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PubMed2026

The role of ferroptosis in juvenile idiopathic arthritis: Causal inference and mediation by immune phenotypes.

This study employed a bidirectional 2-step, two-sample Mendelian randomization approach to investigate the causal relationships between ferroptosis-related genes and juvenile idiopathic arthritis (JIA) and to explore the mediating role of immune cells. Ferroptosis genes were identified from the deCODE database and matched with protein quantitative trait locus data as exposures to evaluate their causal effects on JIA, while immune cell traits were similarly assessed. For genes showing positive Mendelian randomization results, further analyses were conducted to determine whether immune cells mediated the effects on JIA, with mediation analysis performed only in the presence of causal associations. Data were sourced from the GWAS, FerrDb, and other public repositories. Nine ferroptosis-related genes were found to have causal links with JIA: HSPB1, DECR1, LIFR, and CTSB increased JIA risk, whereas PIEZO1, DPP4, BID, and others were protective. Forty immune cell traits were also causally associated with JIA. Mediation analysis revealed that several immune cells, including CD127- CD8+ T cells, partially mediated the genetic effects, with mediation proportions reaching up to 18.6%. Collectively, these results point to a ferroptosis-immune-JIA axis, suggesting that ferroptosis-related genes contribute to JIA pathogenesis through immune cell mediation and offering new mechanistic insights and potential therapeutic targets.

Arthritis, Juvenile↗

PubMed2026

Shared genetic architecture and neurobiological pathways of problematic alcohol use and anxiety disorders.

Problematic alcohol use (PAU) and anxiety disorders (ANX) frequently co-occur, implying shared genetic and neurobiological foundations. However, the directionality of potential causal relationships and the specific mechanisms underlying the overlap remain unclear. Thus, we investigated the shared genetic architecture and neurobiological pathways between PAU and ANX using a multimethod genomic approach. We analyzed summary statistics from genome-wide association studies (GWAS) of PAU and ANX using Mendelian Randomization to assess causal associations between ANX and PAU. We used MiXeR to assess the overall shared genomic architecture, Local Analysis of (co)Variant Association to estimate regional genetic correlations, and conjunctional false discovery rate (conjFDR) to identify individual overlapping loci. We used FUMA to map single-nucleotide polymorphisms (SNPs) to independent loci, conduct differential gene expression analyses across 30 general and 54 specific tissue types, and perform cell-type specificity analyses using a human brain cell atlas. Druggability of identified targets was also evaluated. Mendelian Randomization analyses indicated bidirectional causal associations between ANX and PAU. MiXeR identified moderate polygenic overlap (52.5%) and genetic correlation (rg = 0.44) between the traits, with high effect direction concordance among shared estimated causal variants (86.4%). ConjFDR identified 97 shared lead SNPs, of which 89 had concordant and 8 discordant effects on PAU and ANX. These loci mapped to 97 genes, including DRD2 and PDE4B, genes linked to dopaminergic and cAMP signaling pathways, respectively. Concordant gene expression was enriched in brain, nerve, adrenal gland, esophagus, stomach, and colon, with enriched expression specifically in the prefrontal cortex, anterior cingulate cortex, hippocampus, hypothalamus, substantia nigra and amygdala. FUMA cell-type enrichment analysis identified associations predominantly in neurons from the cerebral cortex, hippocampus, and thalamus. We found substantial genetic and neurobiological overlap between PAU and ANX, highlighting reciprocal, causal relationships between the traits, with differentially expressed genes enriched in addiction- and anxiety-relevant brain regions. These findings support shared genetic and neurobiological mechanisms linking PAU and ANX, while acknowledging that some signals may reflect broader internalizing or psychiatric liability.

Journal Article↗

PubMed2026

GWAS Meta-analysis Identifies Novel Associated Loci and Points to Causal Tissues in Central Serous Chorioretinopathy.

OBJECTIVE: To define CSC genetic architecture and identify implicated ocular tissues, cell types, genes, and circulating proteins. DATA SOURCES: Genome-wide data were assembled from FinnGen, All of Us, Mass General Brigham Biobank, Million Veteran Program, and a Dutch chronic CSC cohort. Serum protein quantitative trait loci, human single-cell ocular atlases, and UK Biobank macular optical coherence tomography (OCT) imaging were used for downstream analyses. STUDY SELECTION: Five European-ancestry cohorts with genome-wide data and cohort-specific CSC case-control definitions were included, comprising 2,584 cases and 1,044,455 controls. Variants present in at least 2 cohorts were meta-analyzed. DATA EXTRACTION AND SYNTHESIS: Cohort-level GWASs were adjusted for age, age squared, sex, genotyping array or batch, and 10 genetic principal components, then combined using fixed-effects inverse-variance meta-analysis. Post-GWAS analyses included gene prioritization, colocalization, Mendelian randomization, single-cell disease-relevance scoring, and testing of a CSC genetic risk score in UK Biobank OCT images. MAIN OUTCOMES AND MEASURES: Genome-wide significant CSC loci, effector genes and proteins, tissue and cell-type enrichment, and CSC-relevant OCT abnormalities. RESULTS: Across 11,068,938 variants, 10 loci reached genome-wide significance (P < 5 × 10-8), including 3 novel loci near TGFB1, LINC00551, and LOC105375630 and 7 replicated loci near CFH, CD46, NOTCH4, PREX1, PTPRB, GATA5, and TNFRSF10A. Integrative analyses prioritized 10 candidate effector genes. Colocalization and Mendelian randomization implicated circulating TNFRSF10A, TGFB1, and CASP10 levels. Single-cell analyses localized genetic risk to sclera (P = 2.0 × 10-4) and vascular endothelial cells (P = 4.0 × 10-4), with fibroblast enrichment. In UK Biobank, OCT abnormalities were more frequent in the top vs bottom 1% of CSC genetic risk (18 of 109 [16.5%] vs 8 of 134 [6.0%]; odds ratio, 4.05; 95% CI, 1.65-10.87; P = .002). CONCLUSIONS AND RELEVANCE: In this GWAS meta-analysis, CSC susceptibility localized predominantly to scleral and vascular biology rather than primary retinal pigment epithelial dysfunction. These findings support CSC as a sclerovascular disorder and nominate complement regulation, endothelial signaling, and extracellular matrix pathways for future study.

Journal Article↗

PubMed2025

Post-traumatic stress disorder and REM-sleep behavior disorder: exploring genetic associations and causal links.

OBJECTIVE: To explore potential genetic and/or causal associations between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder. METHODS: We conducted polygenic risk score, genetic correlation, and Mendelian randomization analyses using the latest genome-wide association studies summary statistics and individual genotyping data. Next, a blinded observer examined dopamine transporter imaging binding status-a marker of neurodegeneration-in patients with isolated/idiopathic rapid-eye movement sleep behavior disorder, with (N = 6) and without Post-Traumatic Stress Disorder (N = 32). RESULTS: Polygenic risk scores for Post-Traumatic Stress Disorder were associated with isolated/idiopathic rapid-eye-movement sleep behavior disorder, with each standard deviation increase linked to 14.7% higher odds (odds ratio = 1.15, 95% confidence interval: 1.04 to 1.26, p = 0.005). However, genetic correlation was weak, and Mendelian randomization did not support a potential causal relationship. The proportion of individuals with abnormal dopamine transporter imaging binding status was significantly higher in the Post-Traumatic Stress Disorder group compared to those without the disorder (p=0.01, X2 = 6.62). INTERPRETATION: Polygenic risk scores analysis identified an association between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder, consistent with the result from the small exploratory substudy. The lack of strong genetic correlation or causation may reflect limited sample size. Further research with larger and more diverse cohorts is crucial to clarify the genetic, biological and physiological mechanisms underlying this association.

Journal Article↗

PubMed2026

Shared genetic architecture of obesity and gastroesophageal reflux disease.

Obesity is identified as a risk factor of gastroesophageal reflux disease (GERD). This study aims to elucidate the shared genetic architecture of obesity-related phenotypes and GERD. Based on the publicly available genome-wide association studies' datasets, this genome-wide pleiotropic association study was conducted with various genetic approaches (including linkage disequilibrium score regression, high-definition likelihood inference for genetic correlations, pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation, Bayesian colocalization, summary-based Mendelian randomization, and multi-marker analysis of genomic annotation analysis) sequentially to unravel the genetic associations from single-nucleotide polymorphism to gene levels, and to reveal the underlying shared genetic architecture between obesity-related phenotypes and GERD. This study discovered shared genetic mechanisms between GERD and several obesity-related phenotypes, including arm fat percentage (left), arm fat percentage (right), leg fat percentage (left), leg fat percentage (right), trunk fat percentage, waist-to-hip ratio, and body mass index. Significant genetic correlations were observed by linkage disequilibrium score regression and high-definition likelihood inference for genetic correlations, with multiple associated pleiotropic loci and their mapped genes identified by pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation, Bayesian colocalization, summary-based Mendelian randomization, and multi-marker analysis of genomic annotation analysis. Additionally, several brain tissues were identified to be linked to both obesity and GERD by multi-marker analysis of genomic annotation. This research provided strong evidence of genetic correlations and brought novel insights into the underlying genetic connections and shared genetic architectures of obesity and GERD.

Humans↗

PubMed2026

Shared genetic architecture between ADHD and intelligence varies across ADHD subtypes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition frequently accompanied by cognitive difficulties. Although previous genetic studies have demonstrated substantial overlap between ADHD and intelligence, most have treated ADHD as a single phenotype. However, whether this shared genetic architecture differs across ADHD subtypes remains unclear. METHODS: We conducted a genome-wide cross-trait analysis integrating large-scale genome-wide association study (GWAS) datasets of overall ADHD, its subtypes-childhood ADHD, persistent ADHD, and late-diagnosed ADHD-and intelligence (total N > 300,000). Genome-wide genetic correlations, polygenic overlap, local genetic correlations, and variant-level associations between ADHD phenotypes and intelligence were evaluated to characterize their shared genetic architecture. Shared variants were identified through cross-trait enrichment analyses and subsequently mapped to genes for functional annotation and gene-set enrichment. Bidirectional associations were evaluated using two-sample Mendelian randomization with sensitivity analyses. Additional GWAS datasets were used to validate the robustness of shared loci by assessing the consistency of effect directions. RESULTS: All ADHD phenotypes showed significant negative genetic correlations with intelligence (rg ranging from -0.3442 to -0.4205). Despite these modest genome-wide correlations, cross-trait analyses revealed substantial genetic overlap, including polygenic overlap, local genetic correlations, and variant-level associations. We identified 184 loci jointly associated with ADHD traits and intelligence, including 64 novel loci, whereas no shared loci were detected for persistent ADHD under the current analysis. Functional annotation revealed biologically distinct enrichment patterns across subtypes: childhood ADHD loci were linked to early neurodevelopmental processes, while late-diagnosed ADHD loci were enriched in synapse-related and neuronal signaling pathways. Mendelian randomization analyses suggested bidirectional associations, with stronger evidence supporting a directional association from intelligence to ADHD risk. Furthermore, these shared loci showed largely consistent effect directions across additional GWAS datasets, providing support for the robustness of the findings. CONCLUSIONS: The shared genetic architecture between ADHD and intelligence varies across ADHD subtypes, highlighting distinct biological pathways underlying cognitive heterogeneity in ADHD. These findings suggest that the relationship between ADHD liability and general cognitive ability is not uniform across ADHD subtypes and may inform future research on risk stratification and early identification in child and adolescent psychiatry.

Humans↗

PubMed2026

Association Between Ticagrelor and Glucose Homeostasis Regulation: Insights from Genetic and Transcriptomic Analyses.

Emerging evidence has demonstrated the additional therapeutic benefits of ticagrelor in acute coronary syndrome (ACS) patients with diabetes. However, the underlying mechanisms of this association remain elusive. Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data on ticagrelor, plasma proteomics and type 2 diabetes was employed to identify causal mediator proteins. RNA sequencing (RNA-seq) of ticagrelor-treated HepG2 cells revealed the molecular pathways regulating glucose metabolism. Genetically proxied ticagrelor was significantly associated with a reduced risk of diabetes (OR = 0.859, 95% CI: 0.783-0.934, P = 7.98E-05), and 24.41% of this effect was mediated by upregulation of BDH2 protein. In vitro experiments confirmed the enhanced effect of ticagrelor on glucose consumption. Transcriptome analysis revealed that mitochondrial respiratory chain transfer and oxidative phosphorylation (OXPHOS) were significantly enriched, and genes related to ATP biosynthesis were significantly upregulated. These findings highlight the non-platelet function of ticagrelor in maintaining glucose homeostasis, providing insights into potential drug repurposing in the future.

Humans↗

PubMed2025

Genomics-informed drug-repurposing strategy identifies two therapeutic targets for preventing liver disease associated with metabolic dysfunction.

Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving the treatment of diseases. We employed a cross-disciplinary approach to identify potential therapeutics for the prevention of metabolic-dysfunction-associated steatotic liver disease (MASLD) in at-risk individuals by using humans as a model organism. We identified 212 putative candidate genes associated with MASLD by using data from a large multi-ancestry genetic association study, of which 158 (74.5%) were previously unreported. From this set, we identified 57 genes that encode for druggable protein targets and for which the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. We then used We then evaluated these potential targets for evidence of efficacy by using Mendelian randomization, pathway analysis, and protein structural modeling. Through these approaches, we present compelling evidence to suggest that the activation of FADS1 by icosapent ethyl, as well as S1PR2 by fingolimod, could be a promising therapeutic strategy for MASLD prevention.

Humans↗

PubMed2026

Cross-tissue multi-omics integration highlights BPHL and mitochondrial targets in Alzheimer's disease.

BACKGROUND: Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD), yet specific molecular targets remain to be fully characterized. METHODS: A summary-data-based Mendelian randomization (SMR) framework integrated AD genome-wide association study (GWAS) statistics (39,918 cases) with blood DNA methylation quantitative trait loci (mQTL), gene expression (eQTL), and protein (pQTL) data for 1136 mitochondria-related genes. Associations were assessed using Bayesian colocalization and HEIDI testing. Tissue relevance was evaluated in four brain regions (hippocampus, amygdala, cortex, frontal cortex) using GTEx and external transcriptomic datasets. RESULTS: Screening identified eight candidates supported across blood mQTL and eQTL layers. Stepwise central nervous system (CNS) evaluation singled out biphenyl hydrolase-like (BPHL) as the consistent candidate. Higher genetically predicted BPHL expression was associated with reduced AD risk across the hippocampus (OR=0.920, 95% CI 0.873-0.970), amygdala (OR=0.925, 95%CI 0.880-0.973), cortex (OR=0.943, 95% CI 0.908-0.978), and frontal cortex (OR=0.938, 95%CI 0.901-0.976). These findings aligned with protein-protein interactions connecting BPHL to respiratory complexes and lower BPHL expression in independent AD brains. Functional enrichment converged on oxidative phosphorylation pathways. CONCLUSIONS: By integrating multi-omics data with tissue-specific validation, this study nominates BPHL as a consistent protective candidate in the brain. These findings provide genetic support for mitochondrial molecular perturbations in AD, offering insights for future validation.

Alzheimer Disease↗

PubMed2025

Association Analysis of the Circulating Proteome With Sarcopenia-Related Traits Reveals Potential Drug Targets for Sarcopenia.

BACKGROUND: Sarcopenia severely affects the physical health of the elderly. Currently, there is no specific drug available for sarcopenia. This study aims to identify pathogenic proteins and druggable targets for sarcopenia through Mendelian randomization (MR)-based analytical framework. METHODS: A sequential stepwise screening method that includes two-sample MR, Steiger filtering test and colocalization (MRSC) was applied to identify causal proteins associated with sarcopenia-related traits. In the MR analyses, 4372 circulating proteins with valid instrumental variables (IVs) from eight proteomic genome-wide association studies were utilized as exposures, and nine sarcopenia-related traits were utilized as outcomes. IVs were classified into cis-protein quantitative trait loci (pQTLs) and trans-pQTLs based on their positions. We conducted cis-only MRSC analyses and cis + trans MRSC analyses using cis-pQTLs and cis + trans pQTLs as IVs, respectively. Post-MRSC analyses were conducted on the prioritized findings of MRSC, including annotation of protein-altering variants (PAVs), assessment of overlap between pQTLs and expression quantitative trait loci (eQTLs), protein-protein interaction (PPI) analysis, pathway enrichment analysis and annotation of drug targets. Utilizing data from the UK Biobank, we performed an observational study to explore the associations between baseline circulating protein levels and the longitudinal changes in nine sarcopenia-related traits. RESULTS: A total of 181 causal associations for 65 proteins were prioritized by the cis-only MRSC analyses and 227 associations for 91 proteins were prioritized by the cis + trans MRSC analyses. Among the prioritized proteins, the majority of them employed non-PAVs as IVs and most of their cis-pQTLs overlapped with corresponding eQTLs and exhibited consistent directionality, with only one trans-pQTL overlapping with an eQTL. The PPI network of cis-only MRSC-prioritized proteins (p = 4.04 × 10-4) and cis + trans MRSC-prioritized proteins (p = 8.76 × 10-5) showed significantly more interactions than expected. Reactome, KEGG and GO pathway enrichment analyses for cis-only MRSC-prioritized proteins identified 52, 12 and 79 enriched pathways, respectively (adjusted p < 0.05). For proteins identified by cis + trans MRSC analyses, only 15 pathways were enriched through the GO pathway enrichment analyses. In the observational study, 197 circulating proteins were identified to be associated with one or more sarcopenia-related traits (p < 0.05/2923). Among them, the significant associations of CTSB (negative association) and ASGR1 (positive association) with sarcopenia-related traits were observed to have consistent directional associations in both MR-based studies and observational studies. Drug target annotations suggested that 52 MRSC-prioritized proteins and 145 biomarkers are drug targets or druggable. CONCLUSIONS: This study identified 89 potential pathogenic proteins and 197 candidate biomarkers for sarcopenia, providing valuable clues for the development of therapeutic drugs for sarcopenia.

Humans↗

PubMed2026

Ferroptosis as a mediator of gut microbiota-driven inflammatory bowel disease: Evidence from genetic analyses.

Gut microbiota dysbiosis is increasingly recognized as a contributor to inflammatory bowel disease (IBD), yet causal relationships and underlying mechanisms remain unclear. Ferroptosis, an iron-dependent form of regulated cell death, plays a key role in epithelial barrier damage and inflammation. This study aimed to determine whether specific gut microbial taxa are causally associated with IBD and whether ferroptosis-related genes mediate this association using Mendelian randomization (MR). Two-sample MR and mediation MR analyses were performed using genome-wide association study summary data from the FinnGen consortium (IBD), the genome-wide association study catalog (473 gut microbial taxa), and the deCODE database (ferroptosis-related genes). Instrumental variables were selected with thresholds of P < 1 × 10-6 for microbes and P < 5 × 10-8 for traits, and linkage disequilibrium clumping (r2 < 0.001) was applied. Twenty-three microbial taxa showed significant causal associations with IBD (e.g., Chromatiales, OR = 0.51; Acetobacterales, OR = 2.61). Several ferroptosis-related genes were linked to IBD risk (e.g., GPX4, STAT3, IDO1). Mediation MR revealed that genes such as MUC1, IDO1, and ADAM23 partially mediated microbial effects on IBD, with mediation proportions up to 7.6%. This study provides novel genetic evidence supporting a gut microbiota-ferroptosis-IBD axis. Ferroptosis-related pathways may partially mediate microbial effects on IBD pathogenesis and represent promising targets for future therapeutic interventions.

Ferroptosis↗

PubMed2026

Plasmacytoid dendritic cell-mediated L-glutamate catabolism links gut microbiota to male infertility.

Emerging evidence suggests that gut microbiota composition influences male reproductive health; however, the immunometabolic mechanisms underlying this association remain insufficiently characterized. We investigated whether specific immune cell-mediated metabolic pathways, particularly plasmacytoid dendritic cell (pDC)-driven L-glutamate catabolism via the hydroxyglutarate pathway, contribute to the causal link between gut microbiota and male infertility. We conducted a 2-sample, 2-step Mendelian randomization (MR) analysis using inverse-variance weighting as the primary estimator and Bayesian weighted MR for robustness. Exposure data comprised 412 gut microbial taxa/metabolic pathways and 731 immune cell phenotypes from large European-ancestry genome-wide association studies. Male infertility genome-wide association studies data (1429 cases; 128,710 controls) were obtained from FinnGen R10. Only exposure-mediator-outcome pairs meeting stringent pleiotropy, heterogeneity, and reverse-causality criteria were retained for mediation analysis. Nine microbial taxa/metabolic pathways and 18 immune traits exhibited putative causal associations with male infertility. The L-glutamate degradation V pathway via hydroxyglutarate was linked to reduced infertility risk (inverse-variance weighting odds ratio [OR] = 0.68; 95% confidence interval, 0.52-0.89; P = .005). Two-step MR suggested that forward scatter area on pDCs may mediate this association, although the mediation effect was imprecise (effect = 0.0277; 95% confidence interval, -0.0348 to 0.0903). This study provides suggestive genetic evidence that pDC-mediated glutamate catabolism may connect gut microbial metabolic activity to male infertility. These findings highlight immunometabolic pathways as testable targets for mechanistic validation and microbiota-directed interventions.

Male↗

PubMed2025

Identifying key palmitoylation-associated genes in endometriosis through genomic data analysis.

BACKGROUND: Palmitoylation, a post-translational lipid modification, has garnered increasing attention for its role in inflammatory processes and tumorigenesis. Emerging evidence suggests a potential association between palmitoylation and inflammatory responses in the pathogenesis of endometriosis. However, the precise mechanistic interplay remains elusive, necessitating further investigation. METHODS: This study integrated transcriptomic analysis and Mendelian randomization (MR) to identify a causal gene set implicated in endometriosis. Differentially expressed genes (DEGs) were first identified in the training dataset using the limma package in R. Weighted gene co-expression network analysis (WGCNA) was subsequently performed, leveraging Single Sample Gene Set Enrichment Analysis (ssGSEA)-derived scores of palmitoylation-related genes (PRGs) as phenotypic traits to identify key modular genes. The intersection of these key modular genes with DEGs yielded a refined gene set. Machine learning algorithms were then applied to further optimize gene selection, followed by external validation, immune infiltration analysis, RNA network construction, and exploration of potential targeted drug candidates. RESULTS: Through a rigorous screening process, VRK1, GALNT12, and RMI1 emerged as key genes associated with palmitoylation, exhibiting significant downregulation in endometriosis samples (P < 0.05), indicative of a potential protective role. Immune infiltration analysis further revealed strong correlations between these genes and M2 macrophages as well as resting Natural Killer (NK) cells. Additionally, investigations into the targeted RNA network and drug association profiling provided novel insights, laying the groundwork for future high-quality validation studies. CONCLUSIONS: This study employed a comprehensive analytical framework to identify palmitoylation-associated key genes in endometriosis. The integration of immunoinfiltration analysis, RNA network construction, and drug association profiling offers valuable insights for advancing clinical diagnostics, disease monitoring, and therapeutic development in endometriosis.

Humans↗

PubMed2026

Microglial PICALM: A novel genetic driver and therapeutic target in vascular dementia.

BACKGROUND: Vascular dementia (VaD) lacks well-defined genetic mechanisms. Cell-type-specific effects of GWAS loci remain unexplored. METHODS: We integrated single‑cell eQTL data (183 donors, eight cell types) with VaD GWAS (3624 cases, 475,484 controls) using Mendelian randomization and Bayesian colocalization, replicated in an independent cohort (2074 cases, 456,366 controls). Subtype, snRNA‑seq, cell‑cell communication, PheWAS, expression profiling, and drug prediction with BBB permeability assessment were performed. RESULTS: Microglial PICALM was the only robustly replicated signal (OR = 0.8334, p = 5.3 × 10⁻⁴; colocalization PP.H4 > 0.75). The effect was strongest in multiple infarctions dementia (OR = 0.7746). Exploratory snRNA-seq analysis (4 VaD vs. 4 controls; GSE282111) provided supporting evidence for microglial PICALM enrichment and downregulation (p < 0.001). PICALM‑high microglia showed enhanced neurovascular‑ and phagocytosis‑related communication (e.g., SPP1, GAS6, GRN). PheWAS revealed no pleiotropy. In silico drug repurposing prioritised three FDA-approved BBB-penetrant compounds (disopyramide, benzocaine, amantadine) as candidates warranting further mechanistic validation. CONCLUSIONS: Microglial PICALM is identified as a likely genetic determinant of VaD, especially in the multiple infarctions subtype. Upregulating PICALM may be associated with a neuroprotective microglial phenotype, highlighting PICALM as a candidate therapeutic target warranting further experimental validation.

Humans↗

PubMed2026

Genetic Association of the Transcriptome and Immunoglobulin G N-glycome with Cognitive Function.

OBJECTIVE: Immunoglobulin G (IgG) N-glycosylation is associated with mild cognitive impairment through the regulation of inflammatory balance; however, the underlying mechanisms remain unclear. METHODS: Our study utilized a post-genome-wide association studies (GWAS) method that integrated GWAS data for cognitive function with gene expression quantitative trait loci (eQTL), protein QTL (pQTL), and IgG N-glycan-QTL data. RESULTS: Mendelian randomization (MR) analyses suggested bidirectional causalities between glycan peaks (GPs) and cognitive function, with GP7, GP12, and GP19 showing a causal effect on cognitive function, while cognitive function conversely showed a causal effect on GP1 and GP8. Two proteins and 10 genes were implicated in the regulation of IgG N-glycosylation. Furthermore, multivariable MR results suggested complex causalities between genes/proteins and IgG N-glycans, which jointly promote or independently affect cognitive function. CONCLUSION: Our study reveals a novel mechanism by which genes, proteins, and modified IgG N-glycans converge to pathologically affect cognitive function.

Immunoglobulin G↗

PubMed2026

Mapping the immune-genetic architecture of Epstein-Barr virus-related phenotypes and multiple sclerosis through a single-cell genetic framework for target prioritization and pharmacologic hypothesis generation.

BACKGROUND: Multiple sclerosis (MS) is a severe neuroinflammatory disease causing substantial long-term disability. Strong epidemiologic evidence links Epstein-Barr virus (EBV) exposure with MS risk, but genetic evidence for immune target prioritization in EBV-related phenotypes remains limited. METHODS: We integrated single-cell cis-eQTL data from 14 immune cell types with GWASs of an EBV-related clinical phenotype and MS using a single-cell Mendelian randomization framework with colocalization analyses. Candidate eGenes were evaluated in independent cohorts. For multi-SNP instruments, we performed heterogeneity, pleiotropy, MR-Egger, weighted median, mode-based, and MR-PRESSO sensitivity analyses. We also conducted phenome-wide association analyses and queried DrugBank to annotate candidate compounds targeting prioritized genes. RESULTS: We prioritized 43 immune-cell-specific candidate eGenes with convergent genetic support, including 6 for the EBV-related phenotype and 37 for MS. SERPINB1 in NK cells was associated with increased risk of the EBV-related phenotype, whereas HLA-G was associated with decreased risk. For MS, APOM and MSH5 showed protective associations, while AHI1 showed cell-type-dependent, bidirectional associations across immune lineages. Colocalization and independent cohort evaluation supported these findings. Among FDR-significant multi-SNP associations, MR-Egger intercept tests did not indicate directional pleiotropy, although a small subset showed heterogeneity or MR-PRESSO signals. Phenome-wide analyses identified no significant adverse phenotypic associations among evaluable genes at the prespecified threshold. DrugBank annotation nominated sodium nitroprusside, fasudil, artenimol, and choline as hypothesis-generating compounds for experimental follow-up. CONCLUSIONS: This study provides a single-cell genetic framework for prioritizing immune-cell-specific candidate targets for EBV-related phenotypes and MS, and nominates genetically supported targets and pharmacologic hypotheses for experimental investigation.

Humans↗

PubMed2026

TL-HDMR: a transfer learning framework for advancing equitable causal inference reveals metabolic signatures of stroke across multiple ancestries.

The limited genetic diversity in genome-wide association studies (GWAS) poses a significant challenge to the generalizability and equity of biomedical discoveries. Most causal inferences, particularly from high-dimensional phenomes (e.g. metabolomics), are primarily based on European populations, and their applicability to other ancestries remains uncertain. Traditional multivariable Mendelian randomization (MVMR) methods further struggle in high-dimensional and correlated settings due to collinearity and model instability. To bridge this gap, we present a two-step transfer learning framework for high-dimensional MR (TL-HDMR), designed to enhance causal exposure detection in understudied populations. Our approach leverages the Minimax Concave Penalty for asymptotically unbiased estimation amidst exposure correlations. Crucially, we introduce two novel pre-transfer procedures-HDMR.TSD for sourcing beneficial data and HDMR.PRESSO for filtering pleiotropic instruments-to ensure robust knowledge transfer. Extensive simulations demonstrated TL-HDMR's superior performance in ROC curves and mean absolute error over alternative methods. When applied to identify causal metabolites for stroke across multi-ancestry cohorts (European, East Asian, South Asian, and African), TL-HDMR successfully pinpointed both shared and ethnic-specific causal biomarkers, showcasing its unique capability for equitable causal inference. This work provides a powerful statistical tool that not only addresses critical methodological challenges but also promotes inclusivity and fairness in human health research.

Humans↗

PubMed2026

Shared Genetic Basis, Biological Function and Causal Relationship Between Sleep Traits and Hypothyroidism: Evidence from a Comprehensive Genetic Analysis.

BACKGROUND: This research attempts to clarify whether there are any genetic similarities between sleep traits and hypothyroidism based on publicly accessible large-scale genomewide association studies. METHODS: The methodology included colocalization analysis, cross-phenotype association analysis, and linkage disequilibrium score regression analysis to find common genetic overlap. Through tissue function specificity and functional mapping, we were able to identify the shared genetic level. Genetic instrumental factors were used for causal inference in two-sample univariate and multivariable Mendelian randomization analyses. RESULTS: A hereditary correlation between hypothyroidism and napping during the day and getting up in the morning (rg= -0.0982, P= 0.0007; rg= -0.101, P= 0.0001). MAGI3, and HLA-DRB1 BX296568.1 may be potential targets for shared treatments. Colocalization and tissue-specific analysis demonstrated that the common genes and SNPs were identified in the thyroid, lung, brain, and lymphatic tissues. Functional analysis emphasized the importance of these common genes in processes like as protein transport, inflammatory response, and MHC class II protein synthesis. Furthermore, an association has been established between hypothyroidism and sleep duration (IVW, OR 1.5208; 95% CI 1.1142-2.0758, P=0.0082) and getting up in the morning (IVW, OR 1.8375; 95%CI: 1.4502-2.3284, P=4.73E-07). Furthermore, the reverse MR analysis revealed no causal connection between aberrant sleep traits and hypothyroidism. The enduring impact of insomnia on hypothyroidism persists despite controlling for alcohol consumption and smoking habits. CONCLUSION: Certain genetic correlations between sleep traits and hypothyroidism have been emphasized. These findings may elucidate the origin of comorbidity and have implications for future clinical trials.

Humans↗