Genome-wide Association Studies Data Research Articles

Exploring genetic associations between immune cells and hypertensive disorder of pregnancy using Mendelian randomization.

Observational epidemiological studies suggested that immunological dysregulation and inflammation play a significant role in the placental and renal dysfunction that leads to maternal hypertension. The immunophenotypes' possible causalities with hypertensive disease of pregnancy remain ambiguous. We performed two-sample Mendelian randomization (MR) analyses to comprehensively investigate the causal effect of immunophenotypes on hypertensive disorder of pregnancy (HDP). The large-scale genome-wide association studies (GWASs) data on immunological traits was taken from public catalog for 731 immunophenotypes. The summarized GWAS data in 4 types of HDP were retrieved from FinnGen database, including 811,605 Finnish individuals. The primary analysis was the inverse variance weighted (IVW) method, supplemented by conducting sensitivity analysis. To confirm whether cardiovascular proteins mediated the causal effect of immune cells on HDP, we additionally executed a mediation MR study. After looking into genetically predicted immunophenotype biomarkers, we discovered 14 highly correlative immunophenotypes and 104 suggestive possible factors. The IVW analysis indicated that HLA DR on myeloid DC, HLA DR on plasmacytoid DC, and HLA DR on DC had a significant association with pre-eclampsia/eclampsia (PE), whereas CD4+ CD8dim AC and CD4+ CD8dim % leukocyte were protective against gestational hypertension (GH). All of HDP in our study had no statistically significant impact on immune cells, according to reverse MR analysis. The mediating role of LOX-1between HLA DR on plasmacytoid DC and chronic hypertension prior to pregnancy was validated. This study showed that many immunophenotypes are implicated in HDP. Furthermore, the level of LOX-1 mediated the pathophysiology relationship between HLA DR on plasmacytoid dendritic cells and chronic hypertension prior to pregnancy.

The protective role of basal metabolic rate in cognitive decline: evidence from epidemiological and genetic studies.

This study aims to explore the relationship between basal metabolic rate (BMR) and cognitive impairment and assess the potential of BMR as a protective factor against cognitive decline. This investigation initially conducted a cross-sectional study of American adults from 2011 to 2014 using data from the National Health and Nutrition Examination Survey. It examined the correlation between participants' BMR and cognitive functions, exploring the association with cognitive impairment. Subsequently, publicly available genome-wide association study data was used to examine potential causal links between genetically determined BMR and specific cognitive disorders using Mendelian randomization. Cross-sectional findings revealed a significant positive correlation between higher BMR and cognitive scores. In Mendelian randomization analysis, BMR demonstrated an inverse causal relationship with Alzheimer's disease and Parkinson's dementia, suggesting BMR as a potential protective factor against these diseases. No causal links were found with vascular dementia, Lewy body dementia, and frontotemporal dementia. This study supports the role of BMR as a potential protective factor against Alzheimer's disease and Parkinson's dementia, suggesting that BMR may play an important role in preventing cognitive decline. However, due to the limitations of cross-sectional studies, further prospective studies and broader demographic samples are necessary to verify these results and explore underlying biological mechanisms. Key messages What is already known on this topic: Existing knowledge suggests a close relationship between BMR and health and cognitive functions, but detailed studies on its connection with specific cognitive impairments are still needed. What this study adds: This study found a significant positive correlation between higher BMR and cognitive improvement, potentially aiding in the prevention of Alzheimer's and Parkinson's dementia. How this study might affect research, practice, or policy: This finding guides public health strategies and personalized medicine, emphasizing the necessity for further research to validate BMR's protective effects.

Gut Microbiota’s role in lipoma development: evidence from mendelian randomization

BackgroundLipoma, a benign tumor derived from mesenchymal tissue, significantly affects patients’ physical and psychological wellbeing. Increasing evidence points to a strong link between the gut microbiome (GM) and lipoma incidence. This study utilizes Mendelian Randomization (MR) to assess the potential causal relationships between the GM and lipoma development.MethodsWe conducted a two-sample MR analysis using genome-wide association study (GWAS) data from MiBioGen and FinnGen to explore the causal relationship between GM and lipoma. The GM dataset included 18,340 participants with 14,587 single nucleotide polymorphisms (SNPs), while the lipoma dataset comprised 412,181 participants with 21,306,349 SNPs. We employed 5 MR methods: Inverse Variance Weighted (IVW), Weighted Median, Simple Mode, MR-Egger, and Weighted Mode. Additional assessments included Cochran’s Q test for result heterogeneity, PRESSO analysis for horizontal pleiotropy, and sensitivity analyses through scatter plots, leave-one-out analyses, funnel plots, and forest plots.ResultsThe IVW method identified 18 gene predictors trans-genus associated with lipoma risk. Protective effects against benign lipoma (BL) were observed in the Eubacterium rectale group, Desulfovibrio, Ruminococcus1, Clostridium sensu stricto1, and Lachnospiraceae UCG001; conversely, Lachnospiraceae UCG008 was linked to increased BL risk. Desulfovibrio provided protection against TS-BL; however, the Family XIII AD3011 group, Eubacterium coprostanoligenes group, Lachnospiraceae NK4A136 group, and Parasutterella were associated with an increased TS-BL risk. The Clostridium innocuum group, Eubacterium rectale group, Anaerotruncus, Ruminiclostridium6, and Lachnospiraceae UCG001 offered protection against LS-BL, while Lachnospiraceae UCG008 was linked to an increased LS-BL risk. The Eubacterium brachy group, Odoribacter, Butyricimonas, Subdoligranulum, and Clostridium sensu stricto1 were protective against HFNS-BL; Ruminococcaceae UCG005 was associated with an increased HFNS-BL risk.ConclusionCompared to malignant tumors, research on lipomas has been relatively limited. This study, through MR analysis, provided new evidence of a causal relationship between specific GM and the development of lipomas. Certain gut bacterial species may act as protective or harmful factors in lipoma formation, offering new avenues for future treatment strategies. However, additional research is required to unravel the complexity of how GM influences the pathogenesis of lipomas.

Genetically Predicted Immune Cell-Mediated Effect of Lipid Metabolism on Allergic Diseases: A Two-Step, Mediation Mendelian Randomization Study.

An increasing number of studies have demonstrated that dynamic changes in lipid species can affect allergic diseases; however, the causal relationship and mediating role of immune cells remain unclear. We conducted a bidirectional two-sample mendelian randomization (MR) analysis using genome-wide association study (GWAS) data on 179 lipid species (n = 7,174) and three types of allergic diseases including allergic rhinitis (AR) (n = 370,158), allergic asthma (n = 219,753), and allergic conjunctivitis (n = 377,277). The principal model used was the inverse variance-weighted approach, and a series of sensitivity analyses were conducted to ensure the robustness of the results. We used a two-step MR approach to assess whether the causal effect was mediated by immune cells (n = 3,757). Sterol ester and sphingomyelin played pathogenic roles in allergic asthma, AR, and allergic conjunctivitis; however, the effective subtypes differed. Among them, CD45RA- CD4+ mature T cells and CCR2 on CD14+ CD16+ monocytes affected the promoting impact of sterol ester's metabolism on allergic asthma and AR with different mediating proportions, while the role of sphingomyelin may not involve the immune cells. Moreover, we observed that HLA-DR on CD33- HLA DR+ myeloid cells, CD11b on CD66b++ myeloid cells, and IgD+ CD38- B cells played the most mediating effect of phosphatidylethanolamine (O-18:2_20:4) in allergic asthma, phosphatidylinositol (16:0_18:1) in AR, and phosphatidylethanolamine (18:0_18:2) in allergic conjunctivitis. This MR study provides evidence for specific lipid species associated with the risk of allergic diseases, especially sterol esters, and identifies the immune cells that mediate this causal relationship.

DNA methylation biomarkers and myopia: a multi-omics study integrating GWAS, mQTL and eQTL data.

This study aimed to identify DNA methylation biomarkers associated with myopia using summary-data-based Mendelian randomization (SMR). A systematic search of the PubMed, Web of Science, Cochrane Library, and Embase databases was conducted up to March 27, 2024. SMR analyses were performed to integrate genome-wide association study (GWAS) with methylation quantitative trait loci (mQTL) and expression quantitative trait loci (eQTL) studies. The heterogeneity in the dependent instrument (HEIDI) test was utilized to distinguish pleiotropic associations from linkage disequilibrium. The systematic review identified 26 DNA methylation biomarkers in five studies, with no overlap observed among those identified by different studies. After integrating GWAS with multi-omics data of mQTL and eQTL, six genes were significantly associated with myopia: PRMT6 (cg00944433 and cg15468180), SH3YL1 (cg03299269, cg11361895, and cg13354988), ZKSCAN4 (cg01192291), GATS (cg17830204), NPAT (cg04826772), and UBE2I (cg03545757 and cg08025960). We identified six methylation biomarkers associated with the risk of myopia that may be helpful to elucidate the etiology mechanisms of myopia. Further experimental validation studies are required to corroborate these findings.

Enhancing disease risk gene discovery by integrating transcription factor-linked trans-variants into transcriptome-wide association analyses.

Transcriptome-wide association studies (TWAS) have been successful in identifying disease susceptibility genes by integrating cis-variants predicted gene expression with genome-wide association studies (GWAS) data. However, trans-variants for predicting gene expression remain largely unexplored. Here, we introduce transTF-TWAS, which incorporates transcription factor (TF)-linked trans-variants to enhance model building for TF downstream target genes. Using data from the Genotype-Tissue Expression project, we predict gene expression and alternative splicing and applied these prediction models to large GWAS datasets for breast, prostate, lung cancers and other diseases. We demonstrate that transTF-TWAS outperforms other existing TWAS approaches in both constructing gene expression prediction models and identifying disease-associated genes, as shown by simulations and real data analysis. Our transTF-TWAS approach significantly contributes to the discovery of disease risk genes. Findings from this study shed new light on several genetically driven key TF regulators and their associated TF-gene regulatory networks underlying disease susceptibility.

Association between immune cells and urticaria: a bidirectional Mendelian randomization study

Urticaria is characterized by transient itchy symptoms on the skin, usually accompanied by swelling, which is caused by mast cell activation leading to increased vascular permeability and dilation of the dermis. Urticaria involves recurrent activation of mast cells, T cells, eosinophils, and other immune cells around lesioned venules, with complex regulatory systems affecting mast cell functions, potentially contributing to urticaria pathogenesis. The direct causal relationship between immune cells and urticaria is currently unclear. To address this, our study utilized a bidirectional Mendelian randomization analysis, employing instrumental variables (IVs) associated with immune cells and urticaria, to investigate this causal relationship. First, by utilizing Genome-wide Association Study (GWAS) data, we identified 31 immunophenotypes associated with urticaria risk, with 18 increasing and 13 decreasing the risk. Through rigorous criteria, we identified 4 immunophenotypes that have a strong causal relationship with urticaria. Notably, HLA DR+ CD4+AC, CD45 on CD8br, and HLA DR on plasmacytoid dendritic cells were associated with an increased risk, while CD8dim NKT %lymphocyte was identified as a protective factor. Sensitivity analyses, including the MR-Egger intercept test, scatter plots, funnel plots, and leave-one-out analysis, supported the robustness of the findings. Reverse MR analysis suggested an inverse causal effect of urticaria on CD8dim NKT %lymphocyte, reinforcing the potential bidirectional nature of the relationship between urticaria and immune cell phenotypes. Our research substantiates the bidirectional causal relationship between immune cells and urticaria, thus benefiting for urticaria-targeted therapy development.

Developing and validating a comprehensive polygenic risk score to enhance keratoconus risk prediction.

This study aimed to develop and validate a comprehensive polygenic risk score (PRS) for keratoconus, enhancing the predictive accuracy for identifying individuals at increased risk, which is crucial for preventing keratoconus-associated visual impairment such as post-Laser-assisted in situ keratomileusis (LASIK) ectasia. We applied a multi-trait analysis approach (MTAG) to genome-wide association study data on keratoconus and quantitative keratoconus-related traits and used this to construct PRS models for keratoconus risk using several PRS methodologies. We evaluated the predictive performance of the PRSs in two biobanks: Estonian Biobank (EstBB; 375 keratoconus cases and 17 902 controls) and UK Biobank (UKB: 34 keratoconus cases and 1000 controls). Scores were compared using the area under the curve (AUC) and odds ratios (ORs) for various PRS models. The PRS models demonstrated significant predictive capabilities in EstBB, with the SBayesRC model achieving the highest OR of 2.28 per standard deviation increase in PRS, with a model containing age, sex and PRS showing good predictive accuracy (AUC = 0.72). In UKB, we found that adding the best-performing PRS to a model containing corneal measurements increased the AUC from 0.84 to 0.88 (P = 0.012 for difference), with an OR of 4.26 per standard deviation increase in the PRS. These models showed improved predictive capability compared to previous keratoconus PRS. The PRS models enhanced prediction of keratoconus risk, even with corneal measurements, showing potential for clinical use to identify individuals at high risk of keratoconus, and potentially help reduce the risk of post-LASIK ectasia.

Genetically Predicted Body Composition and Risk of Surgical Site Infection: A Mendelian Randomization Study.

Objective: This study employed uni-variable and multi-variable Mendelian randomization (MVMR) analyses, utilizing publicly available genome-wide association study (GWAS) data, to assess the causal relationship between body composition measures such as body mass index (BMI), waist circumference (WC), and the occurrence of surgical site infection (SSI). Patients and Methods: GWAS summary statistical data were obtained for BMI, WC, and SSI from the MRC Integrated Epidemiology Unit (MRC-IEU) database, inverse variance weighted (IVW) method was used as the main analysis, and supplement sensitivity analysis (including heterogeneity test, pleiotropy analysis, leave-one-out analysis, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO)) was used to check the robustness of the results. Results: The MR analysis showed that the increase in BMI and WC predicted by genes had a substantial causal effect on the incidence of SSI (IVW: odds ratio [OR] = 1.003, 95% confidence interval [CI] = 1.002-1.004, p < 0.001; IVW: OR = 1.003, 95% CI = 1.002-1.005, p < 0.001), respectively, and the MVMR analysis showed that after jointly incorporating smoking and alcohol parameters, the impact of BMI and WC on SSI remained substantial (OR = 1.003, 95% CI = 1.002-1.004, p < 0.001; OR = 1.004, 95% CI = 1.002-1.005, p < 0.001). Conclusion: We further support the causal relationship between increased body composition including BMI and WC and the occurrence of SSI, highlighting the importance of SSI prevention in patients with obesity. Further research is required to mitigate the occurrence of surgical incisions in patients with obesity in the future.

Plasma Glutaminyl-Peptide Cyclotransferase Mediates Glucosamine-Metabolism-Driven Protection Against Hypertension: A Mendelian Randomization Study

Hypertension is one of the major risk factors for morbidity and mortality worldwide. In this study, Mendelian randomization was utilized to investigate how dietary supplement intake can impact hypertension based on circulating plasma metabolite genome-wide association study (GWAS) datasets, protein quantitative trait loci (pQTLs) of plasma proteins, and multiple public summary-level GWAS data. Pathway enrichment analysis combined with the results of inverse variance weighted Mendelian randomization revealed that a lower risk of hypertension was associated with the dietary intake of glucosamine, an anti-inflammatory supplement: odds ratio (OR) (95% CI): 0.888 (0.824–0.958). Additionally, glucosamine 6-phosphate N-acetyltransferase was identified as a protective factor against hypertension, OR (95% CI): 0.995 (0.992–0.998), shedding light on the potential protective mechanism of glucosamine. Mediation Mendelian randomization indicated that the protective effect of glucosamine metabolism was mediated by glutaminyl-peptide cyclotransferase, with a mediation proportion of 12.1% (5.9–18.2%), p &lt; 0.05. This study offers new insights into preventive strategies for individuals with hypertension risk.

Genetic variants for Alzheimer's disease and comorbid conditions.

Alzheimer's disease and related dementias (ADRD) frequently co-occur with comorbidities such as diabetes and cardiovascular diseases in elderly populations. Utilize a life-course approach to identify genetic variants that are associated with the co-occurrence of ADRD and another comorbid condition. Research data from African American participants of the Indianapolis-Ibadan Dementia Project (IIDP) linked with electronic medical record (EMR) data and genome-wide association study (GWAS) data were utilized. The age of onset for ADRD was obtained from longitudinal follow-up of the IIDP study. Age of onset for comorbid conditions was obtained from EMR. The analysis included 1177 African Americans, among whom 174 were diagnosed with ADRD. A semi-parametric marginal bivariate survival model was used to examine the influence of single nucleotide polymorphisms (SNPs) on dual time-to-event outcomes while adjusting for sex, years of education, and the first principal component of GWAS data. Targeted analysis of 20 SNPs that were reported to be associated with ADRD revealed that six were significantly associated with dual-disease outcomes, specifically congestive heart failure and cancer. In addition, eight novel SNPs were identified for associations with both ADRD and a comorbid condition. Using a bivariate survival model approach, we identified genetic variants associated not only with ADRD, but also with comorbid conditions. Our utilization of dual-disease models represents a novel analytic strategy for uncovering shared genetic variants for multiple disease phenotypes.

Assessing the causal role of the structural connectome in temporomandibular disorders: A Mendelian randomization study

ABSTRACT Objective We examined the relationships between the structural connectome and temporomandibular disorders (TMDs). Methods Bidirectional Mendelian randomization analyses were conducted using Genome-wide association studies data on the structural connectome and TMDs. Results Positive associations with TMD risk were found for white matter structural connectivity from the left hemisphere limbic network to putamen, left hemisphere salience_ventral attention network to caudate, right hemisphere visual network to thalamus, and right hemisphere salience_ventral attention network to right hemisphere control network, while negative associations were observed for connectivity from the left hemisphere control and somatomotor networks to pallidum, left hemisphere somatomotor network to right hemisphere dorsal attention network, and right hemisphere somatomotor network to hippocampus (p< 0.05). In TMD patients, connectivity from the Left-hemisphere visual network to putamen was reduced, whereas connectivity from the Left-hemisphere limbic network to left-hemisphere control network was increased (p< 0.05). Conclusion Our findings provide insights into the TMD pathogenesis.

The protective role of vitamin d in nasopharyngeal carcinoma: insights from Mendelian randomization and meta-analysis

BackgroundIn recent years, the anti-tumor effects of vitamin D have garnered increasing attention. However, previous epidemiological studies on the relationship between vitamin D and nasopharyngeal carcinoma (NPC) have yielded inconsistent results. This study aims to further explore whether vitamin D helps reduce the risk of NPC through Mendelian randomization (MR) and meta-analysis.MethodsBased on the core assumption of MR study, instrumental variables (IVs) for vitamin D, serving as genetic proxies, were obtained from summary data of large genome-wide association study (GWAS). Inverse-variance weighted (IVW) was utilized as the primary MR analytical method to explore the causal relationship between vitamin D and NPC. Sensitivity analyses included heterogeneity testing and horizontal pleiotropy testing. To further validate the robustness of the result, meta-analysis was employed to obtain pooled effects from databases of different sources.ResultsIn the discovery cohort, the IVW result suggest that vitamin D is a potential protective factor against NPC (odds ratio (OR) = 0.35, 95% confidence interval (CI): 0.13–0.89, P = 0.028). The finding was further corroborated by two independent replication cohorts [OR = 0.32, 95% CI: 0.13–0.80, P = 0.018 (ukb-d-30890_irnt); OR = 0.34, 95% CI: 0.13–0.90, P = 0.029(ebi-a-GCST90025967)]. Subsequent meta-analysis indicated that vitamin D markedly reduces the risk of NPC (OR = 0.34, 95% CI: 0.19–0.58, P < 0.001). Multiple sensitivity analyses, including heterogeneity analysis and horizontal pleiotropy tests, did not reveal any significant findings (all P > 0.05).ConclusionThis study provides robust evidence that vitamin D significantly reduces the risk of NPC. Through MR and meta-analysis, we have demonstrated a protective role of vitamin D in NPC development. These findings suggest that maintaining adequate vitamin D levels may be a potential strategy for reducing NPC. Further research is warranted to confirm these results and explore the underlying mechanisms involved.

Associations of schizophrenia with arrhythmic disorders and electrocardiogram traits: genetic exploration of population samples.

An important contributor to the decreased life expectancy of individuals with schizophrenia is sudden cardiac death. Arrhythmic disorders may play an important role herein, but the nature of the relationship between schizophrenia and arrhythmia is unclear. To assess shared genetic liability and potential causal effects between schizophrenia and arrhythmic disorders and electrocardiogram (ECG) traits. We leveraged summary-level data of large-scale genome-wide association studies of schizophrenia (53 386 cases, 77 258 controls), arrhythmic disorders (atrial fibrillation, 55 114 cases, 482 295 controls; Brugada syndrome, 2820 cases, 10 001 controls) and ECG traits (heart rate (variability), PR interval, QT interval, JT interval and QRS duration, n = 46 952-293 051). We examined shared genetic liability by assessing global and local genetic correlations and conducting functional annotation. Bidirectional causal relations between schizophrenia and arrhythmic disorders and ECG traits were explored using Mendelian randomisation. There was no evidence for global genetic correlation, except between schizophrenia and Brugada syndrome (rg = 0.14, 95% CIs = 0.06-0.22, P = 4.0E-04). In contrast, strong positive and negative local correlations between schizophrenia and all cardiac traits were found across the genome. In the most strongly associated regions, genes related to immune and viral response mechanisms were overrepresented. Mendelian randomisation indicated that liability to schizophrenia causally increases Brugada syndrome risk (beta = 0.14, CIs = 0.03-0.25, P = 0.009) and heart rate during activity (beta = 0.25, CIs = 0.05-0.45, P = 0.015). Despite little evidence for global genetic correlation, specific genomic regions and biological pathways emerged that are important for both schizophrenia and arrhythmia. The putative causal effect of liability to schizophrenia on Brugada syndrome warrants increased cardiac monitoring and early medical intervention in people with schizophrenia.

Identifying the impact of ARHGAP and MAP gene families on autism spectrum disorders.

The rising incidence of Autism Spectrum Disorder (ASD) has become a major concern, affecting children's psychological well-being and placing a significant strain on healthcare systems. Despite its impact, the etiological mechanisms underpinning ASD remain elusive. This study leveraged dorsolateral prefrontal cortex gene data from 452 individuals of European descent, sourced from the CommonMindConsortium, and examined ASD-related gene expression data from the Gene Expression Omnibus (GEO) database (GSE18123), along with Genome-Wide Association Studies (GWAS) data from the Lundbeck Foundation Integrated Psychiatric Research and Psychiatric Genomics Consortium. Expression quantitative trait loci data were sourced from the GTExv8 database. We employed Transcriptome-Wide Association Studies (TWAS) and Weighted Gene Co-expression Network Analysis (WGCNA) to pinpoint genes within ASD-associated susceptibility gene families (ARHGAP, MAP). Four genes-ARHGAP27, MAPT, ARHGAP19, and MAP1B-were scrutinized, and their biological implications were elucidated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Protein-Protein Interaction (PPI) analysis and conditional analysis within the TWAS framework helped identify pivotal genes (ARHGAP27, MAPT). A subsequent verification phase involving Mendelian Randomization (MR) evaluated the potential causal links between the identified genes and ASD. The findings revealed no causal association between ARHGAP19, MAP1B, and ASD. In contrast, significant causal relationships were established for ARHGAP27 and MAPT, suggesting that ARHGAP27 may elevate ASD risk as a susceptibility gene, whereas MAPT appears to reduce the risk as a protective gene.

Effect of muscle strength on deep vein thrombosis: A Mendelian randomization study.

Deep vein thrombosis (DVT) is a serious condition characterized by blood clots in deep veins, posing a significant public health burden. Muscle strength has been implicated as a potential risk factor for DVT due to its influence on venous return. This study aims to investigate the causal association between muscle strength and DVT using a Mendelian randomization (MR) approach, leveraging genetic variants as instrumental variables (IVs). We conducted a 2-sample MR analysis using genome-wide association study (GWAS) data for hand-grip strength and DVT. IVs were selected based on their significant associations with muscle strength and DVT, as well as their linkage disequilibrium patterns. We employed statistical methods including inverse-variance weighting (IVW), MR-Egger, and weighted median to address pleiotropy bias. Sensitivity analyses were conducted to evaluate the robustness of the results. A total of 21 and 14 independent IVs were identified for hand grip strength (EWGSOP) and hand grip strength (FNIH), respectively. IVW analysis revealed a consistent causal and negative association between both definitions of hand grip strength and DVT (EWGSOP: OR = 0.702, 95% CI: 0.511-0.964, P = .029; FNIH: OR = 0.715, 95% CI: 0.570-0.898, P = .004). No directional pleiotropy was detected in MR-Egger and MR-PRESSO analyses for either definition (EWGSOP: MR-Egger Intercept P = .516; MR-PRESSO global test P = .162; FNIH: MR-Egger Intercept P = .569; MR-PRESSO global test P = .371).Sensitivity analyses demonstrated the stability of the causal effect estimates, with little influence from individual IVs. The MR analysis provided evidence of a causal association between muscle strength and DVT risk, suggesting that increasing muscle strength may have a protective effect. These findings have implications for preventive strategies and the promotion of resistance exercises and muscle-strengthening activities. Further research and validation of these results could inform clinical guidelines and interventions for DVT prevention.

Causal relationship between gout and liver cancer: A Mendelian randomization and transcriptome analysis.

Gout is an inflammatory arthritis resulting from urate crystal deposition, now recognized as part of metabolic syndrome. Hyperuricemia, a hallmark of gout, is associated with various health complications, including liver cancer. Observational studies indicate a link between gout and increased cancer incidence. However, the causal relationship between gout and hepatocellular carcinoma remains uncertain. This study utilizes Mendelian randomization (MR) to explore this connection, minimizing confounding factors commonly present in observational studies. Genome-wide association study data for gout and liver cancer were sourced from the UK Biobank. We selected single nucleotide polymorphisms that are strongly associated with gout and liver cancer as instrumental variables for the analysis. We conducted 2-sample MR analysis using multiple MR methods (MR-Egger, weighted median, inverse variance weighting, and weighted mode) to evaluate causality. Co-localization and transcriptomic analyses were employed to identify target genes and assess their expression in hepatocellular carcinoma tissues. The 2-sample MR analysis indicated a significant causal relationship between gout and heightened liver cancer risk (P_IVW = .014). Co-localization analysis identified phosphatidylethanolamine N-methyltransferase (PEMT) as a crucial gene associated with gout (pH4 = 0.990). Transcriptomic data showed that PEMT expression was significantly higher in normal liver tissues compared to malignant samples (P < .001), and higher PEMT levels correlated with improved survival outcomes (P = .045). Immunohistochemical analysis revealed lower PEMT expression in hepatocellular carcinoma from patients with concurrent gout compared to those without (P < .05). The results indicate that gout increases the risk of hepatocellular carcinoma, with PEMT potentially playing a key role. Although this study focused on European populations, indicating a need for further research in diverse groups, the results emphasize the potential for liver cancer screening in newly diagnosed gout patients. Understanding the relationship between these conditions may inform future clinical practices and cancer prevention strategies.

Causal association between remnant cholesterol level and risk of cardiovascular diseases: a bidirectional two sample mendelian randomization study

Serum lipids have been associated with an increased risk of various cardiovascular diseases (CVDs) in several observational studies, but the causal inference between the remnant cholesterol (RC) levels and several CVDs risk has not been established. The purpose of this study was to investigate whether there is a causal relationship between RC levels and risk of developing CVDs by a bidirectional two-sample Mendelian randomization (TSMR) analysis. One TSMR analysis was performed using the publicly released large-scale genome-wide association study (GWAS) data. Inverse variance weighted (IVW) method was chosen as the main analysis method, and MR-Egger, weighted median, simple mode, and weighted mode were used as supplementary methods. We conducted a series of sensitivity analyses to assess the robustness of the main results, including the Cochran’s Q test, MR-Egger intercept test, leave-one-out sensitivity analysis, and funnel plot. The main IVW method revealed that genetically predicted serum level of RC is significantly associated with an increased risk of developing ischemic heart disease (OR = 1.409, 95%CI = 1.284–1.546, P value = 4.753E-13), unstable angina pectoris (OR = 1.621, 95%CI = 1.398–1.880, P value = 1.672E-10), myocardial infarction (OR = 1.526, 95%CI = 1.337–1.741, P value = 3.771E-10), cardiac arrest (OR = 1.595, 95%CI = 1.322–1.924, P value = 1.076E-06), heart failure (OR = 1.086, 95%CI = 1.009–1.169, P value = 0.028), hypertension (OR = 1.089, 95%CI = 1.043–1.136, P value = 9.458E-05), major coronary heart disease (CHD) events (OR = 1.515, 95%CI = 1.376–1.669, P value = 3.217E-17), coronary atherosclerosis (OR = 1.388, 95%CI = 1.231–1.564, P value = 7.739E-08), cardiac arrhythmias (OR = 1.067, 95%CI = 1.008–1.130, P value = 0.025), and atrial fibrillation and flutter (OR = 1.122, 95%CI = 1.039–1.211, P value = 0.003). Additionally, the causal associations between the RC levels and these CVDs remained significant after correcting for the false discovery rate (all P value < 0.05). However, this study did not find any significant association of RC with cardiomyopathy and pericarditis (both P value > 0.05). Heterogeneity existed in the IVs of RC and ischemic heart disease, unstable angina pectoris, myocardial infarction, heart failure, hypertension, major CHD events, cardiomyopathy, coronary atherosclerosis, cardiac arrhythmias and atrial fibrillation and flutter using the Cochran’s Q test (all P value < 0.05). Moreover, there was no horizontal pleiotropy in this study (all P value > 0.05). The leave-one-out sensitivity analyses showed that the causal effects between RC level and CVDs (except for heart failure, cardiomyopathy, pericarditis and cardiac arrhythmias) are not driven by a single SNP. The funnel plots showed that there is no obvious potential bias in our study. In the replication analysis, the genetically predicted RC levels were positively associated with a 43.12% higher risk of coronary artery disease. This present study supported the causal link between RC and heightened the risk of CVDs, indicating that RC-lowering treatment might be effective in preventing CVDs.

Investigating the correlation of hip circumference to cardiovascular disease and type-2 diabetes using Mendelian randomization.

This study aimed to assess the correlation between hip circumference (HC) and the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus using Mendelian randomization (MR) to overcome observational study limitations. MR analysis utilized genetic variation from the MR Base in a two-sample analysis. Three methods were employed: MR-Egger regression, weighted median estimator, and inverse variance weighting (IVW). Data was acquired from MR Base, a platform summarizing genome-wide association study (GWAS) data for MR research. Publicly available summary statistics datasets from GWAS meta-analyses were used, with HC and HC adjusted for body mass index (BMI) as exposures. Data for CVD and type 2 diabetes mellitus were obtained as outcomes. Results indicated a positive causal relationship between HC and CVD (IVW: P = 1.84e-07, OR: 1.37, 95% CI: 1.22-1.54) as well as type 2 diabetes mellitus (IVW: P = 0.04, OR: 1.62, 95% CI: 1.02-2.56), independent of BMI. However, HC after BMI adjustment showed no significant causal relationship with CVD (IVW: P = 0.05, OR: 1.09, 95% CI: 1.00-1.19) and exhibited a negative association with type 2 diabetes mellitus (IVW: P = 0.00, OR: 0.76, 95% CI: 0.66-0.88), suggesting a protective effect against type 2 diabetes mellitus. After adjusting for BMI, adipose tissue concentrated in the hip region showed a protective effect against type 2 diabetes mellitus but not against CVD. These findings offer insights into diabetes prevention and treatment strategies, and may inform plastic surgery procedures. Further research is needed to validate these findings and explore underlying mechanisms.

Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease.

Aortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CAD. To identify genetic risk loci and cardiovascular risk factors with AS-specific associations. This was a genomewide association study (GWAS) of AS adjusted for CAD with participants from the European Consortium for the Genetics of Aortic Stenosis (EGAS) (recruited 2000-2020), UK Biobank (recruited 2006-2010), Estonian Biobank (recruited 1997-2019), and FinnGen (recruited 1964-2019). EGAS participants were collected from 7 sites across Europe. All participants were of European ancestry, and information on comorbid CAD was available for all participants. Follow-up analyses with GWAS data on cardiovascular traits and tissue transcriptome data were also performed. Data were analyzed from October 2022 to July 2023. Genetic variants. Cardiovascular traits associated with AS adjusted for CAD. Replication was performed in 2 independent AS GWAS cohorts. A total of 18 792 participants with AS and 434 249 control participants were included in this GWAS adjusted for CAD. The analysis found 17 AS risk loci, including 5 loci with novel and independently replicated associations (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1). Of all 17 associated loci, 11 were associated with risk specifically for AS and were not associated with CAD (ALPL, PALMD, PRRX1, RNF144A, MECOM, AFAP1, PDGFRA, IL6, TPCN2, NLRP6, HAO1). Concordantly, this study revealed only a moderate genetic correlation of 0.15 (SE, 0.05) between AS and CAD (P = 1.60 × 10-3). Mendelian randomization revealed that serum phosphate was an AS-specific risk factor that was absent in CAD (AS: odds ratio [OR], 1.20; 95% CI, 1.11-1.31; P = 1.27 × 10-5; CAD: OR, 0.97; 95% CI 0.94-1.00; P = .04). Mendelian randomization also found that blood pressure, body mass index, and cholesterol metabolism had substantially lesser associations with AS compared with CAD. Pathway and transcriptome enrichment analyses revealed biological processes and tissues relevant for AS development. This GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. These findings provide new targets for future AS research.