Causal relationship between non-alcoholic fatty liver disease and sarcopenia: a bidirectional Mendelian randomization study.

Introduction: A correlation between non-alcoholic fatty liver disease and sarcopenia is demonstrated, but the causality remains unclear. Our study aims to clarify the point of genetics between non-alcoholic fatty liver disease (NAFLD) and sarcopenia at the level of gene prediction through two-sample Mendelian randomization (MR) analysis. Methods: The study employed the two-sample MR approach to investigate the bi-directional causality between NAFLD and sarcopenia. Published summary statistics were used to obtain instrumental variables (IVs) at the genome-wide significance level. Results: IVW analysis showed that the risk of NAFLD was reduced when walking pace was increased (OR = 0.435, 95%CI 0.240-0.789, p = 0.006); Increasing appendicular lean mass (ALM) decreased the risk of NAFLD (OR = 0.906, 95%CI 0.838-0.980, p = 0.014); Those older than 60 were more likely to suffer from NAFLD if they had low grip strength (OR = 1.411, 95%CI 1.087-1.830, p = 0.0012). In the reverse MR study, weight median analysis showed that NAFLD caused a decrease in ALM (OR = 0.953, 95%CI 0.957-0.994, p = 0.001); whereas NAFLD showed no correlation with usual walking pace or grip strength (all with p > 0.05). MR-Egger regression analysis showed that there was no horizontal pleiotropy in the SNPs (all with p > 0.05). Conclusion: The characteristics related to sarcopenia (usual walking pace, appendicular lean mass and low hand grip strength) may play a causal role in the development of nonalcoholic fatty liver disease, although the underlying mechanisms need to be further investigated. The presence of specific single nucleotide polymorphisms (SNPs) such as rs3747207, rs429358, and rs73001065 has been identified in the PNPLA3, APOE, and MAU2 proteins. These genetic markers represent potential targets for future interventions aimed at addressing, managing, or mitigating the risk of NAFLD.

Bidirectional Mendelian Randomization Reveals Causal Effects of Immune Cell Traits on Endometriosis Risk.

PURPOSE: Previous studies have identified associations between immune cell traits and endometriosis, but the causality of these relationships remains uncertain. In this study, we utilized Mendelian randomization (MR) to investigate the causal relationship between immune cell traits and endometriosis for the first time. METHODS: Seven hundred and thirty-one immune cell signatures associated with single-nucleotide polymorphisms (SNPs) were extracted from a published genome-wide association study (GWAS) involving 472 174 individuals, while endometriosis data, including four stages and seven subtypes, were obtained from the FinnGen consortium. Four methods were used for MR. The causal effect of immune cell traits on endometriosis was explored after Bonferroni correction. RESULTS: Significant causal relationship included 92 immune cell traits distributed among B cell (28 cells), cDC (2 cells), maturation stages of T cell (10 cells), monocyte (12 cells), Myeloid cell (5 cells), TBNK (13 cells), and Treg panels (22 cells). One of the most significant findings is that for every 1-standard deviation (SD) increase in CD8 on Central Memory CD8+ T cell, the risks of developing endometriosis of the fallopian tube increased by 72%. In the reverse MR analysis, a one-unit increase in the log odds of endometriosis of the ovary risk corresponded to a decrease in the absolute count of CD4+ CD8dim T cell by 0.10. CONCLUSION: This study represents the first comprehensive evaluation of the causal effects of immune cell traits on the risk/protection of different stages/subtypes of endometriosis. The findings highlight the complex and significant role of immune-derived factors in the pathogenesis of the disease.

Traumatic brain injury increasing risk of meningioma? From the genetic evidence.

BACKGROUND: Numerous studies have demonstrated a strong association between traumatic brain injury (TBI) and an increased risk of meningioma. However, this correlation remains controversial. This study utilized mendelian randomization to explore this relationship from perspective of genetic evidence. METHODS: We employed six traumatic brain injury genome-wide association study (GWAS) datasets from the IEU GWAS database. Summary statistics for meningioma were sourced from the FinnGen R10 database. We assessed heterogeneity and horizontal pleiotropy within the analyzed data. The primary method was inverse variance weighting (IVW) to investigate the causal relationship between TBI and meningioma, excluding cases with horizontal pleiotropy. Four supplementary analysis methods were also used, with abnormal results excluded based on leave-one-out sensitivity analysis. RESULTS: All six Mendelian randomization analyses indicated no causal relationship between TBI and meningiomas (Focal brain injury IVW p-value = 0.98; Diffuse brain injury IVW p-value = 0.41; TBI without concussion IVW p-value = 0.45; Intracranial trauma IVW p-value = 0.34; Traumatic subdural hemorrhage IVW p-value = 0.80; Traumatic subarachnoid hemorrhage IVW p-value = 0.92). CONCLUSIONS: The mendelian randomization study revealed that traumatic brain injury does not increase the risk of meningioma based on genetic evidence.

Causal relationship between green tea intake and gastrointestinal disorders: a two-sample Mendelian randomization study.

Background: The precise association between green tea intake and gastrointestinal disorders remains controversial. This study aimed to investigate the potential causal association between green tea intake and gastrointestinal disorders through a two-sample Mendelian randomization (MR) study. Methods: Utilizing publicly accessible data from genome-wide association studies (GWAS), we identified SNPs strongly linked with the study variables from multiple large databases to serve as instrumental variables (IVs). MR analyses were executed utilizing the inverse variance weighting (IVW) method, with the resultant effect estimates serving as the primary outcome measure. In addition, a multivariate MR design was performed to adjust for smoking and alcohol consumption. To ensure the robustness of our findings, a series of sensitivity analyses were conducted to assess reliability. Results: Univariable MR analysis revealed suggestive associations between green tea intake and gastroesophageal reflux (OR = 0.9950, 95% CI 0.9900-1.0000, p IVW = 0.047), diverticulosis (OR = 0.9998, 95% CI 0.9996-1.0000, p IVW = 0.030), Crohn's disease (OR = 1.0001, 95% CI 1.0000-1.0002, p IVW = 0.019), and cholangitis was observed (OR = 1.0440, 95% CI 1.0100-1.0790, p IVW = 0.011). Multivariate MR analysis indicated after controlling for potential confounders, greater green tea consumption was suggestively associated with the decreased risk of oesophagitis (OR = 0.9667, 95% CI: 0.9405-0.9936, p IVW = 0.016) and gastric cancer (OR = 0.9810, 95% CI: 0.9628-0.9996, p IVW = 0.046). Nevertheless, multivariate MR analysis also showed that greater green tea consumption was suggestively associated with the increased risk of Crohn's disease (OR = 1.0001, 95% CI: 1.0000-1.0002, p IVW = 0.007). Sensitivity analyses confirmed that these results were reliable. Conclusion: Our study provides suggestive evidence that genetically predicted green tea intake is causally associated with the risk of oesophagitis, gastric cancer and Crohn's disease, but a larger GWAS database is needed for validation.

Investigation of the causal relationship between cholelithiasis and Parkinson's disease: A bidirectional Mendelian randomization study.

Background: Parkinson's disease (PD) and cholelithiasis are a huge public health burden. Although observational studies have suggested a potential link between PD and cholelithiasis, the causal relationship between the two remains uncertain. To address this gap, we performed a two-sample bidirectional Mendelian randomization analysis using genetic tools. Method: Genome-wide association study summary statistics for all traits were obtained from publicly available databases. We used strict control steps in instrumental variable selection to screen for single nucleotide polymorphisms (SNPs) from summary-level genome-wide association studies. In addition, all F-statistics were >10, indicating no weak instrumental bias. The inverse variance weighting (IVW) method was the primary method used to assess causal associations. Four other MR methods (MR-Egger, Weighted Median, Simple mode, and Weighted mode) were also used to complement IVW. Various sensitivity tests were also performed to assess reliability: (1) Cochrane's Q test for assessing heterogeneity, (2) MR-Egger intercept test and MR-PRESSO global test for assessing horizontal multiplicity, and (3) leave-one-out sensitivity test for determining stability. Results: We selected a total of 30 SNPs as instrumental variables. It was demonstrated that cholelithiasis had a causal effect on the risk of PD (OR = 1.146, 95% CI: 1.062-1.236, p < 0.001) in IVW method. Conclusion: The results of our analysis revealed an increased risk effect of cholelithiasis against PD, which may give light on new approaches to PD prevention and therapy.

Unraveling the genetic association between knee osteoarthritis and hallux deformities.

OBJECTIVE: Knee osteoarthritis (KOA), hallux valgus (HV) and hallux rigidus (HR) are common musculoskeletal problems of the lower extremities. However, their underlying causal relationships are unclear. This study attempts to clarify the cause-and-effect relationship between KOA and the two common hallux deformities (HV and HR). DESIGN: The summary-level statistics for KOA, HV, and HR were collected from genome-wide association studies (GWAS). The causal analysis of KOA on HV or HR was carried out using two-sample Mendelian randomization (MR). In order to assess the robustness of the MR results, sensitivity analyses were performed. In addition, multivariable MR (MVMR) was implemented to assess the influence of KOA in causation as well as calibrate the effect of anthropometric characteristics. Supplementary backward MR analysis was conducted to determine the causal effect of hallux diseases on KOA. RESULTS: The univariable analysis indicated that KOA has a causative influence on HR (odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.18-1.41, P = 2.25E-8) and HV (OR = 1.43, 95% CI = 1.21-1.68, P = 2.76E-5). In the backward MR analyses, hallux deformities did not appear to be the cause of KOA. In the MVMR analysis, after jointly adjusting for the effects of waist-to-hip ratio (WHR), waist circumference (WC), hip circumference (HC) and BMI, the causal impact of KOA on HV and HR remained robust. CONCLUSION: In this study, the genetic causality between KOA and increased risk of hallux deformities (HV and HR) is established, which can provide evidence-based recommendations for reducing the incidence of hallux deformities in KOA patients. Further high-level studies are warranted to validate the associations and explore its broader implications.

Unveiling causal relationships between addiction phenotypes and inflammatory cytokines: insights from bidirectional mendelian randomization and bibliometric analysis.

Observational studies have suggested associations between multiple inflammatory factors and tobacco and alcohol use, but establishing causation is challenging in epidemiological investigations. We employed genetic association data about the circulating levels of 41 cytokines obtained from the genome-wide association study (GWAS), which contained 8293 Finnish participants. Genetic data on 5 substance use phenotypes were obtained from the GWAS dataset containing 1.2 million European subjects. Then, we conducted a bidirectional mendelian randomization (MR) study. The forward results indicated that smoking cessation was positively correlated with hepatocyte growth factor (HGF), interleukin-10 (IL-10), and stem cell factor (SCF); cigarettes per day was a risk factor associated with high expression in stromal cell-derived factor 1α (SDF-1 A), interferon-γ (IFN-G), IL-4, and granulocyte colony-stimulating factor (G-CSF); drinks per week and smoking initiation were risk factors respectively correlated with reduced HGF and IL-2RA levels. During inverse MR analysis, the findings revealed that both IL-16 and IL-18 increased the risk of cigarettes per day; macrophage inflammatory protein-1ß (MIP-1B) and tumor necrosis factor-ß (TNF-B) inhibited and promoted smoking cessation, respectively; macrophage colony-stimulating factor (M-CSF) elevated the risk of drinks per week, while interferon inducible protein 10 (IP-10) had a contrary role; IL-7 and M-CSF respectively prolonged and shortened age of initiation of regular smoking. This study provides genetic proof supporting a causal relationship between various inflammatory factors and addiction phenotypes. Further comprehensive investigations are required to uncover underlying biological mechanisms. In addition, bibliometric studies have shown that oxidative stress is one of the most important orientations in alcohol and tobacco addiction research, where an in-depth investigation of its pro-inflammatory mechanisms would facilitate the development of potential therapeutic biological targets and drugs.

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

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

Using multi-omics to explore the genetic causal relationship between colorectal cancer and heart failure in gastrointestinal tumors.

Background: Heart failure (HF) and colorectal cancer are significant public health concerns with substantial morbidity and mortality. Previous studies have indicated a close association between HF and various tumors, including colorectal cancer. Further understanding the potential causal relationship between them could provide insights into their shared pathophysiological mechanisms and inform strategies for prevention and treatment. Methods: This study employed a bidirectional Mendelian randomization (MR) approach using genetic variants from large genome-wide association studies (GWAS) as instrumental variables (IVs). The inverse-variance weighted (IVW) method was employed for the MR analysis. Meta-analyses of IVW results from discovery and validation cohorts were performed to enhance the power of detecting causal effects. Sensitivity analyses, including heterogeneity analysis and tests for horizontal pleiotropy, were conducted to test the robustness of the conclusions. Results: Results from the discovery cohort suggest HF is associated with an approximately 30% increased risk of colorectal cancer (OR 1.32, 95% CI 1.03-1.69, P=0.025), although this finding did not reach statistical significance in the validation cohort (OR 1.19, 95% CI 0.97-1.46, P=0.090). However, meta-analysis supports HF as a potential risk factor for colorectal cancer (Pooled OR 1.24, 95% CI 1.06-1.25, P=0.007). Reverse MR analysis found no evidence of colorectal cancer increasing HF risk (Pooled OR 1.03, 95% CI 0.99-1.07, P=0.121). Sensitivity analyses (all P>0.05) indicate robustness against heterogeneity and horizontal pleiotropy. Conclusion: This comprehensive bidirectional MR study provides genetic evidence supporting a causal link between HF and colorectal cancer. The insights gained enhance understanding of their interconnectedness and may guide future research and clinical practices aimed at mitigating their risks through targeted interventions.

Plasma lipidome, circulating inflammatory proteins, and Parkinson's disease: a Mendelian randomization study.

Background: Observational studies have suggested that plasma lipidome play a pivotal role in the occurrence of Parkinson's disease (PD). However, it remains unknown which lipids among plasma lipidome affect PD and how they exert their influence. Clarity is lacking regarding the causal relationship between plasma lipidome and PD, as well as whether circulating inflammatory proteins serve as mediators. Methods: Single nucleotide polymorphisms (SNPs) significantly associated with 179 plasma lipidome were selected as instrumental variables to assess their causal impact on PD. PD data, serving as the outcome, were sourced from the International Parkinson's Disease Genomics Consortium, which boasts the largest sample size to date. The inverse variance weighted (IVW), Weighted median method, MR-Egger method, Simple mode method, Weighted mode method and MR-PRESSO were employed to evaluate the influence of the 179 plasma lipidome on PD. Heterogeneity, pleiotropy tests, and reverse causality analyses were conducted accordingly. Additionally, we analyzed the causal relationship between 91 circulating inflammatory proteins and PD, exploring whether these proteins serve as mediators in the pathway from plasma lipidome to PD. Results: Among the 179 plasma lipidome, three were found to be associated with a reduced risk of PD: Phosphatidylcholine (14:0_18:2) (IVW, OR = 0.877; 95%CI, 0.787-0.978; p = 0.018), Phosphatidylcholine (16:0_16:1) levels (IVW, OR = 0.835; 95%CI, 0.717-0.973; p = 0.021), and Phosphatidylcholine (O-17:0_17:1) levels (IVW, OR = 0.854; 95%CI, 0.779-0.936; p = 0.001). Meanwhile, Sphingomyelin (d38:1) was linked to an increased risk of PD (IVW, OR = 1.095; 95%CI, 1.027-1.166; p = 0.005). Among the 91 circulating inflammatory proteins, three were associated with a lower PD risk: Fibroblast growth factor 21 levels (IVW, OR = 0.817; 95%CI, 0.674-0.990; p = 0.039), Transforming growth factor-alpha levels (IVW, OR = 0.825; 95%CI, 0.683-0.998; p = 0.048), and Tumor necrosis factor receptor superfamily member 9 levels (IVW, OR = 0.846; 95%CI, 0.744-0.963; p = 0.011). Two were associated with a higher risk of PD: Interleukin-17A levels (IVW, OR = 1.285; 95%CI, 1.051-1.571; p = 0.014) and TNF-beta levels (IVW, OR = 1.088; 95%CI, 1.010-1.171; p = 0.026). Additionally, a positive correlation was observed between Phosphatidylcholine (14:0_18:2) levels and Fibroblast growth factor 21 levels (IVW, OR = 1.125; 95%CI, 1.006-1.257; p = 0.038), suggesting that Fibroblast growth factor 21 levels may serve as a mediating factor in the pathway between Phosphatidylcholine (14.0_18.2) levels and PD. The mediation effect was estimated to be -0.024, accounting for approximately 18% of the total effect. Conclusion: Both plasma lipidome and circulating inflammatory proteins demonstrate a causal relationship with PD. Additionally, circulating inflammatory proteins may serve as mediators in the pathway from plasma lipidome to PD. These findings may contribute to the prediction and diagnosis of PD and potentially pave the way for targeted therapies in the future.

Plasma metabolites as potential markers and targets to prevent and treat urolithiasis: a Mendelian randomization study.

Background: Studies on the relationships between diseases of the urinary system and human plasma proteomes have identified several potential biomarkers. However, none of these studies have elucidated the causal relationships between plasma proteins and urolithiasis. Objective: The objective of the study was to investigate the potential risks of plasma metabolites in urolithiasis using a two-sample Mendelian randomization (MR) study. Methods: A total of 1,400 metabolites were identified in the most comprehensive genome-wide association study (GWAS) of plasma metabolomics in a European population to date, and single-nucleotide polymorphisms (SNPs) were used as the instrumental variables for the plasma metabolites. The European GWAS data for urinary calculi included 482,123 case samples and 6,223 control samples (ebi-a-GCST90018935). The associations between the plasma metabolites and risk of urolithiasis were evaluated by inverse variance weighting (IVW) and supplemented by sensitivity analyses of the MR-Egger and MR-PRESSO tests. Results: For the first time, we found a causal relationship between two plasma metabolites (p < 1.03 × 10-4) and urolithiasis (p < 0.05). The chemical 4-hydroxychlorothalonil, which is an intermediate product of the pesticide hydroxychlorothalonil, could promote urolithiasis (odds ratio (OR) = 1.12) as a risk factor. Moreover, 1-stearoyl-2-arachidonoyl-GPC, which is an important component of phospholipid metabolism in the human body, can inhibit urolithiasis (OR = 0.94). Conclusions: Our results suggest that blood metabolites can be used as blood markers and drug targets in the prevention, diagnosis, and treatment of urolithiasis; furthermore, our results can provide a basis for policy makers to formulate prevention and treatment policies for urolithiasis.

Exploring the causal relationship between the immune cell-inflammatory factor axis and lung cancer: a Mendelian randomization study.

Background: Lung cancer is a major health burden globally and smoking is a well-known risk factor. It has been observed that chronic inflammation contributes to lung cancer progression, with immune cells and inflammatory cytokines implicated in tumor development. Clarifying the causal links between these immune components and lung cancer could enhance prevention and therapy. Methods: We performed Mendelian randomization (MR) to explore causal connections between immune cells, inflammatory markers, and lung cancer risk, using genetic variants as instruments. Data from GWAS on these variables underpinned our MR analyses. Results: Our findings indicated an inverse association between some immune cells and lung cancer risk, implying that more immune cells might be protective. NK T cells (CD16-CD56) and myeloid cells (HLA DR+ on CD33dim HLA DR+ CD11b+) had an inverse correlation with lung cancer risk. Furthermore, a direct relationship was observed between inflammatory cytokines and these immune cells. In contrast, IL-18 was inversely associated with lung cancer, while IL-13 showed a direct correlation. Conclusion: The study underscores the role of immune and inflammatory factors in lung cancer. These insights could lead to new therapeutic strategies for combating lung cancer.

The causal effect of hot beverage temperature preference on esophageal cancer risk: a Mendelian randomization study.

Background: Previous research has found a link between the temperature of food and beverages and the risk of esophageal cancer (EC). A causal relationship between the two has not been well established. Herein, we used Mendelian randomization (MR) analysis to assess the causal effect of temperature preference for hot beverages on EC risk. Methods: Genome-wide association studies (GWAS) data for hot beverage temperature preference were obtained from the UK biobank. There were 457,873 European and 2,617 East Asian participants included. GWAS data for EC were obtained from the Integrative Epidemiology Unit (IEU) project database. Two datasets from the European population and two datasets from the East Asian population were included. Totally, 4,426 EC cases and 1,202,270 control subjects were included. The "TwoSampleMR" R package was used to conduct a two-sample MR analysis. A random-effect inverse variance weighted (IVW) was used as the main analytical method to estimate the causal effect, and various sensitivity analyses, including MR Egger, weighted median, simple mode, and weighted mode, were used to examine the potential violation of the second and third MR assumptions. Meta-analyses were performed to further confirm the results. Results: Sixty-eight single nucleotide polymorphisms (SNPs) from the European population and 11 SNPs from the East Asian population were used for MR analysis. No significant causal effect was found between hot beverage temperature preference and EC risk in the European population {for the ieu-b-4960 dataset, inverse variance weighted odds ratio (ORIVW) =1.00 [95% confidence interval (CI): 0.99-1.00], P=0.54; for the ebi-a-GCST90018841 dataset, ORIVW =0.35 (95% CI: 0.10-1.29), P=0.12} or in the East Asian population [for the bbj-a-117 dataset, ORIVW =1.09 (95% CI: 0.80-1.48), P=0.59; for the ebi-a-GCST90018621 dataset, ORIVW =0.11 (95% CI: 0.82-1.50), P=0.49]. Meta-analyses of the European population datasets and the Asian population datasets showed consistent results. Conclusions: The current MR analysis provides new genetic evidence for a null causal relationship between hot beverage temperature preference and EC, both in the European population and the East Asian population. Evidence to prevent EC by reducing the intake of hot beverages is insufficient.

Causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity.

The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618-482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = -0.309, 95% CI: -0.38 to -0.24, p = 1.51E-19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10, 95% CI: -0.188 to -0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.

Genetic Causal Relationship Between Sex Hormones and Basal Cell Carcinoma: A Two-Sample Mendelian Randomization Study.

Background: The primary aim of this study was to explore whether sex hormones affect the occurrence of basal cell carcinoma (BCC) from a genetic perspective using a two-sample Mendelian randomization (MR) study. Methods: Exposure and outcome data for this MR analysis were derived from previously published GWAS studies. In this study, estradiol, sex hormone-binding globulin (SHBG), bioavailable testosterone, and total testosterone were used as exposures, and BCC was used as the outcome for the two-sample MR analysis. The random effects inverse variance weighted (IVW) model was the primary analytical model, and the simple mode, weighted median, MR-Egger, and weighted mode methods were applied as complementary approaches. Furthermore, the "leave-one-out" sensitivity analysis was performed to assess stability, Cochran's Q test to evaluate heterogeneity, and the MR-Egger intercept test to analyze horizontal multiplicity. Results: The two-sample MR analysis of the sex hormone and BCC showed that estradiol, sex hormone-binding globulin (SHBG), bioavailable testosterone, and total testosterone were not a causal factor in BCC (P>0.05). The results of the heterogeneity test and horizontal pleiotropic analysis showed that no heterogeneity or horizontal pleiotropic existed in all MR analyses (Cochran's Q-P>0.05, Egger intercept-P>0.05). Conclusion: The two-sample MR analysis showed that estrogen and testosterone did not affect the occurrence and development of BCC at the genetic level.

Causal effects of obstructive sleep apnea on chronic kidney disease and renal function: a bidirectional Mendelian randomization study.

Background: Observational studies have suggested an association between obstructive sleep apnea (OSA), chronic kidney disease (CKD), and renal function, and vice versa. However, the results from these studies are inconsistent. It remains unclear whether there are causal relationships and in which direction they might exist. Methods: We used a two-sample Mendelian randomization (MR) method to investigate the bidirectional causal relation between OSA and 7 renal function phenotypes [creatinine-based estimated glomerular filtration rate (eGFRcrea), cystatin C-based estimated glomerular filtration rate (eGFRcys), blood urea nitrogen (BUN), rapid progress to CKD, rapid decline of eGFR, urinary albumin to creatinine ratio (UACR) and CKD]. The genome-wide association study (GWAS) summary statistics of OSA were retrieved from FinnGen Consortium. The CKDGen consortium and UK Biobank provided GWAS summary data for renal function phenotypes. Participants in the GWAS were predominantly of European ancestry. Five MR methods, including inverse variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode were used to investigate the causal relationship. The IVW result was considered the primary outcome. Then, Cochran's Q test and MR-Egger were used to detect heterogeneity and pleiotropy. The leave-one-out analysis was used for testing the stability of MR results. RadialMR was used to identify outliers. Bonferroni correction was applied to test the strength of the causal relationships (p < 3.571 × 10-3). Results: We failed to find any significant causal effect of OSA on renal function phenotypes. Conversely, when we examined the effects of renal function phenotypes on OSA, after removing outliers, we found a significant association between BUN and OSA using IVW method (OR: 2.079, 95% CI: 1.516-2.853; p = 5.72 × 10-6). Conclusion: This MR study found no causal effect of OSA on renal function in Europeans. However, genetically predicted increased BUN is associated with OSA development. These findings indicate that the relationship between OSA and renal function remains elusive and requires further investigation.

A causal relationship between bone mineral density and breast cancer risk: a mendelian randomization study based on east Asian population.

BACKGROUND: Breast cancer (BC) poses significant burdens on women globally. While past research suggests a potential link between bone mineral density (BMD) and BC risk, findings remain inconsistent. Our study aims to elucidate the causal relationship between BMD and BC in East Asians using bidirectional Mendelian randomization (MR). METHODS: Genetic association data for bone mineral density T-scores (BMD-T) and Z-scores (BMD-Z) (Sample size = 92,615) and BC from two different sources (Sample size1 = 98,283; Sample size2 = 79,550) were collected from publicly available genome-wide association studies (GWAS). Single-nucleotide polymorphisms (SNPs) associated with BMD-T and BMD-Z as phenotype-related instrumental variables (IVs) were used, with BC as the outcome. As the primary means of causal inference, the inverse variance weighted (IVW) approach was employed. Heterogeneity analysis was conducted using Cochran's Q test, while MR-Egger regression analysis was implemented to assess the pleiotropic effects of the IVs. Sensitivity analyses were performed using methods such as MR-Egger, weighted median, and weighted mode to analyze the robustness and reliability of the results. The MR-PRESSO method and the RadialMR were used to detect and remove outliers. The PhenoScanner V2 website was utilized to exclude confounding factors shared between BMD and BC. Besides, the Bonferroni correction was also used to adjust the significance threshold. Then, the meta-analysis method was applied to combine the MR analysis results from the two BC sources. Finally, a reverse MR analysis was conducted. RESULTS: The results of the IVW method were consolidated through meta-analysis, revealing a positive correlation between genetically predicted BMD-T ([Formula: see text], [Formula: see text], [Formula: see text]) and BMD-Z ([Formula: see text],[Formula: see text], [Formula: see text]) with increased BC risk. The Cochran's [Formula: see text] test and MR-Egger regression suggested that neither of these causal relationships was affected by heterogeneity or horizontal pleiotropy. The sensitivity analyses supported the IVW results, indicating the robustness of the findings. Reverse MR analysis showed no causal relationship between BC and BMD. CONCLUSION: Our MR study results provide evidence for the causal relationship between BMD and BC risk in East Asian populations, suggesting that BMD screening is of great significance in detecting and preventing BC.

Dissecting the causal relationship between moderate to vigorous physical activity levels and cognitive performance: a bidirectional two-sample Mendelian randomization study.

Introduction: Recent studies increasingly suggest that moderate-to-vigorous physical activity (MVPA) impacts cognitive risk. However, the bidirectional nature of this relationship warrants further exploration. To address this, we employed a Mendelian randomization (MR) approach, analyzing two distinct samples. Methods: These analyses utilized published genome-wide association study (GWAS) summary statistics for MVPA (n = 377,234) and cognitive performance (n = 257,841). Our primary method was the inverse variance weighted (IVW) model with random effects, aiming to deduce potential causal links. Additionally, we employed supplementary methods, including MR Egger regression, Weighted median, Weighted mode, and Simple mode. For sensitivity analysis, tools like the MR Egger test, Cochran's Q, MR PRESSO, and leave-one-out (LOO) were utilized. Results: Our findings indicate a decrease in cognitive risk with increased MVPA (Odds Ratio [OR] = 0.577, 95% Confidence Interval [CI]: 0.460-0.723, p = 1.930 × 10-6). Furthermore, enhanced cognitive levels corresponded to a reduced risk of inadequate MVPA (OR = 0.866, 95% CI: 0.839-0.895, p = 1.200 × 10-18). Discussion: In summary, our study demonstrates that MVPA lowers cognitive risk, while poor cognitive health may impede participation in MVPA. Overall, these findings provide valuable insights for developing personalized prevention and intervention strategies in health and sports sciences.

The relationship between metabolites and gout: a Mendelian randomization study.

BACKGROUND: Gout is closely tied to metabolism, yet there is limited evidence on how metabolites may cause or prevent the condition. METHODS: This study utilized a two-sample Mendelian randomization (MR) analysis to evaluate the causal relationship between 1,400 serum metabolites and gout. We primarily employed the inverse variance-weighted (IVW) method to estimate causal effects, supplemented by MR-Egger regression, weighted median, simple mode, and weighted mode for comprehensive evaluations. Additionally, we conducted tests for pleiotropy and heterogeneity. RESULTS: After a rigorous selection process, we identified eight known metabolites and four unknown metabolites associated with gout. Among the eight known metabolites, Glucuronide of piperine metabolite C17H21NO3 and the Phosphate to mannose ratio were positively associated with an increased risk of gout. Conversely, levels of 5 alpha-androstan-3 beta, 17 alpha-diol disulfate, Pantoate, N-carbamoylalanine, Sphingomyelin (d18:0/20:0, d16:0/22:0), Hydroxypalmitoyl sphingomyelin (d18:1/16:0(OH)), and Mannose were linked to a decreased risk of gout. CONCLUSION: This study identified eight metabolites from 1,400 blood samples significantly linked to gout risk. Integrating genomics and metabolomics offers valuable insights for gout screening and prevention, indicating that specific blood metabolites can help identify individuals at higher risk.

Causal relationship between modifiable risk factors and knee osteoarthritis: a Mendelian randomization study.

Background: While several risk factors for knee osteoarthritis (KOA) have been recognized, the pathogenesis of KOA and the causal relationship between modifiable risk factors and KOA in genetic epidemiology remain unclear. This study aimed to determine the causal relationship between KOA and its risk factors. Methods: Data were obtained from published Genome-Wide Association study (GWAS) databases. A two-sample Mendelian randomization (MR) analysis was performed with genetic variants associated with risk factors as instrumental variables and KOA as outcome. First, inverse variance weighting was used as the main MR analysis method, and then a series of sensitivity analyses were conducted to comprehensively evaluate the causal relationship between them. Results: Univariate forward MR analysis revealed that genetically predicted hypothyroidism, hyperthyroidism/thyrotoxicosis, educational level, income level, metabolic syndrome (MS), essential hypertension, height, hot drink temperature, diet (abstaining from sugar-sweetened or wheat products), and psychological and psychiatric disorders (stress, depression, and anxiety) were causally associated with KOA. Reverse MR exhibits a causal association between KOA and educational attainment. Multivariate MR analysis adjusted for the inclusion of potential mediators, such as body mass index (BMI), smoking, alcohol consumption, and sex, exhibited some variation in causal effects. However, hyperthyroidism/thyrotoxicosis had a significant causal effect on KOA, and there was good evidence that height, hypothyroidism, educational level, psychological and psychiatric disorders (stress, depression, and anxiety), and abstaining from wheat products had an independent causal relationship. The mediating effect of BMI as a mediator was also identified. Conclusion: This study used MR to validate the causal relationship between KOA and its risk factors, providing new insights for preventing and treating KOA in clinical practice and for developing public health policies.