 diabetes (T1D) and a slightly increased AD risk (OR = 1.04, 95% CI = [1.01, 1.06]), and type 2 diabetes (T2D) showed a much stronger association with AD risk (OR = 1.34, 95% CI = [1.05, 1.70]). Secondly, further 2SMR analysis revealed that diabetes-related physiological parameters like fasting blood glucose and total cholesterol levels might have a detrimental role in the development of AD. Thirdly, we obtained 74 antidiabetic drugs and identified SNPs to proxy the targets of antidiabetic drugs. 2SMR analysis indicated the expression of three target genes, ETFDH, GANC, and MGAM, were associated with the increased risk of AD, while CPE could be a protective factor for AD. Besides, further PPI network found that GANC interacted with MGAM, and further interacted with CD33, a strong genetic locus related to AD. Conclusions In conclusion, the present study provides evidence of a causal association between diabetes and increased risk of AD, and also useful genetic clues for drug development.

Purpose: Intervertebral disc degeneration (IVDD) considerably impacts global disability and quality of life. Although potential links between plasma proteins and IVDD exist, their causal correlation remains undefined. This study explored the causal links between plasma proteins and IVDD employing genome-wide association study data.For this observational study, summary statistics for plasma proteins were derived from an Icelandic population, paralleled with genome-wide data on IVDD obtained from the FinnGen consortium. Using two-sample Mendelian randomization, we assessed the causal relationship between 4,907 plasma proteins and IVDD. Standard sensitivity analyses encompassing heterogeneity, pleiotropy, and leave-one-out cross-validation tests confirmed the stability and robustness of the findings. Subsequently, through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein interaction analyses, we delved into the functional interrelation among identified plasma proteins.A causal association with IVDD was identified for 47 plasma proteins; myoneurin, intersectin 1, and eukaryotic translation initiation factor 4 gamma 3 maintained significant correlations post multiple correction tests (P < 1.02 × 10− 5), influencing IVDD development positively. GO/KEGG pathway analyses confirmed that multiple pathways may be involved in IVDD development.The study underscores the causal correlation between plasma protein levels and IVDD risk. These identified proteins could emerge as unique biomarkers for IVDD, contributing to its predictive measures. The findings further our understanding of IVDD pathomechanisms and prospective therapeutic targets.Methods: Intervertebral disc degeneration (IVDD) considerably impacts global disability and quality of life. Although potential links between plasma proteins and IVDD exist, their causal correlation remains undefined. This study explored the causal links between plasma proteins and IVDD employing genome-wide association study data.For this observational study, summary statistics for plasma proteins were derived from an Icelandic population, paralleled with genome-wide data on IVDD obtained from the FinnGen consortium. Using two-sample Mendelian randomization, we assessed the causal relationship between 4,907 plasma proteins and IVDD. Standard sensitivity analyses encompassing heterogeneity, pleiotropy, and leave-one-out cross-validation tests confirmed the stability and robustness of the findings. Subsequently, through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein interaction analyses, we delved into the functional interrelation among identified plasma proteins.A causal association with IVDD was identified for 47 plasma proteins; myoneurin, intersectin 1, and eukaryotic translation initiation factor 4 gamma 3 maintained significant correlations post multiple correction tests (P < 1.02 × 10− 5), influencing IVDD development positively. GO/KEGG pathway analyses confirmed that multiple pathways may be involved in IVDD development.The study underscores the causal correlation between plasma protein levels and IVDD risk. These identified proteins could emerge as unique biomarkers for IVDD, contributing to its predictive measures. The findings further our understanding of IVDD pathomechanisms and prospective therapeutic targets.Results: Intervertebral disc degeneration (IVDD) considerably impacts global disability and quality of life. Although potential links between plasma proteins and IVDD exist, their causal correlation remains undefined. This study explored the causal links between plasma proteins and IVDD employing genome-wide association study data.For this observational study, summary statistics for plasma proteins were derived from an Icelandic population, paralleled with genome-wide data on IVDD obtained from the FinnGen consortium. Using two-sample Mendelian randomization, we assessed the causal relationship between 4,907 plasma proteins and IVDD. Standard sensitivity analyses encompassing heterogeneity, pleiotropy, and leave-one-out cross-validation tests confirmed the stability and robustness of the findings. Subsequently, through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein interaction analyses, we delved into the functional interrelation among identified plasma proteins.A causal association with IVDD was identified for 47 plasma proteins; myoneurin, intersectin 1, and eukaryotic translation initiation factor 4 gamma 3 maintained significant correlations post multiple correction tests (P < 1.02 × 10− 5), influencing IVDD development positively. GO/KEGG pathway analyses confirmed that multiple pathways may be involved in IVDD development.The study underscores the causal correlation between plasma protein levels and IVDD risk. These identified proteins could emerge as unique biomarkers for IVDD, contributing to its predictive measures. The findings further our understanding of IVDD pathomechanisms and prospective therapeutic targets.Conclusion: Intervertebral disc degeneration (IVDD) considerably impacts global disability and quality of life. Although potential links between plasma proteins and IVDD exist, their causal correlation remains undefined. This study explored the causal links between plasma proteins and IVDD employing genome-wide association study data.For this observational study, summary statistics for plasma proteins were derived from an Icelandic population, paralleled with genome-wide data on IVDD obtained from the FinnGen consortium. Using two-sample Mendelian randomization, we assessed the causal relationship between 4,907 plasma proteins and IVDD. Standard sensitivity analyses encompassing heterogeneity, pleiotropy, and leave-one-out cross-validation tests confirmed the stability and robustness of the findings. Subsequently, through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein interaction analyses, we delved into the functional interrelation among identified plasma proteins.A causal association with IVDD was identified for 47 plasma proteins; myoneurin, intersectin 1, and eukaryotic translation initiation factor 4 gamma 3 maintained significant correlations post multiple correction tests (P < 1.02 × 10− 5), influencing IVDD development positively. GO/KEGG pathway analyses confirmed that multiple pathways may be involved in IVDD development.The study underscores the causal correlation between plasma protein levels and IVDD risk. These identified proteins could emerge as unique biomarkers for IVDD, contributing to its predictive measures. The findings further our understanding of IVDD pathomechanisms and prospective therapeutic targets. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the causal association between immune cells and VaD based on a two-sample bidirectional Mendelian randomization study. Bidirectional two-sample MR analyses based on pooled datasets from publicly available genome-wide association studies were performed using inverse variance weighted (IVW), weighted median (WE), and MR–Egger regressions to evaluate the causal relationships between immune cells and vascular dementia. Heterogeneity was assessed using Cochran's Q statistic. The reliability of the MR analysis results was verified by using the MR-PRESSO method for outlier detection, the MR–Egger method for horizontal multivariate analysis, and the leave-one-out method for sensitivity analysis. Specifically, 27 immunophenotypes were associated with VaD pathogenesis, including Sw mem %lymphocyte (P = 0.043), CD38 on CD20- (P = 0.039), CD11c+ monocyte AC (P = 0.024), DC AC (P = 0.002), CCR2 on CD62L+ myeloid DC (P = 0.039), Resting Treg %CD4 (P = 0.042), Activated & resting Treg %CD4+ (P = 0.038), CD28+ CD45RA− CD8br %CD8br (P = 0.047), NK %CD3− lymphocyte (P = 0.042), CD45 on B cell (P = 0.029), FSC-A on NKT (P = 0.033), CD45 on CD33br HLA DR+ CD14− (P = 0.039) were significantly correlated with increased VaD risk. Additionally, four immune phenotypes, namely, CD19 on CD20−, Resting Treg %CD4, Activated & resting Treg %CD4+, and CD11c+ monocyte AC, showed bidirectional effects on VaD. MR analysis revealed potential causal relationships between certain immune cells and VaD. Our preliminary exploration through immune cell infiltration analysis highlights the significant value of immune cells in VaD. Therefore, this study may provide a new perspective for the prevention and treatment of VaD. • Genetically based Mendelian randomization studies revealed causal relationships between 731 immunophenotypes and VaD. • Four immune phenotypes were identified as bidirectionally associated with VaD. • The significance of this study is to uncover the critical role of immune cells in VaD pathogenesis. [ABSTRACT FROM AUTHOR]

Background: The interaction between intestinal microbiota and infertility is less researched. This study was performed to investigate the causal association between gut microbiota and infertility. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants of intestinal microbiota were obtained from the MiBioGen consortium, which included 18,340 individuals. Inverse variance weighting (IVW), MR-Egger, weighted median, maximum likelihood, MR Robust adjusted profile score, MR Pleiotropy residual sum, and outlier (MR-PRESSO) methods were used to explore the causal links between intestinal microbiota and infertility. The MR-Egger intercept term and the global test from the MR-PRESSO estimator were used to assess the horizontal pleiotropy. The Cochran Q test was applied to evaluate the heterogeneity of instrumental variables (IVs). Results: As indicated by the IVW estimator, significantly protective effects of the Family XIII AD3011 group (OR = 0.87) and Ruminococcaceae NK4A214 group (OR = 0.85) were identified for female fertility, while Betaproteobacteria (OR = 1.18), Burkholderiales (OR = 1.18), Candidatus Soleaferrea (OR = 1.12), and Lentisphaerae (OR = 1.11) showed adverse effects on female fertility. Meanwhile, Bacteroidaceae (OR = 0.57), Bacteroides (OR = 0.57), and Ruminococcaceae NK4A214 group (OR = 0.61) revealed protective effects on male fertility, and a causal association between Anaerotruncus (OR = 1.81) and male infertility was detected. The effect sizes and directions remained consistent in the other five methods except for Candidatus Soleaferrea. No heterogeneity or pleiotropy were identified by Cochran’s Q test, MR-Egger, and global test (all p > 0.05). Conclusions: This two-sample MR study revealed that genetically proxied intestinal microbiota had potentially causal effects on infertility. In all, the Ruminococcaceae NK4A214 group displayed protective effects against both male and female infertility. Further investigations are needed to establish the biological mechanisms linking gut microbiota and infertility.

BackgroundObservational studies have indicated that psychosocial factors contribute to hypertension; however, the causality of these associations remains unclear due to reverse causality and confounders. We aim to assess the causal associations of mental health disorders with hypertension.MethodsInstrumental variables of anxiety disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, depression, obsessive–compulsive disorder, post-traumatic stress disorder, schizophrenia, and subjective well-being measure were obtained from the corresponding largest genome-wide association studies. Summary statistics for the association of essential hypertension were obtained from the FinnGen Study (42,857 cases and 162,837 controls) and UK Biobank cohort (54,358 cases and 408,652 controls). The multiplicative random-effects inverse-variance weighted method was utilized as the primary analysis and three other statistical methods were conducted in the supplementary analyses. The results were combined using the fixed-effects method.ResultsIn the pooled analyses, genetic liability to depression was associated with higher risk of hypertension (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.17–1.35; p

BackgroundObservational studies have shown that central obesity is associated with adverse cardiac structure and function. However, causal association between central obesity and left ventricular (LV) structure and function in preserved ejection fraction (EF) population is still uncertain.MethodsGenome-wide association studies summary data of waist circumference adjusted for body mass index (WCadjBMI) and waist-to-hip ratio adjusted for body mass index (WHRadjBMI) were selected as instrumental variables from the Genetic Investigation of Anthropometric Traits (GIANT) Consortium (n = 224,459). Outcome datasets for LV parameters including LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF), LV mass (LVM), and LV mass-to-end-diastolic volume ratio (LVMVR) were obtained from the participants without prevalent myocardial infarction or heart failure (LVEF ≥ 50%) in UK Biobank Cardiovascular Magnetic Resonance sub-study (n = 16,923). Two-sample Mendelian randomization (MR) was performed with the inverse-variance weighted (IVW) method as the primary estimate and with the weighted median and MR-Egger as the supplemental estimates. Sensitivity analysis was used to assess the heterogeneity and pleiotropic bias in the MR results.ResultsIn the IVW analysis, every 1-standard deviation (SD) higher WHRadjBMI was significantly associated with higher LVMVR (β = 0.4583; 95% confidence interval [CI]: 0.2921 to 0.6244; P = 6.418 × 10–8) and lower LVEDV (β = –0.2395; 95% CI: –0.3984 to –0.0807; P = 0.0031) after Bonferroni adjustment. No heterogeneity and horizontal pleiotropy were detected in the analysis. No association of WCadjBMI was found with LVEF, LVEDV, LVESV, LVM, or LVMVR.ConclusionOur findings provide evidence of significant causal association between WHRadjBMI and adverse changes in LV structure and function in preserved EF population.

Polygenic risk scores (PRS) are increasingly used to predict diseases (e.g., schizophrenia). However, the proper application of the PRS in psychological studies is sparse. We aimed to evaluate the methodological aspects of using PRS as a covariate in causal association studies in psychology. We conducted a simulation study using realistic scenarios, such as gene and exposure or confounder interaction, gene and gene interaction, gene acts as confounding and instrumental variable and replicated each scenario 1000 times. We found that when the genotype(s) that was used for calculating PRS interacted with the exposure and if the analyses considering this interaction, the exposure effect similar with the true value. However, a significant amount of bias was present even after adjustment for the measured confounders i) when the gene interacted with the unmeasured confounder and this bias amplified when the interaction effect was two times stronger; and ii) when the gene acts as a confounder or instrumental variable. Therefore, theoretical knowledge of psychology should be incorporated when the PRS is utilized in psychological causal association studies in order to reduce systematic bias and improve the precision of the exposure effect.

Background: Previous studies have reported inconsistent results on the causal association between habitual tea consumption and the risk of cardiovascular disease (CVD). This study is aim to determine the association between habitual tea intake and CVD using two-sample Mendelian randomization (MR) analysis. Methods: The genetically predicted causation between tea consumption and 7 common cardiovascular diseases (atrial fibrillation, hypertension, acute myocardial infarction, coronary atherosclerosis, peripheral vascular disease, angina, and heart failure) was evaluated using MR analysis model. We performed a total of 9 MR analysis methods to analyze the final results. The IVW methods was used as the primary outcome. The other MR analysis method (simple mode, weighted mode, simple median, weighted median, penalized weighted median, MR Egger, and MR-Egger (bootstrap)) were performed as the complement to IVW. Also, the robustness of the MR analysis results was assessed using a leave-one-out analysis. Results: The IVW analysis methods indicated that there is no causal association between tea consumption and risk of CVD (AF: OR, 0.997, 95% CI, 0.992-1.0001, p = 0.142; hypertension: OR, 0.976, 95% CI, 0.937-1.017, p = 0.242; AMI: OR, 0.996, 95% CI, 0.991-1.000, p = 0.077; CA: OR, 1.001, 95% CI, 0.993-1.009, p = 0.854; PVD: OR, 1.002, 95% CI, 1.000-1.005, p = 0.096; angina: OR, 0.999, 95% CI, 0.993-1.006, p = 0.818; HF: OR, 0.999, 95% CI, 0.996-1.002, p = 0.338). The other MR analysis method and further leave-oneout sensitivity analysis suggested the results were robust. Conclusion: This MR study indicated that there was no genetically predicted causal association between habitual tea intake and risk of CVD. [ABSTRACT FROM AUTHOR]

Some observational studies suggested that heart failure (HF) is associated with increased risk of late-onset Alzheimer’s disease (AD). On the other hand, a recently published Two-Sample Mendelian Randomization (2SMR) study was reported as inconclusive but the estimated odds ratios (ORs) were less than one indicating a potential causal association between genetically predicted HF and lowered risk of AD. Both HF and AD are quite common among elderly persons and frequently occur together resulting in a series of severe medical challenges and increased financial burden on healthcare. It is of great medical and financial interest to further investigate the statistical significance of the potential causal associations between genetically predicted HF and lowered risk of AD using large independent cohorts. To fill this important knowledge gap, the present study used the 2SMR method based on summary data from a recently published large genome-wide association study (GWAS) for AD on subjects with European ancestry. The 2SMR analysis provided statistically significant evidence of an association with ORs less than one between genetically predicted HF and late-onset AD (Inverse Variance Weighted, OR = 0.752, p = 0.004; MR Egger, OR = 0.546, p = 0.100; Weighted Median, OR = 0.757, p = 0.014). Further investigations of the significant associations between HF and late-onset AD, including specific genes related to the potential protective effect of HF-related medications on cognitive decline, are warranted. [ABSTRACT FROM AUTHOR]

The effect of insomnia and sleep duration on risk of anxiety has been assessed based on traditional epidemiological studies. However, the inconsistent conclusions do not establish causal associations. This study aimed to explore the causal associations of insomnia, short sleep, and long sleep with anxiety. We used summary statistics from three large-scale genome-wide association studies (GWAS) of European ancestry to perform a two-sample Mendelian randomization (MR) study. MR analyses were mainly conducted with the inverse-variance-weighted (IVW) method. To evaluate the robustness of our findings, we performed the weighted-median approach, the MR-Egger method, and the MR-robust adjusted profile score (MR-RAPS) method for sensitivity analyses. There was a statistically significant association of genetically predicted insomnia with anxiety using the IVW method (OR = 1.36, 95% CI = 1.23–1.51, P < 0.001). Genetically predicted short sleep was potentially associated with anxiety using IVW method (OR = 1.67, 95% CI = 1.08–2.60, P = 0.022). However, sensitivity analyses did not find the causal association of short sleep with anxiety (all P > 0.053). We did not observe a statistically significant causal association of genetically predicted long sleep with anxiety (OR = 0.91, 95% CI = 0.48–1.74, P = 0.775). We found strong evidence that insomnia but not short sleep and long sleep has a causal effect on anxiety. The characteristics of insomnia should be incorporated into anxiety prevention and intervention strategies, which have important public health significance. • Insomnia but not short sleep and long sleep has a causal effect on anxiety. • The characteristics of insomnia should be incorporated into anxiety prevention and intervention strategies. • This study focused on European ancestry, and other ethnicities have yet to be explored for this association. [ABSTRACT FROM AUTHOR]

Background: Epidemiological evidence relating obesity to peptic ulcer disease (PUD) has been mixed. Here we sought to determine the causality in the association of obesity with PUD risk using the Mendelian randomization (MR) approach. Methods: This study was based on summary-level data for body mass index (BMI), waist-to-hip ratio (WHR), and PUD derived from large genome-wide association studies (GWASs). Single nucleotide polymorphisms significantly associated with BMI and WHR (P < 5 × 10–8) were leveraged as instrumental variables. Causal estimates were pooled using several meta-analysis methods. In addition, multivariable MR was employed to account for covariation between BMI and WHR, as well as to explore potential mediators. Results: Genetically predicted higher BMI has a causal effect on PUD, with an OR of 1.34 per SD increase in BMI (~ 4.8 kg/m2) (P = 9.72 × 10–16). Likewise, there was a 35% higher risk of PUD (P = 2.35 × 10–10) for each SD increase in WHR (0.09 ratio). Complementary analyses returned consistent results. Multivariable MR demonstrated that adjustment for WHR largely attenuated the BMI-PUD association. However, the causal association of WHR with PUD risk survived adjustment for BMI. Both the associations remained robust upon adjustment for several traditional risk factors. Replication analyses using different instrumental variants further strengthened the causal inference. Besides, we found no evidence for the causal association in the reverse analyses from PUD to BMI/WHR. Conclusions: This MR study revealed that obesity (notably abdominal obesity) is causally associated with higher PUD risk. Programs aimed at weight loss may represent therapeutic opportunities for PUD. [ABSTRACT FROM AUTHOR]

Background: This study aimed to clarify the relationship between tea consumption and osteoarthritis (OA). Methods: Common single-nucleotide polymorphisms (SNPs) from the Open Genome-wide Association Studies database were obtained. Summary statistics on OA were retrieved from the second dataset that enrolled 50,508 participants (10,083 OA cases) of European ancestry. The causal association between tea intake and OA was tested using two-sample Mendelian randomization (MR) analysis. Results: Tea consumption has adverse effects on OA. (inverse-variance weighted method: OR = 1.19, 95% CI = 1.08-1.30; weighted median method: OR = 1.22, 95% CI = 1.07-1.40). The MR--Egger regression intercept (MR intercept = -0.002; p = 0.73) showed no evidence of directional pleiotropy. Moreover, no evidence of underlying heterogeneity in MR analysis was found according to Cochran's Q test and funnel and forest analyses. Conclusion: A genetically predicted high daily tea intake can increase the risk of OA. [ABSTRACT FROM AUTHOR]

Purpose: Observational research has indicated the presence of a causal relationship between sleep disturbances and low back pain (LBP). However, the link may have been biased by confounding factors. The purpose of this study was to examine the potential causal association of insomnia and daytime sleepiness with LBP by using mendelian randomization (MR). Methods: Genome-wide association study (GWAS) summary statistics of insomnia were obtained from a large-scale GWAS meta-analysis (n = 1,331,010; individuals from UK Biobank and 23andMe) or UK Biobank alone (n = 453,379). The summary statistics of daytime sleepiness were from UK Biobank (n = 452,071) and LBP were provided by the FinnGen Release 6 (210,645 individuals with 16,356 LBP cases and 194,289 controls) or UK Biobank (5,423 cases versus 355,771 controls). Linkage disequilibrium score (LDSC) regression and bidirectional MR analysis was employed to estimate genetic correlation and causal relationship. In the MR analysis, the inverse variance weighted method (IVW) was utilized as the main analysis procedure, while MR-Egger, Weighted median and Robust adjusted profile score (RAPS) were utilized for supplementary analyses. Results: LDSC analysis showed that LBP were significantly genetically correlated with insomnia (rg = 0.57, p = 2.26e-25) and daytime sleepiness (rg = 0.18, p = 0.001). The MR analysis revealed that genetically predicted insomnia was significantly associated with an increased risk of LBP (OR = 1.250, 95% CI: 1.186-1.318; p = 1.69e-16). However, the reverse causality was not confirmed. No evidence was identified supporting causality of daytime sleepiness and LBP. Conclusion: This study demonstrates a putative causal link of insomnia on LBP and a null causal effect of LBP on insomnia. Furthermore, a causal link between daytime sleepiness and LBP were not reported. This finding may stimulate new strategies for patient management in clinical practice, benefiting public health. [ABSTRACT FROM AUTHOR]

Objective: Several observational studies have suggested that coffee consumption is associated with a lower risk of bladder cancer. However, observational studies are susceptible to confounding factors and reverse causality. We used a two-sample Mendelian randomization (MR) method to assess the causal nature of this association. Methods: At the genome-wide significance level (p < 5 × 10−8), 12 single nucleotide polymorphisms (SNPs) strongly associated with coffee consumption were used as instrumental variables (IVs). Summary-level data on genetic variation in bladder cancer were obtained from the United Kingdom biobank (420,838 samples) and FinnGen consortium (175,121 samples). Multiple MR methods were used. Heterogeneity and horizontal pleiotropy were detected using Cochran’s Q test and MR-Egger. Results: Twelve SNPs were included in the primary analysis. After excluding 8 SNPs with potential secondary phenotypes, the remaining 4 SNPs were included in the sensitivity analysis. In all analyses, Cochran’s Q statistic indicated that there was no heterogeneity among SNPs, and the MR-Egger analysis did not reveal the existence of horizontal pleiotropy (p > 0.05). In the United Kingdom Biobank, the odds ratio (OR) for bladder cancer was 1.022 (95% confidence interval (CI), 0.679–1.537) for per 50% increase in coffee consumption. Consistent results were obtained in the FinnGen consortium (OR = 0.890, 95% CI, 0.467–1.697). Sensitivity analysis showed consistent results with primary analysis. Conclusion This study does not support a causal association between habitual coffee consumption and bladder cancer risk. [ABSTRACT FROM AUTHOR]

Backgrounds: Epidemiological studies have repeatedly investigated the association between obesity related anthropometric indicators and body compositions and osteoarthritis (OA). However, the results have remained inconsistent. This work aimed to investigate the genetic correlation and causal associations of obesity related anthropometric indicators and body compositions with knee and hip OA. Methods: Single-nucleotide polymorphisms associated with the exposures were searched from the recent genome-wide association studies (GWAS) to obtain full statistics. Summary-level results of knee and hip OA were from the UK Biobank and arcOGEN. First, linkage disequilibrium score regression (LD score regression) was applied to detect the genetic correlation (rg). We further performed a series of sensitivity analyses as validation of primary mendelian randomization (MR) results and the specific evidence of potential causal effects was defined. Results: We found that genetic components in OA had significant correlation with obesity related traits, except waist-to-hip ratio. In the univariable MR analysis, with the exception of waist-to-hip ratio, obesity related anthropometric indicators were causally associated with increased risks of knee and hip OA. For obesity related body compositions, higher fat-free mass in arm, leg, and whole body increased the risk of knee OA but only fat-free mass in leg showed a significant association with hip OA. Meanwhile trunk fat mass and trunk fat percentage, were associated with knee but not with hip OA. Higher fat mass, and fat percentage in arm, leg, and whole body increased the risk of both knee and hip OA. After adjusting for BMI, the multivariable MR showed maintained results in knee OA. However, in hip OA, only fat mass and fat-free mass in arm, leg, trunk and whole body were significantly associated with the risk of hip OA. Conclusion: The present study suggests genetic evidence for certain causal associations of obesity related anthropometric indicators and body compositions with knee and hip OA, which may provide important insights for the prevention and treatment on OA. [ABSTRACT FROM AUTHOR]

Objective: Observational studies have shown the association between iron status and osteoarthritis (OA). However, due to difficulties of determining sequential temporality, their causal association is still elusive. Based on the summary data of genome-wide association studies (GWASs) of a large-scale population, this study explored the genetic causal association between iron status and OA. Methods: First, we took a series of quality control steps to select eligible instrumental SNPs which were strongly associated with exposure. The genetic causal association between iron status and OA was analyzed using the two-sample Mendelian randomization (MR). Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were used for analysis. The results were mainly based on IVW (random effects), followed by sensitivity analysis. IVW and MR-Egger were used for heterogeneity testing. MR-Egger was also used for pleiotropy testing. Leave-one-SNP-out analysis was used to identify single nucleotide polymorphisms (SNPs) with potential impact. Maximum likelihood, penalized weighted median, and IVW (fixed effects) were performed to further validate the reliability of results. Results: IVW results showed that transferrin saturation had a positive causal association with knee osteoarthritis (KOA), hip osteoarthritis (HOA) and KOA or HOA (p < 0.05, OR > 1), and there was a negative causal association between transferrin and HOA and KOA or HOA (p < 0.05, OR < 1). The results of heterogeneity test showed that our IVW analysis results were basically free of heterogeneity (p > 0.05). The results of the pleiotropy test showed that there was no pleiotropy in our IVW analysis (p > 0.05). The analysis results of maximum likelihood, penalized weighted median and IVW (fixed effects) were consistent with our IVW results. No genetic causal association was found between serum iron and ferritin and OA. Conclusions: This study provides evidence of the causal association between iron status and OA, which provides novel insights to the genetic research of OA. [ABSTRACT FROM AUTHOR]

Background: The association between educational attainment (EA) and offspring birth weight (BW) has been reported by several traditional epidemiological studies. However, evidence for this association tends to be mixed and confounded. This study aimed to investigate the causal association between EA of parents and offspring BW. Methods: Here, we carried out a two-sample bidirectional Mendelian randomization (MR) analysis to examine the causal association between EA of males (n = 131,695) and females (n = 162,028) and offspring BW using genetic instruments. Summary statistics of EA associated single nucleotide polymorphisms (SNPs) were extracted from a GWAS incorporating 293,723 individuals of European descent performed by the Social Science Genetic Association Consortium (SSGAC), and the effects of these SNPs on offspring BWwere estimated using a GWAS meta-analysis of 86,577 participants of European descent from 25 studies. Univariable MR analyses were conducted using the inverse-variance weighted (IVW) method and four other methods. Further sensitivity analyses were carried out to test the viability of the results. Multivariable MR was used to examine the confounders between the exposure and outcome. Results: The result shows evidence that the offspring BW is positively causally affected by female EA. Each one standard deviation (SD) increase in female EA was associated with 0.24 SD higher of offspring BW (95% confidence interval [CI], 0.10 to 0.37, p < 0.001 for the IVW method). Similarly, change in offspring BWwas 0.21 SD (95% CI: 0.07 to 0.34, p = 2.82 × 10-3) per one SD higher in male EA. No causal effect of BW on EA was found by any of the five methods. The causal association between female EA and offspring BW maintained after adjusting for alcoholic drinks per week and BMI. The effect of male EA on offspring BW was attenuated when we adjusted for BMI and alcoholic drinks per week using multivariable MR analysis. Conclusion: Our study indicated that female EA is positively causally associated with offspring BW. The association between male EA and offspring BW may be confounded by alcoholic drinks per week and BMI. [ABSTRACT FROM AUTHOR]

Background and Aim: Observational studies have shown that there is a connection between blood biomarkers and the occurrence of acute pancreatitis (AP). Nevertheless, the causal relationships are still not clear. The purpose of this study was to evaluate causal association between biomarkers and AP., Method(s): A bidirectional two-sample Mendelian randomization (MR) analysis was applied to investigate the causal association between blood biomarkers and AP. Summary statistics obtained from genome-wide association studies were utilized for this analysis. The primary statistical approach employed was the inverse variance weighted (IVW) method, complemented by sensitivity analyses aimed at assessing heterogeneity and pleiotropy. Furthermore, a multivariable MR (MVMR) analysis was performed to adjust for confounders., Results: A total of 11 red blood cell (RBC) traits, 6 white blood cell traits, platelet count, and 30 blood biomarkers were analyzed in this study. Genetically predicted RBC count (IVW odds ratio [OR] = 1.144, P = 0.004), the high light scatter reticulocyte count (HLSR) (OR = 1.127, P = 0.022), blood glucose (BG) (OR = 1.480, P = 0.019), and leptin (OR = 1.234, P = 0.050) were suggestively associated with an increased risk of AP. Reverse MR analysis showed no causal effect of AP on RBC, HLSR, BG, and leptin (IVW P > 0.05). Sensitivity analyses and MVMR analysis still supported the earlier causality., Conclusion(s): Our findings provide evidence of a suggestive association between RBC count, HLSR, BG, and leptin with an increased susceptibility to AP. These findings aid in our comprehension of the cause of AP and may be used as potential prognostic markers or predictors of severity with AP., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Observational studies and experimental evidence have shown that chemokines play important roles in lung cancer development, progression, and treatment. However, few studies have examined the causal association between them., Methods: Summary data of chemokines and lung cancer were obtained from genome-wide association studies. Mendelian randomization (MR) analyses were performed by five methods, Inverse variance weighted (IVW), Weighted median estimation, MR-Egger, Simple mode and Weighted, with IVW as the primary analysis method. Sensitivity analysis was used to assess the reliability of the MR results. Multivariate Mendelian randomization studies were used to infer whether causality was influenced by potential mediators. The expression levels of CCL21 were analyzed by quantitative real-time PCR., Results: We found that CCL21 was negatively associated with lung adenocarcinoma risk. CCL25 was positively associated with lung squamous cell carcinoma risk. CCL5 was negatively associated with small cell lung cancer risk. CCL21, CCL24, CCL27, and CCL28 was positively associated with small cell lung cancer risk. After multivariate Mendelian randomization adjustment for smoking behavior, it was found that the effect of CCL25 on lung squamous cell cancer disappeared, and the effect of CCL21 on small cell lung cancer was quite opposite to the univariate. The receiver operating characteristic curve indicated that chemokines had high accuracy in the diagnosis of lung cancer. CCL21 expression levels showed large differences in lung adenocarcinoma cells., Conclusion: These results highlighted the causal effects of chemokines on lung cancer and suggested a mediating role of smoking behavior in the association between chemokines and lung cancer., (© 2024. The Author(s).)

Background: To explore the genetic causal association between lymphoma and the circulating levels of vitamins through Mendelian randomization (MR)., Research Design and Methods: We performed MR analysis using publicly available genome-wide association study (GWAS) summary data. Seven indicators related to the circulating levels of vitamins (vitamin D, vitamin C, vitamin B6, vitamin B12, folic acid, vitamin E, and carotene) served as exposures, while lymphoma was the outcome. The genetic causal association between these circulating levels of vitamin indicators and lymphoma was assessed using the inverse variance weighted (IVW) method., Results: Based on IVW method, vitamin B12 (OR = 0.48; 95% CI: 0.28-5.19; p  = 0.018) and folic acid (OR = 0.62; 95% CI: 0.40-0.96; p  = 0.032) both showed substantial evidence of a relationship with lymphoma. Moreover, the Weighted median method similarly indicated potential evidence of an association between vitamin B12 (OR = 0.40; 95% CI: 0.18-0.90; p  = 0.027) and lymphoma. The Simple mode, and Weighted mode methods showed no potential genetic causal association ( p  > 0.05 in the two analyses)., Conclusions: This study suggests a potential association between folic acid and vitamin B12 and lymphoma. Further research is required to assess the reproducibility of this finding in different contexts and to gain deeper insights into the potential underlying mechanisms.