Genome-wide Association Studies Catalog Research Articles

Association of triglyceride glucose index with stroke: from two large cohort studies and mendelian randomization analysis.

The triglyceride glucose index (TyG) is associated with cardiovascular diseases; however, its association with stroke remains unclear. This study aimed to elucidate this relationship by examining two extensive cohort studies using two-sample Mendelian randomization (MR). Using data from the 1999-2018 National Health and Nutrition Examination Survey (NHANES) and the Medical Information Mart for Intensive Care (MIMIC)-IV, the correlation between TyG (continuous and quartile) and stroke was examined using multivariate Cox regression models and sensitivity analyses. Two-sample MR was employed to establish causality between TyG and stroke using the inverse variance weighting method. Genome-wide association study catalog queries were performed for single nucleotide polymorphism-mapped genes, and the STRING platform used to assess protein interactions. Functional annotation and enrichment analyses were also conducted. From the NHANES and MIMIC-IV cohorts, we included 740 and 589 participants with stroke, respectively. After adjusting for covariates, TyG was linearly associated with the risk of stroke death (NHANES: hazard ratio [HR] 0.64, 95% confidence interval [CI]: 0.41-0.99, P=0.047; Q3 vs. Q1, HR 0.62, 95%CI: 0.40-0.96, P=0.033; MIMIC-IV: HR 0.46, 95%CI: 0.27-0.80, P=0.006; Q3 vs. Q1, HR 0.32, 95%CI: 0.12-0.86; Q4 vs. Q1, HR 0.30, 95%CI: 0.10-0.89, P=0.030, P for trend=0.017). Two-sample MR analysis showed genetic prediction supported a causal association between a higher TyG and a reduced risk of stroke (odds ratio 0.711, 95%CI: 0.641-0.788, P=7.64e-11). TyG was causally associated with a reduced risk of stroke. TyG is a critical factor for stroke risk management.

Circulating metabolites and coronary heart disease: a bidirectional Mendelian randomization.

Numerous studies have established a link between coronary heart disease and metabolic disorders. Yet, causal evidence connecting metabolites and Coronary Heart Disease (CHD) remains scarce. To address this, we performed a bidirectional Mendelian Randomization (MR) analysis investigating the causal relationship between blood metabolites and CHD. Data were extracted from published genome-wide association studies (GWASs) on metabolite levels, focusing on 1,400 metabolite summary data as exposure measures. Primary analyses utilized the GWAS catalog database GCST90199698 (60,801 cases and 123,504 controls) and the FinnGen cohort (43,518 cases and 333,759 controls). The primary method used for causality analysis was random inverse variance weighting (IVW). Supplementary analyses included MR-Egger, weighted mode, and weighted median methods. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Reverse MR analysis was employed to evaluate the direct impact of metabolites on coronary heart disease. Additionally, replication and meta-analysis were performed. We further conducted the Steiger test and colocalization analysis to reflect the causality deeply. This study identified eight metabolites associated with lipids, amino acids and metabolite ratios that may influence CHD risk. Findings include: 1-oleoyl-2-arachidonoyl-GPE (18:1/20:4) levels: OR = 1.08; 95% CI 1.04-1.12; P = 8.21E-06; 1-palmitoyl-2-arachidonoyl-GPE (16:0/20:4) levels: OR = 1.07; 95% CI 1.04-1.11; P = 9.01E-05; Linoleoyl-arachidonoyl-glycerol (18:2/20:4): OR = 1.08; 95% CI 1.04-1.22; P = 0.0001; Glycocholenate sulfate: OR = 0.93; 95% CI 0.90-0.97; P = 0.0002; 1-stearoyl-2-arachidonoyl-GPE (OR = 1.07; 95% CI 1.03-1.11; P = 0.0002); N-acetylasparagine (OR = 1.04; 95% CI 1.02-1.07; P = 0.0030); Octadecenedioate (C18:1-DC) (OR = 0.93; 95% CI 0.90-0.97; P = 0.0004); Phosphate to linoleoyl-arachidonoyl-glycerol (18:2-20:4) (1) ratio (OR = 0.92; 95% CI 0.88-0.97; P = 0.0005). The integration of genomics and metabolomics offers novel insights into the pathogenesis of CHD and holds significant importance for the screening and prevention of CHD.

Causal effects and metabolites mediators between immune cell and risk of breast cancer: a Mendelian randomization study.

Introduction: The incidence and mortality of female breast cancer remain high, and the immune microenvironment of breast cancer has undergone significant alterations. However, the impact of blood immune cell levels on the risk of breast cancer is not fully understood. Therefor this study aims to investigate the causal relationship between blood immune cell levels and the risk of breast cancer. Methods: A Mendelian randomization (MR) analysis was employed to assess the causal relationship between immune cells and the risk of breast cancer, as along with their potential mediating factors. Genetic statistics of metabolites breast cancer and immune cells were obtained from the GWAS Catalog, while the genome-wide association study (GWAS) statistics of breast cancer were extracted from the UK biobank. Two-sample MR analysis were performed using inverse-variance weighted (IVW) to ascertain the causal association between immune cells and the risk of breast cancer. Furthermore, 1,400 metabolites were analyzed for their mediating role between immune cells and the risk of breast cancer. Results: MR analysis through IVW method revealed that genetically predicted CD24+ CD27+ B cells were associated with a decreased risk of breast cancer (OR = 0.9978, 95% CI: 0.996-0.999, p = 0.001), while IgD- CD38+ B cells were linked to an increased risk of breast cancer (OR = 1.002, 95% CI: 1.001-1.004, p = 0.005). Additional CD14+ CD16+ monocytes were associated with an increased risk of breast cancer (OR = 1.000, 95% CI: 1.000-1.001, p = 0.005). Mediation analysis revealed a positive causal relationship between IgD- CD38+ B cells and Glycerate levels, with the latter also exhibiting a positive causal relationship with the risk of breast cancer (p < 0.05). Conversely, IgD- CD38+ B cells displayed a negative causal relationship with Succinoyltaurine levels, and the latter also demonstrated a negative causal relationship with the risk of breast cancer (p < 0.05). Conclusion: This MR study provides novel genetic evidence supporting a causal relationship between IgD- CD38+ B cells and the risk of BC. Moreover, it is identified that IgD- CD38+ B cells contribute to an increased risk of BC through both positive and negative mediation effects involving Glycerate and Succinoyltaurine.

Genetically predicted fatty liver disease and risk of psychiatric disorders: A mendelian randomization study.

Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ArLD) constitute the primary forms of chronic liver disease, and their incidence is progressively increasing with changes in lifestyle habits. Earlier studies have documented a correlation between the occurrence and development of prevalent mental disorders and fatty liver. To investigate the correlation between fatty liver and mental disorders, thus necessitating the implementation of a mendelian randomization (MR) study to elucidate this association. Data on NAFLD and ArLD were retrieved from the genome-wide association studies catalog, while information on mental disorders, including Alzheimer's disease, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, multiple personality disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and schizophrenia was acquired from the psychiatric genomics consortium. A two-sample MR method was applied to investigate mediators in significant associations. After excluding weak instrumental variables, a causal relationship was identified between fatty liver disease and the occurrence and development of some psychiatric disorders. Specifically, the findings indicated that ArLD was associated with a significantly elevated risk of developing ADHD (OR: 5.81, 95%CI: 5.59-6.03, P < 0.01), bipolar disorder (OR: 5.73, 95%CI: 5.42-6.05, P = 0.03), OCD (OR: 6.42, 95%CI: 5.60-7.36, P < 0.01), and PTSD (OR: 5.66, 95%CI: 5.33-6.01, P < 0.01). Meanwhile, NAFLD significantly increased the risk of developing bipolar disorder (OR: 55.08, 95%CI: 3.59-845.51, P < 0.01), OCD (OR: 61.50, 95%CI: 6.69-565.45, P < 0.01), and PTSD (OR: 52.09, 95%CI: 4.24-639.32, P < 0.01). Associations were found between genetic predisposition to fatty liver disease and an increased risk of a broad range of psychiatric disorders, namely bipolar disorder, OCD, and PTSD, highlighting the significance of preventive measures against psychiatric disorders in patients with fatty liver disease.

RNA Polymerase Subunits and Ribosomal Proteins: An Overview and Their Genetic Impact on Complex Human Traits.

Accurate gene expression is fundamental for sustaining life, enabling adaptive responses to routine tasks and management of urgent cellular environments. RNA polymerases (RNAP I, RNAP II, and RNAP III) and ribosomal proteins (RPs) play pivotal roles in the precise synthesis of proteins from DNA sequences. In this review, we briefly examined the structure and function of their constituent proteins and explored to characterize these proteins and the genes encoding them, particularly in terms of their expression quantitative trait loci (eQTL) associated with complex human traits. We gathered a comprehensive set of 4007 genome-wide association study (GWAS) signal-eQTL pairs, aligning GWAS Catalog signals with eQTLs across various tissues for the genes involved. These pairs spanned 16 experimental factor ontology (EFO) parent terms defined in European Bioinformatics Institute (EBI). A substantial majority (83.4%) of the pairs were attributed to the genes encoding RPs, especially RPS26 (32.9%). This large proportion was consistent across all tissues (15.5~81.9%), underscoring its extensive impact on complex human traits. Notably, these proportions of EFO terms differed significantly (p < 0.0031) from those for RNAPs. Brain-specific pairs for POLR3H, a component of RNAP III, were implicated in neurological disorders. The largest number of pairs in RNAP I was found for POLR1H, encoding RPA12, a built-in transcription factor essential for high transcriptional efficiency of RNAP I. RNAP II-related pairs were less abundant, with unique structural organization featuring minimal subunits for flexible transcription of a diverse range of genes with customized dissociable subunits. For instance, RPB4 encoded by POLR2D, the RNAP II gene with the most pairs, forms its dissociable stalk module with RPB7. This study provides insightful genetic characteristics of RPs and RNAPs, with a priority emphasis on RPS26, POLR1H, POLR2D, and POLR3H, for future studies on the impact of individual genetic variation on complex human traits.

Genome-Wide Epistatic Network Analyses of Semantic Fluency in Older Adults.

Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683, p = 2.52 × 10-8; rs880179, p = 4.83 × 10-8) mapped to the CMYAS gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10-5 < p < 7.35 × 10-3), of which two were replicated (p < 3.10 × 10-3). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.

Application of two-sample Mendelian randomization method to assess the causal relationship between rheumatoid arthritis and osteoporotic fracture.

The association between rheumatoid arthritis (RA) and osteoporotic fracture has garnered considerable attention; however, the causal relationships between diseases remain uncertain. Therefore, this study employed Mendelian randomization (MR) analysis to investigate the causal effects of RA on osteoporotic fracture. The summary data for RA and osteoporotic fracture were extracted from the genome-wide association studies (GWAS) catalog and the Finn Biobank database. The database provides information about diseased and health control subjects. We searched the database for the following conditions: RA, osteoporosis (OP), and osteoporotic fractures. Entries were published by investigating centers, which had established definitions and diagnostic criteria. We downloaded and processed the data to obtain the single-nucleotide polymorphisms (SNPs) strongly associated with RA, OP, and osteoporotic fracture. RA genetic associations were obtained from the GWAS catalog, including 1961 cases and 454,387 controls. The osteoporosis of the GWAS catalog involved 991 cases and 455,357 controls, and the data of the Finn Biobank involved 8,017 cases and 391,037 controls. Genetic associations for osteoporotic fracture were taken from the Finn Biobank of 1822 cases and 311,210 controls. Independent SNPs that are significantly associated with meeting the criteria of p < 5 × 10-8, r2 < 0.001, and kb = 10,000 were selected for MR analysis. The inverse variance-weighted (IVW) method along with other MR methods was employed for analysis, while sensitivity analyses were conducted to assess reliability and stability. The results provided strong evidence that RA was causally and positively associated with osteoporosis from the GWAS catalog (OR = 1.16590; 95% CI: 1.04067-1.30619; p = 0.00811) and the Finn Biobank database (OR = 1.07314; 95% CI: 1.03455-1.11317; p = 0.00016). Moreover, a positive causal relationship was detected between RA and osteoporotic fracture (OR = 1.10132; 95% CI: 1.00506-1.20680; p = 0.03863). The results were robust according to sensitivity tests. This study showed positive causal relationships between RA and osteoporotic fracture. These results should be considered in further studies and public health measures on osteoporosis prevention strategies.

Exploring the casual association between gut microbiome, circulating inflammatory cytokines and chronic pancreatitis: A Mendelian randomization analysis.

It has been established that gut dysbiosis contributed to the pathogenesis of digestive disorders. We aimed to explore the causal relationships between intestinal microbiota, circulating inflammatory cytokines and chronic pancreatitis (CP). Summary statistics of genome-wide association studies (GWAS) of intestinal microbiome was retrieved from the MiBioGen study and the GWAS data of 91 circulating inflammatory cytokines and CP were obtained from the GWAS catalog. The 2-sample bidirectional Mendelian randomization (MR) analysis was performed between gut microbiota, circulating inflammatory cytokines and CP, in which the inverse variance weighted (IVW) method was regarded as the primary analysis approach. To prove the reliability of the causal estimations, multiple sensitivity analyses were utilized. IVW results revealed that genetically predicted 2 genera, including Sellimonas and Eubacteriumventriosumgroup, and plasm C-C motif chemokine 23 (CCL23) level were positively associated with CP risk, while genus Escherichia Shigella, Eubacteriumruminantiumgroup and Prevotella9, and plasma Caspase 8, Adenosine Deaminase (ADA), and SIR2-like protein 2 (SIRT2) level, demonstrated an ameliorative effect on CP. Leave-one-out analysis confirmed the robustness of the aforementioned causal effects and no significant horizontal pleiotropy or heterogeneity of the instrumental variables was detected. However, no association was found from the identified genera to the CP-related circulating inflammatory cytokines. Besides, the reverse MR analysis demonstrated no causal relationship from CP to the identified genera and circulating inflammatory cytokines. Taken together, our comprehensive analyses offer evidence in favor of the estimated causal connections from the 5 genus-level microbial taxa and 4 circulating inflammatory cytokines to CP risk, which may help to reveal the underlying pathogenesis of CP.

The causal relationship between COVID-19 and ten esophageal diseases: a study utilizing Mendelian randomization.

Clinical signs of dysphagia, pancreatic achalasia, and esophagitis have been reported in patients with COVID-19. However, the causal relationship between COVID-19 and esophageal diseases is not clear. Therefore, we utilized Mendelian randomization to explore the potential association between COVID-19 and esophageal diseases. The summary statistics for a Genome-wide association study (GWAS) were obtained from The COVID-19 Host Genetics Initiative, encompassing four types of COVID-19 as exposure: severe COVID-19, hospitalized COVID-19 versus ambulatory COVID-19, hospitalized COVID-19 versus uninfected, and confirmed COVID-19. Additionally, summary statistics for ten esophageal diseases as outcomes were sourced from the GWAS Catalog and FinnGen databases. Univariate Mendelian randomization (MR) analysis was utilized to thoroughly investigate and validate the potential causal association between COVID-19 and various esophageal conditions, including esophageal varices, Barrett's esophagus, esophagitis, esophageal obstruction, esophageal ulcer, esophageal perforation, gastroesophageal reflux, congenital esophageal malformations, benign esophageal tumors, and esophageal adenocarcinoma. An inverse variance-weighted (IVW) model was utilized for univariate Mendelian randomization (MR) analysis, which revealed that genetic liability in patients with confirmed COVID-19 was associated with esophageal obstruction (OR [95% CI]: 0.5275458 [0.2822400-0.9860563]; p-value = 0.0450699). Furthermore, a suggestive causal association was found between genetic liability and a reduced risk of benign esophageal tumors (OR [95% CI]: 0.2715453 [0.09368493-0.7870724]; p-value = 0.0163510), but with a suggestively increased risk of congenital esophageal malformations (OR [95% CI]: 6.959561 [1.1955828-40.51204]; p-value = 0.03086835). Additionally, genetic liability in hospitalized COVID-19 patients, compared to non-hospitalized COVID-19 patients, was suggestively associated with an increased risk of esophagitis (OR [95% CI]: 1.443859 [1.0890568-1.914252]; p-value = 0.01068201). The reliability of these causal findings is supported by Cochran's Q statistic and the MR-Egger intercept test. The results of this study suggest the existence of a causal relationship between COVID-19 and esophageal diseases, highlighting differing risk effects of COVID-19 on distinct esophageal conditions.

The impact of neurocognitive and psychiatric disorders on the risk of idiopathic normal pressure hydrocephalus: A bidirectional Mendelian randomization study.

Neurocognitive and psychiatric disorders have been proved that they can comorbid more often with idiopathic normal pressure hydrocephalus (iNPH) than general population. However, the potential causal association between these disorders and iNPH has not been assessed. Thus, our study aims to investigate the causal relationship between them based on a bidirectional Mendelian randomization (MR) analysis. Random effects of the inverse variance weighted (IVW) method were conducted to obtain the causal association among the neurocognitive disorders, psychiatric disorders, and iNPH. Genome-wide association studies (GWAS) of 12 neurocognitive and psychiatric disorders were downloaded via the OpenGWAS database, GWAS Catalog, and Psychiatric Genomics Consortium, whereas GWAS data of iNPH were obtained from the FinnGen consortium round 9 release, with 767 cases and 375,610 controls of European ancestry. We also conducted the sensitivity analysis in these significant causal inferences using weighted median model, Cochrane's Q test, MR-Egger regression, MR Pleiotropy Residual Sum and Outlier detect and the leave-one-out analysis. For most of the neurocognitive and psychiatric disorders, no causal association was established between them and iNPH. We have found that iNPH (odds ratio [OR]=1.030, 95% confidence interval [CI]: 1.011-1.048, p=.001) is associated with increased risk for schizophrenia, which failed in validation of sensitivity analysis. Notably, genetically predicted Parkinson's disease (PD) is associated with increased risk of iNPH (OR=1.256, 95% CI: 1.045-1.511, p=.015). Our study has revealed the potential causal effect in which PD associated with an increased risk of iNPH. Further study is warranted to investigate the association between PD and iNPH and the potential underlying mechanism.

Association of serum uric acid level with intracranial aneurysms: A Mendelian randomization study

ObjectiveNumerous studies have posited the involvement of serum uric acid (SUA) in the pathogenesis and progression of various cardiovascular diseases, particularly aortic aneurysms. However, the casual effect of SUA level on intracranial aneurysms (IAs) was rarely studied. Consequently, we aimed to explore the causal association between SUA and IAs using Mendelian randomization (MR) analysis. MethodsWe conducted a two-sample MR analysis with SUA as the exposure variable and IAs as the outcome variable. Genome-wide association study (GWAS) datasets for SUA were acquired from the Open GWAS catalog, including 389,404 European and 129,405 East Asian individuals. The dataset for IAs was sourced from a meta-analysis of GWASs comprising 317,636 individuals across different ancestral populations (European: 7495 cases and 71,934 controls; East Asian: 3259 cases and 234,948 controls). The MR analyses were performed according to populations (European and East Asian) and IAs status [unruptured IAs (uIAs) or aneurysmal subarachnoid hemorrhage (aSAH)], respectively. The inverse variance weighted (IVW) method was employed as primary analysis to discern causal estimates. ResultsOur findings revealed that an elevated genetically predicted SUA level (mg/dL) correlated with an increased risk of IAs among the European population (OR = 1.29 [95%CI:1.05–1.57], P = 0.013) and East Asian population (OR = 1.56 [95%CI: 1.27–1.92], P < 0.001). Among European individuals, subgroup analysis indicated a persistent causal association of SUA with uIAs (OR = 1.50 [95%CI: 1.08–2.08], P = 0.015) and aSAH (OR = 1.26 [95%CI: 1.00–1.60], P = 0.049). However, subgroup analysis in East Asian populations was not conducted due to the lack of separate data on uIAs and aSAH. ConclusionsOur MR analysis demonstrated a causal relationship between elevated SUA levels and an amplified risk of IAs. Further rigorous investigations are imperative to provide evidence and elucidate the underlying mechanisms.

Integrated Analysis of Genomic and Genome-Wide Association Studies Identified Candidate Genes for Nutrigenetic Studies in Flavonoids and Vascular Health: Path to Precision Nutrition for (Poly)phenols.

Flavonoids exert vasculoprotective effects in humans, but interindividual variability in their action has also been reported. This study aims to identify genes that are associated with vascular health effects of flavonoids and whose polymorphisms could explain interindividual variability in response to their intake. Applying the predetermined literature search criteria, we identified five human intervention studies reporting positive effects of flavonoids on vascular function together with global genomic changes analyzed using microarray methods. Genes involved in vascular dysfunction were identified from genome-wide association studies (GWAS). By extracting data from the eligible human intervention studies, we obtained 5807 differentially expressed genes (DEGs). The number of identified upstream regulators (URs) varied across the studies, from 227 to 1407. The search of the GWAS Catalog revealed 493 genes associated with vascular dysfunction. An integrative analysis of transcriptomic data with GWAS genes identified 106 candidate DEGs and 42 candidate URs, while subsequent functional analyses and a search of the literature identified 20 top priority candidate genes: ALDH2, APOE, CAPZA1, CYP11B2, GNA13, IL6, IRF5, LDLR, LPL, LSP1, MKNK1, MMP3, MTHFR, MYO6, NCR3, PPARG, SARM1, TCF20, TCF7L2, and TNF. In conclusion, this integrated analysis identifies important genes to design future nutrigenetic studies for development of precision nutrition for polyphenols.

A clustering approach to improve our understanding of the genetic and phenotypic complexity of chronic kidney disease

Chronic kidney disease (CKD) is a complex disorder that causes a gradual loss of kidney function, affecting approximately 9.1% of the world's population. Here, we use a soft-clustering algorithm to deconstruct its genetic heterogeneity. First, we selected 322 CKD-associated independent genetic variants from published genome-wide association studies (GWAS) and added association results for 229 traits from the GWAS catalog. We then applied nonnegative matrix factorization (NMF) to discover overlapping clusters of related traits and variants. We computed cluster-specific polygenic scores and validated each cluster with a phenome-wide association study (PheWAS) on the BioMe biobank (n = 31,701). NMF identified nine clusters that reflect different aspects of CKD, with the top-weighted traits signifying areas such as kidney function, type 2 diabetes (T2D), and body weight. For most clusters, the top-weighted traits were confirmed in the PheWAS analysis. Results were found to be more significant in the cross-ancestry analysis, although significant ancestry-specific associations were also identified. While all alleles were associated with a decreased kidney function, associations with CKD-related diseases (e.g., T2D) were found only for a smaller subset of variants and differed across genetic ancestry groups. Our findings leverage genetics to gain insights into the underlying biology of CKD and investigate population-specific associations.

Exploring the immunological landscape of osteomyelitis through mendelian randomization analysis.

Osteomyelitis is a severe bone marrow infection, whose pathogenesis is not yet fully understood. This study aims to explore the causal relationship between immune cell characteristics and osteomyelitis, hoping to provide new insights for the prevention and treatment of osteomyelitis. Based on two independent samples, this study employed a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between 731 immune cell characteristics (divided into seven groups) and osteomyelitis. Genetic variants were used as proxies for risk factors to ensure that the selected instrumental variables meet the three key assumptions of MR analysis. Genome-Wide Association Studies (GWAS) data for immune characteristics were obtained from the public GWAS catalog, while data for osteomyelitis was sourced from the FinnGen. At a significance level of 0.05, 21 immune phenotypes were identified as having a causal relationship with osteomyelitis development. In the B cell group, phenotypes such as Memory B cell % B cell (percentage of memory B cells within the total B cell population, % finger cell ratio), CD20- %B cell (percentage of B cells that do not express the CD20 marker on their surface), and Memory B cell % lymphocyte showed a positive causal relationship with osteomyelitis, while Naive-mature B cell %B cell and IgD-CD38-absolute cell counts (AC) phenotypes showed a negative causal relationship. In addition, specific immune phenotypes in the conventional dendritic cells (cDCs) group, Myeloid cell group, TBNK (T cells, B cells, natural killer cells) cell group, T cell maturation stage, and Treg cell group also showed significant associations with osteomyelitis. Through reverse MR analysis, it was found that osteomyelitis had no significant causal impact on these immune phenotypes, suggesting that the occurrence of osteomyelitis may not affect these immune cell phenotypes. To our knowledge, this is the first study to shed light on the causal relationship between specific immune cell characteristics and the development of osteomyelitis, thereby providing a new perspective to understand the immune mechanism of osteomyelitis. These findings are significant for formulating targeted prevention and treatment strategies, and hold promise to improve the treatment outcomes for patients with osteomyelitis.

Vitamin D-associated genetic variants in the Brazilian population: Investigating potential instruments for Mendelian randomization

Introduction. Vitamin D is required for bone and mineral metabolism and participates in the regulation of the immune response. It is also linked to several chronic diseases and conditions, usually in populations of European descent. Brazil presents a high prevalence of vitamin D deficiency and insufficiency despite the widespread availability of sunlight in the country. Thus, it is important to investigate the role of vitamin D as a risk factor for disease and to establish causal relationships between vitamin D levels and health-related outcomes in the Brazilian population.Objective. To examine genetic variants identified as determinants of serum vitamin D in genome-wide association studies of European populations and check whether the same associations are present in Brazil. If so, these single nucleotide polymorphisms (SNPs) could be developed locally as proxies to use in genetically informed causal inference methods, such as Mendelian randomization.Materials and methods. We extracted SNPs associated with vitamin D from the genomewide association studies catalog. We did a literature search to select papers ascertaining these variants and vitamin D concentrations in Brazil.Results. GC was the gene with the strongest association with vitamin D levels, in agreement with existing findings in European populations. However, VDR was themost investigated gene, regardless of its non-existing association with vitamin D in the genomewide association studies.Conclusions. More research is needed to validate sound proxies for vitamin D levels in Brazil, for example, prioritizing GC rather than VDR.

Cross-ancestry genetic architecture and prediction for cholesterol traits.

While cholesterol is essential, a high level of cholesterol is associated with the risk of cardiovascular diseases. Genome-wide association studies (GWASs) have proven successful in identifying genetic variants that are linked to cholesterol levels, predominantly in white European populations. However, the extent to which genetic effects on cholesterol vary across different ancestries remains largely unexplored. Here, we estimate cross-ancestry genetic correlation to address questions on how genetic effects are shared across ancestries. We find significant genetic heterogeneity between ancestries for cholesterol traits. Furthermore, we demonstrate that single nucleotide polymorphisms (SNPs) with concordant effects across ancestries for cholesterol are more frequently found in regulatory regions compared to other genomic regions. Indeed, the positive genetic covariance between ancestries is mostly driven by the effects of the concordant SNPs, whereas the genetic heterogeneity is attributed to the discordant SNPs. We also show that the predictive ability of the concordant SNPs is significantly higher than the discordant SNPs in the cross-ancestry polygenic prediction. The list of concordant SNPs for cholesterol is available in GWAS Catalog. These findings have relevance for the understanding of shared genetic architecture across ancestries, contributing to the development of clinical strategies for polygenic prediction of cholesterol in cross-ancestral settings.

Potential biomarker signatures in male infertility: integrative genomic analysis

BackgroundStudies have attributed 50% of infertility cases to male infertility, 15% of which is caused by idiopathic genetic factors. Currently, no specific biomarkers have been revealed for male infertility. Furthermore, research on genetic factors causing male infertility is still limited. As with other multifactorial genetic disorders, numerous risk loci for male infertility have been identified by genome-wide association studies (GWAS), although their clinical significance remains uncertain. Therefore, we utilized an integrative bioinformatics-based approach to identify biomarkers for male infertility. Bioinformatics analysis was performed using Open Targets Platform, DisGeNet, and GWAS Catalog. After that, the STRING database and the Cytoscape program were used to analyze protein–protein interaction. CytoHubba was used to determine the most significant gene candidates. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used to assess biological functions that correspond to the male infertility disease pathway.ResultsWe identified 305 genes associated with male infertility and highlighted 10 biological risk genes as potential biomarkers for male infertility such as TEX11, SPO11, SYCP3, HORMAD1, STAG3, MSH4, SYCP2, SYCE1, RAD21L1, and AMH. Of all the genes, we took the top three genes, namely, TEX11, SPO11, and SYCP3 as the genes that have the most potential as biomarkers.ConclusionsTEX11, SPO11, and SYCP3 are involved in meiosis and spermatogenesis. We propose that further research in regarding these genes in detecting male infertility.

The causal effect of inflammatory proteins and immune cell populations on diabetic nephropathy: evidence from Mendelian randomization.

Diabetic nephropathy (DN) is one of the diabetic microvascular complications with complex pathophysiology, and exploring the landscape of immune dysregulation in DN is valuable for pathogenesis and disease treatment. We crystallized possible inflammatory exposures into 91 circulating inflammatory proteins and 109 blood immune cells; and assessed the causal relationship between inflammation and DN using Mendelian randomization (MR). Based on publicly available genetic data, we explored causal associations between inflammation and DN risk by two-sample MR analysis. Genome-wide association study (GWAS) summary statistics for 91 circulating inflammatory proteins, 109 immune cells absolute counts, and DN were acquired from the GWAS Catalog. Inverse Variance Weighted (IVW) was the main MR method, while MR-Egger and MR-pleiotropy residuals and outliers (MR-PRESSO) were utilized for sensitivity analysis. Cochrane's Q was used to test for heterogeneity. The leave-one-out method ensured the stability of the MR results. This study revealed that higher levels of TNF-related activation-induced cytokine and tumor necrosis factor ligand superfamily member 14 were possibly associated with the increased risk of DN according to the IVW approach, with estimated odds ratios (OR) of 1.287 (95% confidence interval [CI] 1.051 to 1.577, P = 0.015) and 1.249 (95% CI 1.018 to 1.532, P = 0.033). Five immune cell traits were identified that might be linked to increased DN risk, including the higher absolute counts of HLA DR+ natural killer cell (OR = 1.248, 95% CI 1.055 to 1.476, P = 0.010), IgD+ CD38+ B cell (OR = 1.148, 95% CI 1.033 to 1.276, P = 0.010), CD25++ CD8+ T cell (OR = 1.159, 95% CI 1.032 to 1.302, P = 0.013), CD4- CD8- T cell (OR = 1.226, 95% CI 1.032 to 1.457, P = 0.020), and IgD- CD38- B cell (OR = 1.182, 95% CI 1.009 to 1.386, P = 0.039). In addition, elevated levels of interleukin-1 alpha (OR = 0.712, 95% CI 0.514 to 0.984, P = 0.040) and unswitched memory B cell (OR = 0.797, 95% CI 0.651 to 0.974, P = 0.027) may reduce the risk of developing DN. We identified inflammation-related exposures that may be associated with the risk of DN at the level of genetic prediction, which contributes to a better understanding of the etiologic of DN and facilitates the development of targeted therapies for DN.

Abstract P250: Vascular Contributions to Alzheimer's Disease

Introduction: Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that affects over 50 million people worldwide. The role of vascular risk factors have been described as a contributor to and a major comorbidity of AD pathogenesis; yet there is discordant evidence of this complex relationship between cardiovascular diseases (CVD) and its risk factors (like hypertension, hyperlipidemia, obesity, etc.) with AD pathophysiology and cognitive decline. AD associated Genome-wide association studies (GWAS) and derived polygenic risk scores (AD PRS) have uncovered some significant common genetic variants relating to CVD risk factors; however, we are still yet to unravel the comprehensive impact of these vascular genetic contributions to AD pathogenesis and cognitive decline. Method: In this study, we used 1800 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort spanning the full spectrum of clinical and pathological diagnoses of the AD spectrum, as our target dataset used for polygenic risk score calculation. Thereafter, we obtained GWAS summary statistics for cumulative cardiovascular risk by searching the Polygenic Score (PGS) GWAS Catalog using CVD as the ‘mapped trait” and then calculated cardiovascular-based PRS using HRS-based imputed GWAS data of the ADNI cohort. We conducted association analysis using a multivariate linear regression model with appropriate covariates (age, sex, APOE, education, etc.) between CVD-related polygenic risk score (CVD-PRS) with the different clinical AD diagnoses groups (Cognitively Normal/CN, Significant Memory Concerns/SMC, Mild Cognitive Impairment/MCI, Alzheimer's Disease/AD). We also performed association analysis of this CVD-PRS with white matter hyperintensity (WMHI) values, a vascular biomarker, at baseline using a linear regression model. Furthermore, we extended our analyses of CVD-related PRS with cognitive performance at baseline using composite scores for memory (MEM) and executive functioning (EF). Results and Conclusion: We found significantly strong correlation of CVD-related PRS with only certain AD Diagnoses groups (Significant Memory Concerns: SMC and Alzheimer's: AD) in the AD continuum. Additionally, we found strong associations (p &lt; 0.05) of this cardiovascular based- polygenic risk score with baseline memory as well as White Matter Hyperintensity (WMH) in our sample, specifically the group with a clinical diagnosis of AD. Furthermore, we are performing longitudinal association analysis of CVD-related PRS with longitudinal cognitive decline using a linear mixed effects model. Our findings will help us understand 1) how a cumulative CVD-related PRS associates with different AD diagnoses subgroups as well as vascular biomarkers for AD and 2) how CVD-related PRS associates with cognitive performance and longitudinal cognitive decline.

Mendelian randomization supports genetic liability to hospitalization for COVID-19 as a risk factor of pre-eclampsia.

Pre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence. Two-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p < 5 × -8 were obtained and pruned for linkage disequilibrium to generate instrumental variables for COVID-19. Inverse variance weighted estimates were used as the primary MR results, with weighted median and MR-Egger as auxiliary analyses. The robustness of the MR findings was also evaluated through sensitivity analyses. Bonferroni correction was applied to primary results, with a p < 0.0083 considered significant evidence and a p within 0.083-0.05 considered suggestive evidence. Critical ill COVID-19 [defined as hospitalization for COVID-19 with either a death outcome or respiratory support, OR (95% CI): 1.17 (1.03-1.33), p = 0.020] and hospitalized COVID-19 [defined as hospitalization for COVID-19, OR (95% CI): 1.10 (1.01-1.19), p = 0.026] demonstrated suggestive causal effects on pre-eclampsia, while general severe acute respiratory syndrome coronavirus 2 infection did not exhibit a significant causal effect on pre-eclampsia. None of the three COVID-19 severity phenotypes exhibited a significant causal effect on eclampsia. Our investigation demonstrates a suggestive causal effect of genetic susceptibility to critical ill COVID-19 and hospitalized COVID-19 on pre-eclampsia. The COVID-19 severity exhibited a suggestive positive dose-response relationship with the risk of pre-eclampsia. Augmented attention should be paid to pregnant women hospitalized for COVID-19, especially those needing respiratory support.