European Genome-wide Association Studies Research Articles

Genome-wide association studies for pelvic organ prolapse in the Japanese population

Pelvic organ prolapse (POP) affects approximately 40% of elderly women, characterized by the descent of the pelvic organs into the vaginal cavity. Here we present the results of a genome-wide association study (GWAS) for susceptibility to POP comprising 771 cases and 76,625 controls in the Japanese population. We identified a significant association of WT1 locus with POP in the Japanese population; rs10742277; odds ratio (OR) = 1.48, 95% confidence interval (CI), 1.29–1.68, P = 6.72 × 10−9. Subsequent cross-ancestry GWAS meta-analysis combining the Japanese data and previously reported European data, including 28,857 cases and 622,916 controls, identified FGFR2 locus as a novel susceptibility locus to POP (rs7072877; OR = 1.06, 95% CI, 1.04–1.08, P = 4.11 × 10−8). We also observed consistent directions of the effects for 21 out of 24 European GWAS derived loci (binomial test P = 2.8 × 10−4), indicating that most of susceptibility loci for POP are shared across the Japanese and European populations.

Causal effects of cardiovascular health on five epigenetic clocks

BackgroundThis work delves into the relationship between cardiovascular health (CVH) and aging. Previous studies have shown an association of ideal CVH with a slower aging rate, measured by epigenetic age acceleration (EAA). However, the causal relationship between CVH and EAA has remained unexplored.Methods and resultsWe performed genome-wide association studies (GWAS) on the (12-point) CVH score and its components using the Taiwan Biobank data, in which weighted genetic risk scores were treated as instrumental variables. Subsequently, we conducted a one-sample Mendelian Randomization (MR) analysis with the two-stage least-squares method on 2383 participants to examine the causal relationship between the (12-point) CVH score and EAA. As a result, we observed a significant causal effect of the CVH score on GrimAge acceleration (GrimEAA) (β [SE]: − 0.993 [0.363] year; p = 0.0063) and DNA methylation-based plasminogen activator inhibitor-1 (DNAmPAI-1) (β [SE]: − 0.294 [0.099] standard deviation (sd) of DNAmPAI-1; p = 0.0030). Digging individual CVH components in depth, the ideal total cholesterol score (0 [poor], 1 [intermediate], or 2 [ideal]) was causally associated with DNAmPAI-1 (β [SE]: − 0.452 [0.150] sd of DNAmPAI-1; false discovery rate [FDR] q = 0.0102). The ideal body mass index (BMI) score was causally associated with GrimEAA (β [SE]: − 2.382 [0.952] years; FDR q = 0.0498) and DunedinPACE (β [SE]: − 0.097 [0.030]; FDR q = 0.0044). We also performed a two-sample MR analysis using the summary statistics from European GWAS. We observed that the (12-point) CVH score exhibits a significant causal effect on Horvath’s intrinsic epigenetic age acceleration (β [SE]: − 0.389 [0.186] years; p = 0.036) and GrimEAA (β [SE]: − 0.526 [0.244] years; p = 0.031). Furthermore, we detected causal effects of BMI (β [SE]: 0.599 [0.081] years; q = 2.91E-12), never smoking (β [SE]: − 2.981 [0.524] years; q = 1.63E-7), walking (β [SE]: − 4.313 [1.236] years; q = 0.004), and dried fruit intake (β [SE]: − 1.523 [0.504] years; q = 0.013) on GrimEAA in the European population.ConclusionsOur research confirms the causal link between maintaining an ideal CVH and epigenetic age. It provides a tangible pathway for individuals to improve their health and potentially slow aging.

Genome-wide association study and polygenic risk score analysis for schizophrenia in a Korean population

Although large-scale genome-wide association studies (GWASs) have revealed the genetic architecture of schizophrenia, these studies have mainly focused on populations of European ancestry. This study aimed to identify common genetic variants associated with schizophrenia in the Korean population and evaluate the performance of polygenic risk scores (PRSs) derived from large-scale GWASs across ancestries. In the Korean psychiatric GWAS project (KPGP), seven academic institutes and their affiliated hospitals across South Korea recruited a cohort of 1670 patients with DSM-IV-defined schizophrenia and 2271 healthy controls. A total of 6690,822 SNPs were tested for association with schizophrenia. We identified one previously unreported genome-wide significant locus rs2423464 (P = 2.83 × 10−11; odds ratio = 1.65; 95 % confidence interval = 1.43–1.91, minor allele frequency = 0.126). This variant was also associated with increased lysosomal-associated membrane protein family member 5 (LAMP5) gene expression. The PRS derived from the meta-analysis results of East Asian and European GWASs explained a larger proportion of the phenotypic variance in the Korean schizophrenia sample than the PRS of an East Asian or European GWAS. (R2 = 0.073 for meta-analysis; 0.028 for East Asian GWAS; 0.037 for European GWAS). GWASs involving diverse ethnic groups will expand our understanding of the genetic architecture of schizophrenia.

Causal inference between physical activity and chronic diseases: Insights from a two-sample Mendelian randomization study

Chronic diseases are major causes of global death and disability, significantly impacting individual health and imposing economic burdens. This study aims to investigate the causal relationship between physical activity (PA) and the development of chronic diseases. Using a Mendelian randomization (MR) approach, we incorporated average PA and its subtypes (more than 450 ​000 participants) as exposure measures and eight chronic diseases as outcome measures. Data were obtained from the European Genome-Wide Association Study (GWAS). The primary causal analysis technique employed was the inverse variance weighting (IVW) method, with MR-Egger, weighted median, weighted mode, and simple mode used to validate the results. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. The IVW approach results show that vigorous physical activity (VPA) is associated with a modest reduction in the risk of major coronary heart disease (OR ​= ​0.95, 95% CI: 0.91–0.99, p ​= ​0.01). The causal directions of the other four MR methods are consistent with this result and validated by sensitivity analysis. No substantial associations were found between other levels of PA and chronic disease. Our findings underscore the importance of VPA in preventive cardiology and suggest its potential role in public health initiatives. Further research should explore the impact of PA on different demographic groups and the dose-response relationship of VPA on heart health.

Causality of Genetically Determined Metabolites on Chronic Kidney Disease: A Two-Sample Mendelian Randomization Study In Silico.

Introduction: Chronic kidney disease (CKD) is associated with metabolic disorders. However, the evidence for the causality of circulating metabolites to promote or prevent CKD is still lacking. Methods: The two-sample Mendelian randomization (MR) analysis was conducted to evaluate the latent causal relationship between the genetically proxied 486 blood metabolites and CKD. Genome-wide association study (GWAS) data for exposures were derived from 7824 European GWAS on metabolite levels, which have been extensively utilized in the medical field to elucidate the mechanisms underlying disease onset and progression. The random inverse variance weighted (IVW) is the primary analysis for causality analysis while MR-Egger and weighted median as complementary analyses. For the further identification of metabolites, reverse MR and linkage disequilibrium score regression were performed for further evaluation. The drug target for N-acetylornithine was subsequently supplemented into the analysis, with MR and colocalization analysis being utilized. Key metabolic pathways were identified via MetaboAnalyst 4.0 (https://www.metaboanalyst.ca/) online website. Results: N-acetylornithine was identified as a reliable metabolite that increases the susceptibility to estimated glomerular filtration rate (eGFR) decrease (β = 0.047; 95% confidence interval: -0.068 to -0.026; PIVW = 1.5E-5). The "glyoxylate and dicarboxylate metabolism" pathway showed significant relevance to CKD development (P = 6E-4), whereas the "glycine, serine, and threonine metabolism" pathway was also recognized as associated with CKD by general practitioners (P = 7E-4). Colocalization analysis revealed a robust genetic link between N-acetylornithine and both CKD and eGFR, with 85.1% and 99.4% colocalization rates, respectively. IVW-MR analysis substantiated these findings with a significant positive association for CKD (odds ratio = 1.43, P = 4.7E-5) and a negative correlation with eGFR (b = -0.04, P = 1.13E-31). Conclusions: MR was utilized to explore the potential causal links between 61 genetic serum metabolites and CKD. N-acetylornithine and NAT8 were further explored as a potential therapeutic target for CKD treatment.

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

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. The objective of the study was to investigate the potential risks of plasma metabolites in urolithiasis using a two-sample Mendelian randomization (MR) study. 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. 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). 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.

Genetic overlap and Mendelian randomization analysis highlighted the causal relationship between psoriatic disease and migraine.

Despite observational studies suggesting a link between psoriatic disease (including psoriasis and psoriatic arthritis) and migraine, it is unclear whether there is a shared genetic etiology or a causal relationship between the two conditions. We aimed to reveal the genetic overlap and causality using the Mendelian randomization (MR) framework. The genetic analysis utilized summary data from the most extensive European genome-wide association study (GWAS) of migraine. Well-powered psoriatic disease GWAS data were obtained from two independent cohort studies, which served as discovery and validation datasets. Global and regional genetic correlations between psoriatic disease and migraine were assessed, and pleiotropic regions identified by pairwise GWAS analysis were further annotated. We further applied a two-sample MR multivariate MR to investigate the potential causal relationship between them. The global genetic correlation test indicated weak correlations between psoriatic disease and migraine, while regional correlation analyses delineated one significant shared locus between psoriasis and migraine. Pathway enrichment analysis revealed that shared genes were involved biological processes to the major histocompatibility and antigen processing and presentation. In terms of causality estimates, genetically predicted psoriasis (Pmeta = 0.003) and psoriatic arthritis (Pmeta = 0.028) were associated with an increased risk of migraine. Multivariate MR analysis indicated that psoriasis was an independent risk factor for migraine (P < 0.05). No significant associations were found in the reverse direction. Our study supported the causal role of psoriasis on migraine, and the central role for immunomodulatory etiology. These findings have significant implications for the management of migraine and clinical practice in patients with psoriasis.

Abstract Mo078: Identifying Genetic Determinants of Phytosterol Levels: A Genome-Wide Association and Meta-Analysis Study Unveils a New Locus Influencing Campesterol Serum Concentrations

Background: Sitosterolemia, a rare inherited disorder, stems from mutations in the ABCG5/ABCG8 genes, which play a critical role in plant sterol transport. These genetic anomalies result in reduced phytosterol excretion, causing an accumulation in the body that can lead to serious health issues, such as premature coronary artery disease. Hypothesis: The study aimed to uncover the genetic determinants influencing plant sterol levels within the Middle East/North Africa (MENA) population, focusing on individuals from Qatar. It hypothesized that unique genetic variations might influence these levels, contributing to the development of sitosterolemia. Aims: To conduct the first genome-wide association study (GWAS) in the MENA region to identify genetic variants affecting plant sterol levels in the Qatari population, and to compare these findings with those from populations of European ancestry. Methods: The study utilized the Metabolon platform for analyzing serum levels of β-sitosterol and campesterol, combined with genome sequence data from the Qatar Genome Program. A trans-ancestry meta-analysis compared our findings with those from a large European cohort, while conditional analysis helped identify specific single nucleotide polymorphisms (SNPs) associated with these sterols. Results: The research identified two independent SNPs related to β-sitosterol ((rs145164937 and rs4299376) and two to campesterol (rs7598542 and rs75901165) in the Qatari population, alongside previously reported variants ( P &lt;5.0 ×10 -8 ) .Notably, one variant (rs75901165) was located in the Intraflagellar Transport 43 (IFT43) gene, diverging from the common ABCG5/8 locus. The study also supported the association of variants in the SCARB1 and ABO genes with sitosterolemia and assessed a polygenic risk score's efficacy based on European GWAS data in the Qatari cohort. Conclusion(s): The findings underscore the significance of conducting population-specific genetic research to understand better and manage conditions like sitosterolemia. This research highlights the importance of personalized treatment approaches for hyperlipidemia and the value of establishing comprehensive multi-omics databases tailored to specific populations.

Genome-wide association study and meta-analysis of phytosterols identifies a novel locus for serum levels of campesterol

Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of β-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with β-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R2 = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies.

Polygenic prediction of major depressive disorder and related traits in African ancestries UK Biobank participants.

Genome-Wide Association Studies (GWAS) over-represent European ancestries, neglecting all other ancestry groups and low-income nations. Consequently, polygenic risk scores (PRS) more accurately predict complex traits in Europeans than African Ancestries groups. Very few studies have looked at the transferability of European-derived PRS for behavioural and mental health phenotypes to Africans. We assessed the comparative accuracy of depression PRS trained on European and African Ancestries GWAS studies to predict major depressive disorder (MDD) and related traits in African ancestry participants from the UK Biobank. UK Biobank participants were selected based on Principal component analysis clustering with an African genetic similarity reference population, MDD was assessed with the Composite International Diagnostic Interview (CIDI). PRS were computed using PRSice2 software using either European or African Ancestries GWAS summary statistics. PRS trained on European ancestry samples (246,363 cases) predicted case control status in Africans of the UK Biobank with similar accuracies (R2 = 2%, β = 0.32, empirical p-value = 0.002) to PRS trained on far much smaller samples of African Ancestries participants from 23andMe, Inc. (5045 cases, R² = 1.8%, β = 0.28, empirical p-value = 0.008). This suggests that prediction of MDD status from Africans to Africans had greater efficiency relative to discovery sample size than prediction of MDD from Europeans to Africans. Prediction of MDD status in African UK Biobank participants using GWAS findings of likely causal risk factors from European ancestries was non-significant. GWAS of MDD in European ancestries are inefficient for improving polygenic prediction in African samples; urgent MDD studies in Africa are needed.

Evaluation of the associations of interlukin-7 genetic variants with toxicity and efficacy of immune checkpoint inhibitors: A replication study of a Japanese population, based on the findings of a European genome-wide association study.

Recent genome-wide association studies of European populations have identified rs16906115, a single-nucleotide polymorphism in the interleukin-7 gene, as a predictor of immune-related adverse events (irAEs) and the therapeutic efficacy of immune checkpoint inhibitors. We evaluated this single-nucleotide polymorphism in a Japanese population. From January 2021, we stored host DNA from individuals who received various types of immune checkpoint inhibitors. From this population, we categorized 510 participants into cases (grade ≥2 irAEs) and controls (received ≥3 immune checkpoint inhibitor doses, follow-up ≥12weeks, no irAEs), and divided 339 hepatocellular carcinoma patients treated with atezolizumab/bevacizumab into responders and non-responders, evaluated using the modified response evaluation criteria in solid tumors. We compared the minor allele frequencies of rs16906115 between cases and controls, and responders and non-responders. In the irAE prediction analysis of 234 cases and 276 controls, the minor allele frequency was 0.244 in the case group and 0.265 in the control group. This difference is not significant. In the analysis predicting the therapeutic efficacy for hepatocellular carcinoma patients, the responders had a significantly lower minor allele frequency of 0.220, compared with 0.300 for the non-responders (p=0.022). Univariate and multivariate analyses identified the minor allele homozygosity as a significant predictor of treatment response, with odds ratios of 0.292 (p=0.015) in the univariate analysis and 0.315 (p=0.023) in the multivariate analysis. In our Japanese cohort, no association was found between the rs16906115 minor allele and irAEs or treatment efficacy. The minor allele homozygosity may be associated with a negative therapeutic outcome. UMIN Clinical Trials Registry with the number UMIN000043798.

O-136 A comprehensive evaluation of spermatogenesis-related genes identifies novel common and rare risk loci for idiopathic severe spermatogenic failure

Abstract Study question Can genome-wide genotyping data be analysed in a hypothesis-driven fashion to better understand the genetic component of male infertility due to severe spermatogenic failure (SPGF)? Summary answer We revealed that both common and rare genetic variants in genomic regions involved in spermatogenesis contribute to the development of idiopathic SPGF. What is known already Spermatogenesis is a tightly regulated process involving the controlled expression of over 2,000 genes. Mutations in spermatogenesis-related genes have been associated with SPGF development. Next-generation sequencing methods are useful for identifying rare mutations that explain monogenic forms of this condition. Additionally, genome-wide association studies (GWAS) have provided valuable insights into the role of common polymorphisms in complex forms of SPGF. Interestingly, novel methods have shown that GWAS datasets can be used to infer rare coding variants that are causal for male infertility phenotypes, but this approach has never been applied to characterise the genetic component of a whole case-control cohort. Study design, size, duration We conducted a thorough examination of both common (minor allele frequency, MAF &amp;gt; 0.01) and rare (MAF &amp;lt; 0.01) genetic variation within a set of 1,797 spermatogenesis genes. This gene panel was meticulously curated through an exhaustive search in the literature and in different databases of male infertility genetics. The genotype data were obtained from a previously published GWAS in Europeans, encompassing over 6 million polymorphisms. Participants/materials, setting, methods We analysed a cohort that included 1,274 SPGF patients and 1,951 unaffected controls with European ancestry. Three independent approaches were follow: (1) variant-wise analysis using logistic regression models followed by a meta-analysis of the study cohorts; (2) gene-wise analysis using a Combined Multivariate and Collapsing (CMC) burden test; and (3) identification and characterisation of highly damaging rare coding variants in homozygosity. Multiple testing correction was applied to determine statistical significance Main results and the role of chance Our results suggested a potential association between SPGF and the rs12347237*T variant of the SHOC1 gene in the GWAS population (P = 3.17E-05, OR = 2.94). This association was subsequently validated in an independent Iberian cohort (Pcombined = 6.992E-06, OR = 2.61). Furthermore, our gene-wise analysis showed putative associations through the cumulative effect of some rare and low-frequency variants in SHOC1 (P = 4.9E-03), PCSK4 (P = 1E-04), AP3B1 (P = 5E-04), and DLK1 (P = 5E-04). Remarkably, the rare and common variants identified in SHOC1 are part of the same haplotype block, impacting both coding and non-coding regions. Additionally, we identified 35 individuals carrying 32 very rare and potentially pathogenic variants in homozygosity within the coding regions of the selected genes. Limitations, reasons for caution The analysis of low-frequency variants presents challenges in achieving sufficient statistical power to detect genetic associations. Consequently, independent studies involving large sample sets are essential to replicate our findings. In addition, the specific role of the identified variants in the pathogenic mechanisms of SPGF should be assessed using functional experiments. Wider implications of the findings The discovery of novel genetic risk factors for SPGF and the elucidation of the genetic causes underlying both monogenic and complex forms of SPGF provide new perspectives for personalized medicine and reproductive counselling. Trial registration number not applicable

Genome-wide association and polygenic risk score estimation of type 2 diabetes mellitus in Kinh Vietnamese-A pilot study.

A genome-wide association study (GWAS) is a powerful tool in investigating genetic contribution, which is a crucial factor in the development of complex multifactorial diseases, such as type 2 diabetes mellitus. Type 2 diabetes mellitus is a major healthcare burden in the Western Pacific region; however, there is limited availability of genetic-associated data for type 2 diabetes in Southeast Asia, especially among the Kinh Vietnamese population. This lack of information exacerbates global healthcare disparities. In this study, 997 Kinh Vietnamese individuals (503 with type 2 diabetes and 494 controls) were prospectively recruited and their clinical and paraclinical information was recorded. DNA samples were collected and whole genome genotyping was performed. Standard quality control and genetic imputation using the 1000 Genomes database were executed. A polygenic risk score for type 2 diabetes was generated in different models using East Asian, European, and mix ancestry GWAS summary statistics as training datasets. After quality control and genetic imputation, 107 polymorphisms reached suggestive statistical significance for GWAS (≤5 × 10-6) and rs11079784 was one of the potential markers strongly associated with type 2 diabetes in the studied population. The best polygenic risk score model predicting type 2 diabetes mellitus had AUC = 0.70 (95% confidence interval = 0.62-0.77) based on a mix of ancestral GWAS summary statistics. These data show promising results for genetic association with a polygenic risk score estimation in the Kinh Vietnamese population; the results also highlight the essential role of population diversity in a GWAS of type 2 diabetes mellitus.

Antihypertensive Drugs for the Prevention of Atrial Fibrillation: A Drug Target Mendelian Randomization Study.

We investigated the potential impact of antihypertensive drugs for atrial fibrillation (AF) prevention through a drug target Mendelian randomization study to avoid the potential limitations of clinical studies. Validated published single-nucleotide polymorphisms (SNPs) that mimic the action of 12 antihypertensive drug classes, including alpha-adrenoceptor blockers, adrenergic neuron blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta-adrenoceptor blockers, centrally acting antihypertensive drugs, calcium channel blockers, loop diuretics, potassium-sparing diuretics and mineralocorticoid receptor antagonists, renin inhibitors, thiazides and related diuretic agents, and vasodilators were used. We estimated, via their corresponding gene and protein targets, the downstream effect of these drug classes to prevent AF via systolic blood pressure using 2-sample Mendelian randomization analyses. The SNPs were extracted from 2 European genome-wide association studies for the drug classes (n=317 754; n=757 601) and 1 European genome-wide association study for AF (n=1 030 836). Drug target Mendelian randomization analyses supported the significant preventive causal effects of lowering systolic blood pressure per 10 mm Hg via alpha-adrenoceptor blockers (n=11 SNPs; odds ratio [OR], 0.34 [95% CI, 0.21-0.56]; P=2.74×10-05), beta-adrenoceptor blockers (n=17 SNPs; OR, 0.52 [95% CI, 0.35-0.78]; P=1.62×10-03), calcium channel blockers (n=49 SNPs; OR, 0.50 [95% CI, 0.36-0.70]; P=4.51×10-05), vasodilators (n=19 SNPs; OR, 0.53 [95% CI, 0.34-0.84]; P=7.03×10-03), and all 12 antihypertensive drug classes combined (n=158 SNPs; OR, 0.64 [95% CI, 0.54-0.77]; P=8.50×10-07) on AF risk. Our results indicated that lowering systolic blood pressure via protein targets of various antihypertensive drugs seems promising for AF prevention. Our findings inform future clinical trials and have implications for repurposing antihypertensive drugs for AF prevention.

The causal effect of Alzheimer's disease and family history of Alzheimer's disease on non-ischemic cardiomyopathy and left ventricular structure and function: a Mendelian randomization study.

Previous studies have shown that Alzheimer's disease (AD) can cause myocardial damage. However, whether there is a causal association between AD and non-ischemic cardiomyopathy (NICM) remains unclear. Using a comprehensive two-sample Mendelian randomization (MR) method, we aimed to determine whether AD and family history of AD (FHAD) affect left ventricular (LV) structure and function and lead to NICM, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The summary statistics for exposures [AD, paternal history of AD (PH-AD), and maternal history of AD (MH-AD)] and outcomes (NICM, HCM, DCM, and LV traits) were obtained from the large European genome-wide association studies. The causal effects were estimated using inverse variance weighted, MR-Egger, and weighted median methods. Sensitivity analyses were conducted, including Cochran's Q test, MR-Egger intercept test, MR pleiotropy residual sum and outlier, MR Steiger test, leave-one-out analysis, and the funnel plot. Genetically predicted AD was associated with a lower risk of NICM [odds ratio (OR) 0.9306, 95% confidence interval (CI) 0.8825-0.9813, p = 0.0078], DCM (OR 0.8666, 95% CI 0.7752-0.9689, p = 0.0119), and LV remodeling index (OR 0.9969, 95% CI 0.9940-0.9998, p = 0.0337). Moreover, genetically predicted PH-AD was associated with a decreased risk of NICM (OR 0.8924, 95% CI 0.8332-0.9557, p = 0.0011). MH-AD was also strongly associated with a decreased risk of NICM (OR 0.8958, 95% CI 0.8449-0.9498, p = 0.0002). Different methods of sensitivity analysis demonstrated the robustness of the results. Our study revealed that AD and FHAD were associated with a decreased risk of NICM, providing a new genetic perspective on the pathogenesis of NICM.

Associations Between Genetically Predicted Iron Status and Cardiovascular Disease Risk: A Mendelian Randomization Study.

Mendelian randomization (MR) studies suggest a causal effect of iron status on cardiovascular disease (CVD) risk, but it is unknown if these associations are confounded by pleiotropic effects of the instrumental variables on CVD risk factors. We aimed to investigate the effect of iron status on CVD risk controlling for CVD risk factors. Iron biomarker instrumental variables (total iron-binding capacity [n=208 422], transferrin saturation [n=198 516], serum iron [n=236 612], ferritin [n=257 953]) were selected from a European genome-wide association study meta-analysis. We performed 2-sample univariate MR of each iron trait on CVD outcomes (all-cause ischemic stroke, cardioembolic ischemic stroke, large-artery ischemic stroke, small-vessel ischemic stroke, and coronary heart disease) from MEGASTROKE (n=440 328) and CARDIoGRAMplusC4D (Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics) (n=183 305). We then implemented multivariate MR conditioning on 7 CVD risk factors from independent European samples to evaluate their potential confounding or mediating effects on the observed iron-CVD associations. With univariate MR analyses, we found higher genetically predicted iron status to be associated with a greater risk of cardioembolic ischemic stroke (transferrin saturation: odds ratio, 1.17 [95% CI, 1.03-1.33]; serum iron: odds ratio, 1.21 [95% CI, 1.02-1.44]; total iron-binding capacity: odds ratio, 0.81 [95% CI, 0.69-0.94]). The detrimental effects of iron status on cardioembolic ischemic stroke risk remained unaffected when adjusting for CVD risk factors (all P<0.05). Additionally, we found diastolic blood pressure to mediate between 7.1 and 8.8% of the total effect of iron status on cardioembolic ischemic stroke incidence. Univariate MR initially suggested a protective effect of iron status on large-artery stroke and coronary heart disease, but controlling for CVD factors using multivariate MR substantially diminished these associations (all P>0.05). Higher iron status was associated with a greater risk of cardioembolic ischemic stroke independent of CVD risk factors, and this effect was partly mediated by diastolic blood pressure. These findings support a role of iron status as a modifiable risk factor for cardioembolic ischemic stroke.

Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Exploring causal correlations between inflammatory cytokines and knee osteoarthritis: a two-sample Mendelian randomization.

Knee osteoarthritis (KOA) and certain inflammatory cytokines (such as interleukin 1 [IL-1] and tumor necrosis factor alpha [TNF-a]) are related; however, the causal relationship remains unclear. Here, we aimed to assess the causal relationship between 41 inflammatory cytokines and KOA using Mendelian randomization (MR). Two-sample bidirectional MR was performed using genetic variation data for 41 inflammatory cytokines that were obtained from European Genome-Wide Association Study (GWAS) data (n=8293). KOA-related genetic association data were also obtained from European GWAS data (n=40,3124). Inverse variance weighting (IVW), MR, heterogeneity, sensitivity, and multiple validation analyses were performed. Granulocyte colony-stimulating factor (G-CSF) or colony-stimulating factor 3 (CSF-3) levels were negatively associated with the risk of developing KOA (OR: 0.93, 95%CI:0.89-0.99, P=0.015). Additionally, macrophage inflammatory protein-1 alpha (MIP-1A/CCL3) was a consequence of KOA (OR: 0.72, 95%CI:0.54-0.97, P=0.032). No causal relationship was evident between other inflammatory cytokines and KOA development. This study suggests that certain inflammatory cytokines may be associated with KOA etiology. G-CSF exerts an upstream influence on KOA development, whereas MIP-1A (CCL-3) acts as a downstream factor.

Essential Nutrients and White Matter Hyperintensities: A Two-Sample Mendelian Randomization Study.

Stroke and dementia have been linked to the appearance of white matter hyperintensities (WMHs). Meanwhile, diffusion tensor imaging (DTI) might capture the microstructural change in white matter early. Specific dietary interventions may help to reduce the risk of WMHs. However, research on the relationship between specific nutrients and white matter changes is still lacking. We aimed to investigate the causal effects of essential nutrients (amino acids, fatty acids, mineral elements, and vitamins) on WMHs and DTI measures, including fraction anisotropy (FA) and mean diffusivity (MD), by a Mendelian randomization analysis. We selected single nucleotide polymorphisms (SNPs) associated with each nutrient as instrumental variables to assess the causal effects of nutrient-related exposures on WMHs, FA, and MD. The outcome was from a recently published large-scale European Genome Wide Association Studies pooled dataset, including WMHs (N = 18,381), FA (N = 17,663), and MD (N = 17,467) data. We used the inverse variance weighting (IVW) method as the primary method, and sensitivity analyses were conducted using the simple median, weighted median, and MR-Egger methods. Genetically predicted serum calcium level was positively associated with WMHs risk, with an 8.1% increase in WMHs risk per standard deviation unit increase in calcium concentration (OR = 1.081, 95% CI = 1.006-1.161, p = 0.035). The plasma linoleic acid level was negatively associated with FA (OR = 0.776, 95% CI = 0.616-0.978, p = 0.032). Our study demonstrated that genetically predicted calcium was a potential risk factor for WMHs, and linoleic acid may be negatively associated with FA, providing evidence for interventions from the perspective of gene-environment interactions.

Investigation of the causal relationship between inflammatory bowel disease and type 2 diabetes mellitus: a Mendelian randomization study.

Background: Type 2 diabetes mellitus (T2DM) and inflammatory bowel disease (IBD) have been associated, according to various epidemiological research. This study uses Mendelian randomization (MR) to investigate the causal link between T2DM and IBD. Methods: To investigate the causal relationship between IBD and T2DM risk using European population data from the genome-wide association study (GWAS) summary datasets, we constructed a two-sample MR study to evaluate the genetically predicted impacts of liability towards IBD outcomes on T2DM risk. As instrumental variables (IVs), we chose 26 single nucleotide polymorphisms (SNPs) associated with IBD exposure data. The European T2DM GWAS data was obtained from the IEU OpenGWAS Project database, which contains 298,957 cases as the outcome data. The causal relationship between T2DM and IBD using a reverse MR analysis was also performed. Results: The two-sample MR analysis, with the Bonferroni adjustment for multiple testing, revealed that T2DM risk in Europeans is unaffected by their IBD liability (odds ratio (OR): 0.950-1.066, 95% confidence interval (CI): 0.885-1.019, p = 0.152-0.926). The effects of liability to T2DM on IBD were not supported by the reverse MR analysis either (OR: 0.739-1.131, 95% confidence interval (CI): 0.651-1.100, p = 0.058-0.832). MR analysis of IBS on T2DM also have no significant causal relationship (OR: 0.003-1.007, 95% confidence interval (CI): 1.013-5.791, p = 0.069-0.790). FUMA precisely mapped 22 protein-coding genes utilizing significant SNPs of T2DM acquired from GWAS. Conclusion: The MR study showed that the existing evidence did not support the significant causal effect of IBD on T2DM, nor did it support the causal impact of T2DM on IBD.