Dissecting the shared genetic architecture between anxiety and cognitive function.

Idiopathic inflammatory myositis (IIM), comprising polymyositis (PM) and dermatomyositis (DM), is a collective term for immune-mediated diseases characterized by skeletal muscle inflammation. Emerging evidence points to an increased incidence of epilepsy in patients with PM/DM. However, the causality and underlying mechanisms behind this association are unclear. Our study aimed to explore the potential causal link between PM/DM and epilepsy, with a focus on immune-mediated mechanisms, using Mendelian randomization (MR) and transcriptome analyses. Initially, summary data from genome-wide association studies (GWAS) related to polymyositis (PM; finn-b-M13_POLYMYO), dermatomyositis (DM; finn-b-DERMATOPOLY_FG), and epilepsy (ebi-a-GCST90018840) were obtained from the Integrative Epidemiology Unit Open GWAS database. These data were utilized for Mendelian randomization (MR) analysis and generalized summary data based Mendelian randomization (GSMR). To ensure the robustness of the findings, sensitivity analyses were conducted to corroborate the results of the MR analyses. Subsequently, the study leveraged publicly accessible databases and bioinformatics tools to conduct comprehensive analyses of gene expression data. This included differential expression analysis, immune infiltration analysis, and gene enrichment analysis. Differentially expressed SNP-related genes (DE-SRGs) were further analyzed using single-cell transcriptomics. Finally, the expression of four key genes (IER3, TNF, GPANK1, and ATF6B) in the hippocampus of epilepsy mouse model was quantified using PCR. The MR analysis disclosed a causal association between PM and epilepsy, whereas the reverse MR analysis did not identify a significant causal effect of epilepsy on PM. However, there was no association between DM and epilepsy of MR analysis. The Transcriptome analysis not only identified DE-SRGs but also revealed distinct immune cell infiltration patterns in epilepsy patients. Specifically, we observed SRGs are mainly expressed in endothelial cells, microglia, and T cells, indicative of a proinflammatory state. Furthermore, the gene set variation analysis (GSVA) highlighted the differential activation of pathways in these cell types, including inflammatory response and allograft rejection, which were significantly upregulated. PCR results show the expression of IER3, TNF, GPANK1, and ATF6B in hippocampus of epilepsy model largely consistent with bioinformatics predictions. The study reveals a causal association between PM and epilepsy, with no significant impact of epilepsy on PM. There is no causal association between DM and epilepsy. The absence of a DM-epilepsy link may reflect fundamental differences in immunopathology: while PM is driven by T cell-mediated muscle invasion, DM involves predominant humoral immunity and complement deposition, suggesting distinct neuroinflammatory implications. Our findings establish immune-mediated neuroinflammation as the central mechanistic link between PM and epileptogenesis. These findings implicate shared immunopathogenic mechanisms and suggest therapeutic targets for epilepsy associated with polymyositis.

Novel insights into genetic associations and drug targets of mitochondria-associated proteins with major depressive disorder.

Exploring the causal relationship between telomere regulation, aging and neurological disorders.

Gut microbiota mediates the protective effects of SGLT-2 inhibitors on bipolar disorder: An intermediary Mendelian randomization study.

Integrative multi-omics genomics prioritizes causal therapeutic targets for salt sensitive of blood pressure.

hepatocellular carcinoma (HCC) is a major cancer, and PTTG1 alters asparagine metabolism to promote HCC progression, but its diagnostic and prognostic significance in HCC remains unclear. This study aimed to evaluate the prognostic value of PTTG1-related genes in hepatocellular carcinoma by integrating Mendelian randomization, transcriptomic analysis, and single-cell sequencing approaches. This study identified PTTG1-interacting differential genes (PTTG1-IDGs) through differential analysis and protein network construction, then applied Mendelian randomization (MR) to assess their causal relationship with HCC. Univariate Cox regression and machine learning methods screened prognostic genes and constructed prognostic model. CDC45 and CENPE were prognostic genes with a causal relationship to HCC. Notably, the odds ratios (ORs) of these prognostic genes were close to 1, indicating that although the two genes had a statistically significant causal association with HCC, the independent effect of each allele on HCC risk was weak. This reflected that PTTG1-related genes played a subtle regulatory role rather than a strong direct causal role in the pathogenesis of HCC. nomogram analysis indicated that risk score and pathological T-stage were independent prognostic factors. Immune infiltration and molecular network analysis highlighted the biological value of CDC45 and CENPE. Single-cell analysis demonstrated the key role of hepatocytes in HCC, while pseudotime analysis revealed the distribution of different cell subtypes. Cell communication analysis showed enhanced interactions between PTTG1-highly expressed cells and fibroblasts, myeloid cells, and endothelial cells; experimental validation confirmed elevated expression of CDC45 and CENPE in the HCC group in addition to PTTG1. Overall, CDC45 and CENPE, as prognostic genes related to PTTG1, provided new research perspectives and potential therapeutic targets for HCC treatment.

Investigating the causal relationships between lipid traits and dementia with lewy bodies: A mendelian randomization study.

Investigating the relationship between dietary vitamin B12 and bone mineral density: Observational and genetic analyses.

Lipoprotein(a) testing trends in young ischemic stroke patients from 2015-2024: An analysis of 188,000 individuals.

Background Endometriosis is a chronic inflammatory disease with a prevalence of approximately 10% in women of childbearing age. Metabolic pathways have been demonstrated by previous studies to be potential avenues for the development of new therapeutic strategies and may be used for early diagnosis of the disease. This study aimed to investigate the potential causal relationships between 1400 metabolites and various endometriosis subtypes using Mendelian randomisation (MR) analysis. Methods Data from a genome-wide association study were analysed. MR analysis was performed using the inverse-variance weighted, MR-Egger, and weighted-median methods, accompanied by heterogeneity testing, sensitivity analysis, and pleiotropy analysis. Metabolic-pathway enrichment analysis was conducted on the preliminarily screened differential metabolites, and colocalisation analysis was subsequently performed for exposure–outcome pairs that remained causally associated after multiple-testing correction. Results After multiple-testing correction, only the glycerol-to-palmitoylcarnitine (C16) ratio reduced the risk of stage 1–2 endometriosis (P FDR = 0.045; odds ratio [OR], 0.737; 95% confidence interval [CI], 0.638–0.852) and pelvic peritoneal endometriosis (P FDR = 0.039; OR, 0.721; 95% CI, 0.619–0.841). Colocalisation analysis revealed that they did not share causal variant loci at the genetic level. No reverse causal associations were found in the reverse Mendelian analysis. Metabolic pathway enrichment analysis identified major metabolic pathways, including caffeine metabolism, glutathione metabolism, arginine biosynthesis, sphingolipid metabolism, pantothenate and CoA biosynthesis, plasmalogen synthesis, and biosynthesis of unsaturated fatty acids. Conclusions Our study suggests potential causal relationships between metabolites and various endometriosis subtypes from an MR perspective. However, the limited number of associations that survived multiple-testing correction indicates that these findings are preliminary and require validation in larger cohorts. This exploratory analysis may contribute to advancing future research on metabolomics-based diagnosis, treatment, and prevention of endometriosis.

ABSTRACT Objective: Venous thromboembolism (VTE) is a significant global health concern. Recent investigations indicate that anemia may increase the risk of VTE. Nevertheless, the presence of confounding variables in observational studies has rendered the causal association between anemia and VTE inconclusive. Methods: This study utilized a two-sample Mendelian Randomization methodology, employing genetic variants derived from specific large-scale genome-wide association studies as instrumental variables to investigate the causal relationship between anemia and VTE. Rigorous statistical analyses were conducted, including the primary analysis based on the inverse-variance weighted (IVW) method, along with supplementary analyses such as MR-Egger, weighted median, and MR-PRESSO, to ensure the reliability and validity of our results. Results: Our analysis suggests a potential causal association between anemia and certain thrombotic events. Anemia was associated with an increased risk of thrombosis and embolism in unusual sites (OR = 1.446, 95% CI: 1.104–1.895, p = 0.007), while aplastic anemia showed a weak positive association with overall VTE risk (OR = 1.065, 95% CI: 1.003–1.131, p = 0.040). Conclusions: Anemia individuals face an increased risk of embolism and thrombosis events, and AA exhibits a potential association with VTE. Nevertheless, a comprehensive comprehension of the precise underlying mechanisms linking anemia/AA and VTE necessitates further exploration through supplementary research.

Background Hypertension is thought to accelerate biological aging. However, evidence of a causal effect is lacking. This study aimed to provide evidence of a relationship between hypertension and biological aging by analyzing data from the 2005–2010 National Health and Nutrition Examination Survey (NHANES) and by Mendelian randomization (MR). Methods The association of hypertension with PhenoAge and PhenoAge acceleration was assessed by weighted multivariable-adjusted linear regression using the NHANES data. Two-sample MR was then performed using summary data from genome-wide association studies to determine causal associations of hypertension with accelerated DNA methylation (DNAm) and proxies of age, including telomere length, frailty index, and facial aging. Inverse variance weighting and complementary MR methods were used to confirm the causal relationship between hypertension and biological aging. The robustness of the results was confirmed by sensitivity analyses. Results Data for 6102 NHANES participants were analyzed. Weighted multivariable-adjusted linear regression analyses showed that hypertension increased PhenoAge (β = 12, 95% CI: 11–13, p < 0.001) and was positively associated with PhenoAge acceleration (β = 0.56, 95% CI: 0.15–0.98, p = 0.009). The MR results also suggested a potential causal association of hypertension with DNAm PhenoAge acceleration (OR 1.31, 95% CI: 1.07–1.60, p < 0.05), DNAm GrimAge acceleration (OR 1.33, 95% CI: 1.13–1.57, p < 0.05), and the frailty index (OR 1.09, 95% CI: 1.07–1.11, p < 0.05). Sensitivity analyses confirmed the robustness and reliability of these findings. Conclusion Hypertension increases PhenoAge and is correlated with PhenoAge acceleration. The potential causal association between hypertension and multiple biological indicators of aging provides clues to the relationship between hypertension and epigenetic aging.

Type 1 and 2 diabetes have been variably associated with reduced forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), but mechanisms remain unclear. This study examined the role of glucose and insulin metabolism for pulmonary function across diabetes (sub)types and normal glucose tolerance as the control (CON) in the German Diabetes Study (GDS) and assessed causality by Mendelian randomization (MR) analyses in independent cohorts. In GDS, 426 spirometry measurements of participants with type 1 diabetes, 482 of participants with type 2 diabetes, and 244 of CON were cross-sectionally analyzed after phenotyping, including Botnia clamps for insulin sensitivity (M value), secretion, and clearance. Associations between metabolic measures and lung function were assessed using generalized linear models, adjusting for confounders. MR analysis used data from the MAGIC (Meta-Analyses of Glucose and Insulin-Related Traits Consortium) consortium (HOMA-insulin resistance [IR], n = 37,037) and the UK Household Longitudinal Study (pulmonary function, n = 321,047). In GDS, higher M value (all β > 0.18, P < 0.0001) and insulin clearance (all β = 0.05, P < 0.050) were associated with higher FEV1 and FVC. Compared with type 1 diabetes and CON, type 2 diabetes had lower FEV1 and FVC, which associated with M value (all β > 0.17, P < 0.050). FEV1 was associated with daily insulin doses in type 1 diabetes (β = -0.21, P = 0.0006). FEV1 was associated with type 2 diabetes (β = -0.19, P = 0.0052), severe insulin resistant (β =-0.27, P = 0.039), and mild age-related diabetes (β = -0.23, P = 0.0033). MR supported a causal association between HOMA-IR and lower FEV1 (β = -0.13, P = 0.0018). Lower FEV1 and FVC in diabetes are linked to insulin resistance, impaired clearance, and higher insulin doses, all of which result in higher insulinemia and likely represent underlying pathogenic mechanisms.

Objective The concurrent prevalence of major depression and hypertension represents a significant clinical concern. This study aims to investigate the potential causal relationship among these conditions from a genetic standpoint. Methods The genome-wide association studies (GWAS) summary data for major depression were obtained from the IEU OpenGWAS database. Concurrently, GWAS summary data for hypertension were sourced from the Finnish consortium. All the participants have European ancestry. A two-sample bidirectional Mendelian randomization (MR) study was conducted to examine the relationship between major depression and hypertension. To ensure the reliability of the results, several sensitivity analyses were performed, addressing heterogeneity, horizontal pleiotropy, outliers, the influence of individual single nucleotide polymorphisms (SNPs), and adherence to normal distribution assumptions. Results The findings revealed a significant positive genetic causal association between major depression and hypertension (P = 0.016, odds ratio [OR] = 1.160, 95% confidence interval [CI] = 1.029−1.308). Conversely, no genetic causal relationship was identified between hypertension and major depression (P = 0.670, OR = 1.004, 95% CI = 0.985−1.024). Our MR analysis indicated the absence of heterogeneity and horizontal pleiotropy, with no detected outliers. Additionally, the analysis was not influenced by any SNP and demonstrated a normal distribution. Conclusion The results of this study indicate that severe depression is a risk factor for hypertension of European ancestry. The conclusion of this study should be used with caution when applied to other populations. Clinically depressed patients should be closely monitored for the onset of hypertension.

ABSTRACT Introduction Recombinant Zoster Vaccine (RZV) is recommended for Herpes Zoster (HZ) prevention in high-risk patients over 18 years of age. Research design and methods This is a prospective population-based study conducted over a three-year period in a Southern Italian General Hospital. The study population was represented by RZV recipients with diverse chronic comorbidities. Adverse Events Following Immunization (AEFIs), baseline disease flares and post-vaccination HZ episodes were evaluated through sequential follow-ups conducted 7 days, 3 months, and 3–38 months post-vaccination, respectively. Results Study population included 787 RZV recipients, mostly affected by onco-hematological, cardiovascular and rheumatological disorders. The AEFIs reporting rate was 44.15%. The most frequent symptoms were injection site pain/itching (37.19%), asthenia/malaise (12.74%) and fever (10.30%). Three serious AEFIs with consistent causal association with vaccination were recorded (0.22%), all of which underwent full recovery. Sixteen patients (2.37%) experienced a baseline condition flare-up within 3 months (mean interval 33.88 ± 24.88 days). Multiple baseline disorders (OR:1.97; 95%CI:1.37–2.83; p-value < 0.001) and rheumatological conditions (OR:11.67; 95%CI:2.00–68.27; p-value < 0.01) increased flare risk, while male sex decreased it. Twenty-six vaccinees manifested HZ post-vaccination (cumulative incidence rate 5.05/100,000 person-days), with particularly increased incidence in patients with recurrent/severe HZ history (IRR:14.35; 95%CI:5.64–34.04; p-value < 0.001). Conclusion The study demonstrates RZV safety and HZ protection in vulnerable patients, consistently with available evidence.

To investigate the causal association between gastroesophageal reflux disease (GERD) and chronic kidney disease (CKD) progression and its potential metabolic mediators. Summary-level data were extracted from the overall genome-wide association studies of the FinnGen and UK Biobank databases. This study employed two-sample, bidirectional, two-step, and multivariable Mendelian randomization (MR) techniques, utilizing single-nucleotide polymorphisms (SNPs) as genetic instruments for exposure and mediators, thereby minimizing bias due to confounders and reverse causation. We harnessed summary-level data from a genome-wide association study of GERD, proposed mediators, and CKD progression, including CKD, kidney failure, and dialysis-dependent kidney failure. The total effect of GERD on CKD progression was decomposed into direct effects and indirect effects through multiple mediators. GERD was associated with an increased risk of CKD (odds ratio [OR]: 1.18, 95% confidence interval [CI]: 1.05–1.33), kidney failure (1.23, 1.11–1.36), dialysis-dependent kidney failure (1.26, 1.19–1.34), whereas the reverse causality hypothesis did not hold. Type 2 diabetes mellitus (T2DM) mediated 14.33%–43.24% of the effect of GERD on CKD progression, which was followed by systolic blood pressure (mediation: 3.85%–5.46%). These results supported a potentially causal damage effect of GERD against CKD progression, which T2DM and SBP considerably mediate. Interventions with these factors could significantly decrease the burden of CKD attributable to GERD.

ABSTRACT Objective Based on Mendelian randomization (MR) methods, this study aims to explore causal associations of uric acid (UA) levels with aortic aneurysms (AAs). Methods In this MR study, data on UA levels and gout were extracted from genome-wide association study (GWAS) meta-analysis conducted by UK Biobank (UKB) for European population and the Biobank Japan Project (BBJ) for Asian population. Summary statistics of AAs were obtained from different databases. Inverse variance weighted (IVW), weighted-mode, weighted median, MR-Egger, and MR-PRESSO methods were used to examine the potential causal association of UA with AAs. Results The IVW estimates indicated that elevated UA level was associated with higher AAA risk among the European population (OR = 1.315, 95%CI: 1.024–1.689). In the Asian population, the UA level was positively linked to the odds of AA (OR = 1.393, 95%CI: 1.061–1.829). In addition, sensitivity analyses through MR leave-one-out and single SNP effect methods showed that these results were relatively robust. Conclusions UA may be a potential risk factor for AAs, indicating that clinicians should focus on serum UA levels among populations with high-risk of AAs. Studies to reveal the true relationship between them and clarify the underlying mechanism are still needed in the future.

Abstract Background Although Genome-Wide Association Studies (GWAS) link genetic variants to kidney disease, the specific role of phase separation-related genes (PSGs) in renal failure pathogenesis is unknown. This study investigates the potential of PSGs as novel biomarkers to improve the early detection and treatment of renal failure. Methods We created ten gene co-expression modules and associated cluster trees using enrichment and differential expression analysis. The final phase separation-related biomarkers were screened using three machine classification algorithms, and each gene's functional pathways and relationship to immune function were examined. In order to thoroughly confirm the link between potentially linked genes and the onset of renal failure, the study also employed Mendelian Randomization (MR) and supervised and unsupervised machine learning. It also showed the statistical power of unsupervised learning and the results of additional verification. Results According to the correlation of gene expression, ten genes that may be related to renal failure were screened out. Linking phase separation to renal failure identified two core phase separation-related genes, ARL6IP4 and MRRF . Mendelian randomization provided suggestive evidence of a potential causal association between genetically predicted constipation and increased risk of renal failure. Conclusions This study points to a higher potential of MRRF as a biomarker for renal failure than ARL6IP4 . There may also be a potential causal association between the prevalence of constipation and the incidence of renal failure.

ABSTRACTBackgroundAlthough previous studies have suggested an association between hemoglobin (Hb) concentration and amyotrophic lateral sclerosis (ALS), the precise cause‐and‐effect relationship between them is still unclear. This study aims to investigate the causal correlation between Hb concentration and ALS, and explore the potential genes related to their association.MethodsWe extracted summary statistical data of Hb concentration and ALS from genome‐wide association studies (GWAS), performed Mendelian randomization (MR) analyses, and conducted RNA sequencing of motor neurons different from ALS patient‐derived induced pluripotent stem cells (iPSCs), followed by an intersection analysis between differentially expressed genes (DEGs) in ALS motor neurons and selected instrumental variables (IVs) associated with Hb concentration.ResultsAs a result, Hb concentration had a negative causal relationship with the risk of ALS, established through IVW (OR = 0.854; 95% CI: 0.767–0.951; p = 0.00418) of the univariable MR analysis. A multivariable MR further confirmed that this causal link remained robust, even when accounting for confounders including systolic blood pressure, total cholesterol levels, body mass index, LDL cholesterol, diastolic blood pressure, and smoking. Importantly, genetically predicted ALS did not show a causal connection to Hb concentration. Additionally, RNA sequencing analysis and qRT‐PCR results revealed that transcripts for BACH1 and FLVCR1 were upregulated, while those for TRIM58 were downregulated in SOD1D90A ALS motor neurons, compared to the control. In motor neurons differentiated from a sporadic ALS patient‐derived iPSCs, qRT‐PCR showed increased transcript levels of BACH1, and decreased transcript levels of FLVCR1 and TRIM58. These three genes were intersected with harmonized SNPs between Hb concentration and ALS.ConclusionOur study concludes that genetically predicted Hb concentration exhibited an independent inverse causal association with the risk of developing ALS, with potential involvement of genes such as BACH1, FLVCR1, and TRIM58.