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PubMed2025

Neuroimaging PheWAS and molecular phenotyping implicate PSMC3 in Alzheimer's Disease.

INTRODUCTION: Neuroimaging genetics have advanced Alzheimer's disease (AD) research, yet frameworks mechanistically connecting genes to neurological outcomes via functional genomics are needed to elucidate genetic associations. To address this challenge, we assessed relationships between AD-associated variants and disease via their impact on gene expression and neuroimaging phenotypes. METHODS: We mapped established AD genes to neuroimaging traits using NeuroimaGene atlas and predicted transcript-driven AD neurological features by comparing gene-derived neuroimaging features to clinical neuroimaging data. Genetic correlation and covariance analyses characterized shared genetic architecture between AD endophenotypes and neuroimaging features and identified neuroimaging features associated with dementia family history. RESULTS: Our analyses implicate PSMC3 expression as a strong contributor to AD pathophysiology and indicate AD endophenotypes, including dementia family history, linked to frontal cortex thickness, volume, and cerebrospinal fluid volume changes. DISCUSSION: Our findings prioritize AD genes whose regulation is associated with vulnerable brain regions, offering a potential mechanistic framework for downstream functional validation.

Alzheimer’s Disease↗

PubMed2026

Systemic Comorbidities of Keloid and Hypertrophic Scars: A Phenome-Wide Association Study in a Multiethnic U.S. Pediatric Cohort.

BACKGROUND: Excessive scarring (ES), including keloids and hypertrophic scars, impairs function, appearance, and quality of life in children. Its pediatric comorbidity spectrum is not well defined, limiting anticipatory guidance and multidisciplinary care. This research aims to investigate comorbidities of ES in a diverse pediatric cohort using a phenome-wide association study (PheWAS). METHODS: This population-based study leveraged longitudinal electronic health record (EHR) data from participants enrolled in the Children's Hospital of Philadelphia (CHOP) from 2006. Diagnosis codes (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] and Tenth Revision [ICD-10-CM]) were mapped to 3109 phenotype codes (PheCodes). PheWAS analyses were conducted using logistic regression, with Bonferroni correction applied to account for multiple testing. RESULTS: Among 86,092 pediatric participants, 662 (0.77%) were identified with ES; the remaining served as controls. Multivariable PheWAS screening identified 154 significant associations across 16 disease categories, of which 105 were not reported previously to our knowledge. Dermatologic phenotypes (n = 28; 18%) were most enriched, including acne and other follicular disorders, eczema, pigmentary changes, papulosquamous and granulomatous disorders, and cutaneous infections. Respiratory phenotypes (n = 21; 14%) included respiratory failure, pneumonia, asthma, allergic rhinitis, pharyngitis, and tonsillar hypertrophy. Sense organ disorders (n = 19; 12%) comprised conjunctivitis, refractive errors, otitis, and hearing impairment. Infection-related phenotypes (n = 14; 9%) highlighted susceptibility to viral (influenza, human papillomavirus [HPV], molluscum contagiosum), fungal (candidiasis, dermatophytosis), and bacterial infections. CONCLUSIONS: These findings suggest that ES in children indicates not only localized wound-healing impairment, but also systemic immune, developmental, and proliferative dysregulations, emphasizing the need for genetic and mechanistic studies to clarify causal pathways and multidisciplinary surveillance beyond dermatologic care.

Humans↗

PubMed2025

Clinical implications of bone marrow adiposity identified by phenome-wide association and Mendelian randomization in the UK Biobank.

Bone marrow adiposity changes in diverse diseases, but the full scope of these, and whether they are directly influenced by marrow adiposity, remains unknown. To address this, we previously measured the bone marrow fat fraction of the femoral head, total hip, femoral diaphysis, and spine of over 48,000 UK Biobank participants. Here, we first use these data for PheWAS to identify diseases associated with marrow adiposity at each site. This reveals associations with 47 incident diseases across 12 disease categories, including osteoporosis, fracture, type 2 diabetes, cardiovascular diseases, cancers, and other conditions that burden public health worldwide. Intriguingly, type 2 diabetes associates positively with spine bone marrow adiposity but negatively with marrow adiposity at femoral sites. We then establish PRSs based on bone-marrow-fat-fraction-associated SNPs and use PRS-PheWAS and Mendelian randomization to explore causal associations between marrow adiposity and disease. PRS-PheWAS reveals that genetic predisposition to increased marrow adiposity is positively associated with osteoporosis and fractures. Mendelian randomization further suggests that increased marrow adiposity at the diaphysis and total hip is causally associated with osteoporosis. Our findings substantially advance understanding of how marrow adiposity impacts human health and highlight its potential as a biomarker and/or therapeutic target for diverse human diseases.

Humans↗

PubMed2026

Cross-tissue Mendelian randomization prioritizes RAB27B as a brain-derived candidate protein for postpartum depression.

OBJECTIVE: Postpartum depression (PPD) is one of the most common and debilitating complications of childbirth, yet the candidate proteins linking genetic risk to disease remain poorly defined. Building on recent genome-wide association studies (GWAS), we sought to integrate cross-tissue proteogenomic data to identify candidate proteins for PPD and explore therapeutic opportunities. METHODS: We conducted two-sample Mendelian randomization (MR) using genome-wide significant cis-protein QTLs from brain (n = 608 proteins), cerebrospinal fluid (CSF; n = 214), and plasma (n = 612). PPD summary statistics were obtained from FinnGen R8 (13,657 cases, 236,178 controls) and replicated in an independent GWAS. Phenome-wide association (PheWAS) was used to assess pleiotropy. Potential therapeutic targets were evaluated through DSigDB drug repurposing, molecular docking, and molecular dynamics simulations. RESULTS: Among all proteins tested, RAB27B was the only brain-derived protein surpassing Bonferroni correction (OR = 1.60; 95% CI: 1.30-1.96; P = 6.6 × 10⁻⁶), whereas no significant proteins were identified in CSF or plasma. This association was replicated in an independent GWAS (OR = 1.27; 95% CI: 1.02-1.58; P = 0.037). PheWAS identified no pleiotropic associations at genome-wide significance. In silico drug repurposing identified pregnenolone as a candidate ligand with computationally predicted stable binding to RAB27B, providing a starting point for future experimental validation. CONCLUSION: This study provides the first cross-tissue proteogenomic evidence that RAB27B is a brain-derived, reproducible candidate protein genetically associated with PPD. By extending GWAS signals to functional protein-level mechanisms and therapeutic inference, our findings nominate RAB27B and pregnenolone as promising directions for postpartum psychiatric research.

Humans↗

PubMed2026

Identifying potential drug targets for physical and cognitive frailty: an integrative analysis of CHARLS cohort, mendelian randomization, and gene colocalization.

With the aging of the population, frailty has become a common syndrome that severely affects the quality of life of older adults. This study aims to analyze the correlation between cognition and frailty, physical activity and frailty, and elucidate the potential pharmacological targets of cognitive frailty and physical frailty.We conducted logistic regression analyses using data from the China Health and Retirement Longitudinal Study (CHARLS) to examine the associations between total cognition and frailty, physical activity and frailty. Furthermore, summary-data-based Mendelian randomization (SMR) and two-sample Mendelian randomization (TSMR) were employed to explore potential pharmacological targets for frailty. Genes associated with physical frailty and cognitive frailty were identified, followed by analysis via colocalization analysis, phenome-wide association studies (PheWAS), and DsigDB drug prediction. Cross-sectional analysis of CHARLs revealed that total cognition(OR 0.93, 95% CI 0.92-0.95) and middle physical activity(OR 0.95, 95% CI 0.92-0.97) were negatively correlated with frailty. SMR identified 41 drug genes associated with frailty, and subsequent TSMR validation and co-localization analysis showed that 11 candidate genes exhibited strong colocalization (PP.H4 > 0.8). GRPEL 1, PABPC 4, and WBP 2NL were ultimately identified as potential drug targets associated with physical frailty, while LANCL1, LRPPRC, FADS1, and WBP2NL were identified as potential drug targets associated with cognitive frailty. Phenome-wide association analysis(PheWAS) did not reveal any significant associations between these genes and other phenotypes at the genome-wide significance threshold. Laudanosine, 25-hydroxycholesterol, and hexadecanal emerged as the top three candidate compounds for therapeutic intervention. We identified potential drug targets for physical frailty and cognitive frailty through comprehensive analysis and elucidated drugs associated with potentially relevant genetic markers, thereby laying the foundation for a deeper understanding of the mechanisms of frailty.

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↗

PubMed2025

Polygenic Risk Factors for Comorbid Diagnoses in Individuals with Substance Use Disorders: A Phenome-Wide Survival Analysis.

OBJECTIVE: Persons with substance use disorders (SUD) often suffer from additional comorbidities. Researchers have explored this overlap via phenome wide association studies (PheWAS). However, PheWAS are largely cross-sectional, limiting our understanding of whether diagnoses predate development of an SUD. We characterize whether polygenic scores (PGS) are associated with time to comorbid diagnoses in electronic health records (EHR) after the first documented SUD diagnosis. METHODS: Using data from All of Us (N = 393,596), we explored: 1) whether social determinants of health (SDoH) are associated with lifetime risk of SUD (N cases = 42,568) and 2) within a subset those with a diagnosed SUD and available genetic data SUD (N = 21,357), whether PGS for alcohol use disorders, cannabis use disorders, depression, externalizing, post-traumatic stress disorder, and schizophrenia were associated with subsequent diagnoses via a phenome-wide survival analysis. RESULTS: Multiple SDoH were associated with lifetime SUD diagnosis, with annual household income having the largest overall associations (e.g., <$10K annually vs $100K-$150K annually: OR = 3.89, 95% CI = 3.66, 4.13). There were 101 phenome-wide significant PGS associations with subsequent diagnoses across various bodily systems. PGSs for alcohol use disorders, post-traumatic stress disorder, and schizophrenia were each associated with time to their respective diagnoses. CONCLUSIONS: Social determinants, especially those related to income, have profound associations with lifetime SUD risk. Additionally, PGS for psychiatric conditions are associated with multiple post-SUD diagnoses within those with a SUD, suggesting PGS may capture information beyond lifetime risk, including timing and severity of comorbidities related to SUD.

Journal Article↗

PubMed2025

Genetic liability to meniscus degeneration and its comorbidity patterns: a phenome-wide association study in the UK Biobank.

Meniscus degeneration is a common knee pathology causing pain, disability, and osteoarthritis. While mechanical factors are established, the contribution of inherited genetic liability to its systemic disease patterns remains unclear. We applied a polygenic risk score (PRS) for meniscus degeneration, derived from FinnGen genome-wide association study (GWAS) results to 323,999 UK Biobank participants and conducted a phenome-wide association study (PRS-PheWAS) across 962 clinical phenotypes. The PRS-PheWAS revealed significant associations beyond musculoskeletal traits, extending to metabolic, cardiovascular, psychiatric, and gastrointestinal domains, indicating broad shared genetic architecture. To support these findings, linkage disequilibrium score regression confirmed strong genetic correlations with osteoarthritis and related arthropathies, and genotype-tissue expression (GTEx) analysis highlighted tissue-specific expression of lead genes (e.g., GDF5, SOX5, BMP6) in connective and metabolic tissues. The results demonstrate that genetic liability to meniscus degeneration extends beyond the knee, sharing pathways with systemic conditions. This systemic genetic architecture underscores the need for integrative management approaches that combine orthopedic care with metabolic and lifestyle interventions.

Journal Article↗

PubMed2026

Optimizing Control Definitions in Opioid Use Disorder Genetic Research Using Electronic Health Records.

Amidst the opioid crisis, understanding the genetic basis of opioid use disorder (OUD) is crucial for identifying biological mechanisms and intervention points. However, genome-wide association studies (GWASs) have been hampered by inadequate sample sizes and often the use of control populations not assessed for prior opioid exposure. Because opioid exposure is a prerequisite for the development of OUD, consideration of exposure history in controls is important. Electronic health record data (EHR) paired with genomic information allow a broader sampling of patients with OUD and exposed controls. We leveraged data across two healthcare systems to evaluate the impact of using controls not screened for opioid exposure ('generic') versus minimally opioid-exposed control ('exposed'). First, at the phenotypic level, we conducted phenome-wide association studies (PheWAS) to compare the medical comorbidity profiles of OUD cases when using generic versus exposed controls. While PheWAS results for OUD-related comorbidities were more pronounced when using the generic group, 83% of the disease associations were overlapping and of similar effect sizes. Second, at the genetic level, we conducted GWAS (cases vs. generic; cases vs. exposed) and assessed differences in genetic correlations and degrees of phenotypic misclassification. Genetic results were concordant across control groups based on heritability (generic: 0.16 ± 0.07 vs. 0.10 ± 0.07), associations with the coding OPRM1 variant rs1799971 (pgeneric = 8.83E-03 vs. pexposed = 1.83E-02) and genetic correlations with prior OUD GWAS (rg-generic = 0.83 ± 0.26 vs. rg-exposed = 0.78 ± 0.27). Although GWASs were limited by sample size (Ngeneric = 6269, Nexposed = 6365), compared to an independent OUD GWAS (N = 425 944), the dilution value for the two GWAS was not different from 1, suggesting no major impact of phenotypic misclassification. This study represents the first effort to enhance OUD genetic research through optimization of control definitions using EHR data. Generic controls ascertained within the US health systems, where exposure to prescription opioids is high, offer a practical alternative for genetic studies of OUD.

Humans↗

PubMed2026

Cell Type-Resolved Causal Inference and Spatial Transcriptomic Integration Reveal Immune-Specific Genetic Drivers of Autoimmune and Malignant Thyroid Disease.

BACKGROUND: Thyroid diseases, including autoimmune thyroid disease (AITD) and thyroid cancer, are characterized by immune dysregulation, yet the cell type-specific genetic mechanisms underlying these conditions remain poorly understood. Most genome-wide association studies (GWAS) have relied on bulk tissue expression quantitative trait loci (eQTL), which cannot resolve the heterogeneity of immune cell populations. METHODS: We performed two-sample Mendelian randomization (MR) analyses using single-cell cis-eQTLs from 14 immune cell subtypes (OneK1K cohort) as instrumental variables against GWAS summary statistics for four thyroid outcomes: autoimmune hyperthyroidism, autoimmune hypothyroidism, thyroid cancer and autoimmune thyroiditis. Causal associations were validated through Bayesian colocalization, phenome-wide association analysis (PheWAS) and multi-layered transcriptomic validation encompassing spatial transcriptomics of AITD tissue (GSE248205), bulk RNA-seq of thyroid cancer (GSE3678) and single-cell RNA-seq of thyroid tumours (GSE250521). gsMap spatial LD score regression was applied to map disease heritability onto spatial tissue architecture. RESULTS: We identified six Bonferroni-significant causal gene-cell type pairs for autoimmune hyperthyroidism, including protective effects of ABHD16A in naïve/immature B cells (OR = 0.440), HIST1H3H in CD8 NC T cells (OR = 0.324), HMGN4 in NK recruiting cells (OR = 0.556) and ZKSCAN4 in CD8 S100B T cells (OR = 0.427), with five pairs showing strong colocalization (PP.H4 ≥ 86%). Three pairs reached significance for autoimmune hypothyroidism, including a risk association of HLA-F in CD4 NC T cells (OR = 1.139). For autoimmune thyroiditis, FAM134B/RETREG1 showed consistent suggestive protective associations across both CD4 and CD8 NC T cells (PP.H4 ≥ 90% for both), suggesting a possible involvement of ER phagy regulation in thyroiditis susceptibility. Thyroid cancer showed a suggestive association with HLA-G in classical monocytes (OR = 1.899, PP.H4 = 53%). Spatial transcriptomic validation demonstrated progressive immune infiltration from control tissue to Graves' disease to Hashimoto's thyroiditis (7.7%-15.7%, 46.1%-54.1%, respectively) and strong spatial correlation between target gene expression and corresponding cell type enrichment (e.g., plasma cell-HLA-DQB1: r = 0.491, p < 10-300). HLA-G was independently validated in thyroid cancer bulk (log2fc = 0.542, p = 9.51 × 10-3, AUC = 0.857) and single-cell datasets. PheWAS revealed no significant associations detected for the core candidates. gsMap identified significant enrichment of autoimmune hypothyroidism heritability in gastrointestinal tract, adrenal gland and adipose tissue (all Bonferroni p < 0.002). CONCLUSIONS: This study establishes a multi-scale analytical framework integrating cell type-resolved genetic inference with spatial tissue validation, revealing distinct immunogenetic architectures underlying autoimmune versus malignant thyroid disease. Protective genetic programs in autoimmune hyperthyroidism converge on chromatin remodelling (HIST1H3H, HMGN4, ZKSCAN4) and lipid metabolism (ABHD16A) across lymphocyte subsets, whereas thyroid cancer risk involves immune escape mediated by HLA-G in myeloid cells. The ER-phagy receptor RETREG1 represents a candidate pathway warranting further investigation in autoimmune thyroiditis. These findings provide genetically supported, cell type-specific therapeutic targets and demonstrate a generalizable strategy for dissecting the immune-mediated mechanisms of complex thyroid diseases.

Mendelian randomization↗

PubMed2026

Single-cell expression quantitative trait locus Mendelian randomization reveals immune cell-specific causal regulatory networks and actionable targets in polycystic ovary syndrome.

ObjectiveTo systematically investigate whether the pathogenesis of polycystic ovary syndrome (PCOS) is causally related to dysregulated gene expression in specific immune cell subsets, and to evaluate the potential of these causal genes as actionable drug targets.MethodsThis study employed a two-sample Mendelian randomization (MR) framework using publicly available genome-wide association study (GWAS) summary statistics. The participant data included 797 PCOS cases and 140,558 controls (no direct patient recruitment was involved). Instrumental variables were derived from high-resolution immune cell-specific single-cell expression quantitative trait locus (sc-eQTL) data (OneK1K project) across 14 immune cell types. Primary analyses utilized the inverse-variance weighted (IVW) method. Shared causal variants were validated using Bayesian colocalization. Phenome-wide association analysis (PheWAS), external transcriptomic dataset validation (GSE8157), and DrugBank database screening were conducted for pleiotropy assessment and drug repositioning.ResultsMR analysis revealed genome-wide significant causal associations for GLIPR1 in non-classical monocytes (Mono NC) and XBP1 in CD4+ effector memory T cells (CD4 ET) with PCOS risk. Higher GLIPR1 expression was associated with a decreased PCOS risk (OR = 0.669, P = 4.34×10-6), whereas higher XBP1 expression was associated with an increased risk (OR = 1.406, P = 9.53×10-8). Colocalization analysis confirmed that GLIPR1 shares a causal variant with PCOS (PP.H4 = 96.73%). PheWAS and external validation confirmed the safety profile and significant upregulation (P = 0.03) of GLIPR1. Drug repositioning identified SOT-107, a Phase III protein therapy drug, as a potential interacting agent for GLIPR1.ConclusionsThis sc-eQTL MR study reveals immune cell-specific causal regulatory networks in PCOS. GLIPR1 in non-classical monocytes represents a high-confidence protective target, while XBP1 provides suggestive evidence for immune-mediated pathogenesis. The candidate drug SOT-107 highlights theoretical repositioning opportunities, though rigorous preclinical validation remains required.

Female↗

PubMed2026

Genetic Susceptibility to Incisional Hernia Evaluation of Hernia Polygenic Risk Scores.

OBJECTIVES: Incisional hernia (IH) affects 13-30% of people after abdominal surgery, resulting in substantial morbidity and costs. While clinical risk factors have been studied extensively, genomic risk for IH is incompletely understood. We aimed to evaluate the impact of polygenic risk scores (PRS) on IH risk prediction. METHODS: We created and evaluated three PRS for abdominal hernia, ventral hernia and latent hernia susceptibility for prediction of IH in an institutional biobank. The primary outcome was defined as the diagnosis or repair of an IH based on ICD-9/10-CM/PCS and CPT codes. Clinical covariates included age, sex, body mass index (BMI), smoking status, index procedure type, and perioperative surgical site infection. A phenome-wide association study (PheWAS) was performed to assess clinical associations with increased PRS. We then tested the ability of the PRS to improve prediction for IH by modeling clinical covariates with and without PRS in patients who underwent abdominal surgery. Model performance was assessed using 10 iterations of 5-fold cross-validation to estimate Brier scores and area under the receiver operating characteristic curve (AUROC), which were compared using cross-model Bayesian analysis of variance. RESULTS: In 55,809 subjects, assessed PRS was significantly associated with incisional, umbilical, and ventral hernia on PheWAS, with 1.19 greater odds of developing IH per 1-SD increase in PRS (95% CI: 1.13-1.25, P < 0.001). Of 9,909 subjects who underwent qualifying abdominal surgery, 706 developed IH. In this cohort, the latent hernia susceptibility PRS was associated with a 16% increased hazard of developing IH per 1-SD increase (HR 1.16; 95% CI: 1.07-1.26; P < 0.001). Compared to a predictive model using clinical covariates (Brier score = 0.047, 95% CI: 0.046-0.048; AUROC = 0.660, 95% CI: 0.653-0.666), addition of the PRS showed similar Brier score and AUROC estimates (Brier score = 0.047, 95% CI: 0.046-0.048; AUROC: 0.667, 95% CI: 0.661-0.673) at five years. Cross-model Bayesian analysis demonstrated >99% probability of practical equivalence when trying to detect a difference of ≥ 0.02. CONCLUSION: All three PRS for hernia were independently associated with IH, suggesting that genomic factors contribute significantly to IH development. However, none of the three PRS meaningfully improved clinical IH risk prediction in patients who underwent abdominal surgery. This suggests that clinical comorbidities and surgical techniques may be equally as important as genomic architecture.

Bayesian analysis↗

PubMed2026

Common genetic mechanisms between obesity and COVID-19 severity: unravelling pleiotropic loci and biological pathways.

COVID-19 and obesity are complex conditions marked by immune and metabolic dysfunction, with the former still ranking among the leading causes of death from infectious diseases worldwide and the latter reaching pandemic proportions. Clinical evidence consistently shows that obesity increases the risk of severe COVID-19, yet the biological mechanisms underlying this association remain unclear. Given their physiological and clinical overlap, they may share genetic pathways. We investigated genetic variants jointly associated with body mass index (BMI) and COVID-19 using publicly available genome-wide data. A conjunctional false discovery rate (conjFDR) approach identified shared variants between BMI and three COVID-19 phenotypes: infection, hospitalization and very severe respiratory illness. Functional annotation and pathway enrichment analyses were performed to explore the biological context of these variants, followed by a phenome-wide association study (PheWAS) to characterize pleiotropy. Shared variants were enriched in immune, metabolic and hormonal signaling pathways, including metal ion transport and glycosylation. The overlap with BMI was strongest for hospitalized and severe cases, suggesting common mechanisms underlying disease progression rather than infection. These findings suggest a biologically meaningful genetic overlap between obesity and COVID-19 severity, highlighting pleiotropy as a key feature in complex disease interactions and potential shared therapeutic targets.

BMI↗

PubMed2026

Integrated Genome-Wide Association Studies and Selection Signature Analysis Reveal the Genetic Architecture of the Wattle Trait in Goats.

Wattles are finger-like appendages on the ventral neck of goats, serving as a distinctive morphological marker for breed identification that serves potential implications for production performance. However, their genetic basis remains incompletely characterized. Here, we integrated a genome-wide association study (GWAS) and selection signature analysis to identify candidate genes and genomic regions associated with the wattle trait in goats. Using a linear mixed model, GWAS on 463 goats (23 wattled and 440 non-wattled) identified 385 quantitative trait loci (QTLs) at a 5% false discovery rate, yielding 346 candidate genes. The most significant association signal was observed on chromosome 10 (72.61-73.48 Mb), where the lead SNP (rs636481767) is located within a region containing GJD2, GREM1, and FMN1, showing strong linkage disequilibrium (r2 > 0.6) with surrounding loci. Subsequent selection signature analysis (23 wattled and 23 non-wattled) identified 83 genomic regions harboring 119 candidate genes. The strongest signals were detected at MFSD14B on chromosome 8 (FST = 0.154, log2π-ratio = 2.611) and PDLIM7 on chromosome 7 (FST = 0.144, log2π-ratio = 0.806). KEGG pathway enrichment analysis revealed that GWAS-associated genes were involved in glycosylation and immune responses, whereas selection-signature genes were enriched in DNA repair and the Hippo, Notch, and Wnt pathways. Furthermore, cross-species PheWAS revealed that human FMN1 is associated with dermatological, skeletal, and metabolic phenotypes, while porcine FMN1 is associated with backfat thickness and loin muscle depth. Overall, this study provides molecular markers of potential value for goat breeding and pinpoints key candidate genes for future functional validation of wattle development.

Animals↗

PubMed2026

Integrative TWAS and multi-omics analyses prioritize HSPE1 as a candidate risk gene for bipolar disorder with immune cell-specific regulatory evidence.

BACKGROUND: Bipolar disorder (BD) is a severe psychiatric disorder associated with substantial disability. Although genome-wide association studies have identified multiple BD-associated loci, the underlying genes and mechanisms remain incompletely understood. METHODS: We integrated a European-ancestry BD genome-wide association dataset with cross-tissue and tissue-specific transcriptome-wide association studies (TWAS) and complementary gene-based analysis. Candidate genes were further evaluated using differential expression analysis, consensus clustering, immune infiltration analysis, machine learning, summary-data-based Mendelian randomization, Mendelian randomization using single-cell expression quantitative trait locus data, single-nucleus transcriptomics, phenome-wide association analysis, and virtual screening. RESULTS: The integrative analyses prioritized 37 candidate genes. Peripheral-blood differential-expression analysis identified 14 genes that remained significant after FDR correction, and their expression profiles separated BD samples into two expression-defined clusters. Machine-learning analysis selected UNC50, LMAN2L, LYG2, HSPE1, and KANSL3 for an exploratory classification nomogram. SMR associated genetically predicted higher HSPE1 expression with increased BD risk in two blood eQTL datasets. Cell-type-specific analyses indicated HSPE1-related associations in T-cell and natural killer cell subsets, while single-nucleus analysis descriptively showed higher HSPE1 expression in medial thalamic T cells from BD samples. PheWAS identified no genome-wide significant associations for HSPE1, whereas virtual screening identified candidate compounds with favorable predicted docking scores against the HSPE1 structure. CONCLUSION: This integrative multi-omics study identified HSPE1 as a candidate BD risk gene with immune-cell-related regulatory evidence, providing insight into BD pathogenesis and supporting functional validation.

Humans↗

PubMed2025

Potential therapeutic targets for ovarian hyperstimulation syndrome revealed by proteome-wide mendelian randomization and colocalization analysis.

Ovarian hyperstimulation syndrome (OHSS) is a severe complication associated with assisted reproductive technologies, characterized by metabolic, immune and vascular disorders. Understanding the molecular mechanisms underlying OHSS could reveal potential therapeutic targets and improve patient outcomes. In this study, We aimed to utilize proteome-wide Mendelian randomization (MR) and colocalization analysis to identify plasma proteins associated with OHSS and evaluate their potential as therapeutic targets through druggability assessment. We employed proteome-wide MR analysis summary data-based Mendelian randomization (SMR) analysis and phenome-wide association study (PheWAS) analysis to establish causal relationships between plasma proteins and OHSS. Colocalization analysis confirmed overlaps between proteins and genetic signals associated with OHSS. Pathway and network analyses were conducted to explore biological functions and protein interactions, while drug-target databases were queried for potential therapeutic interventions. Our results showed that 4 key proteins, including Suprabasin (SBSN), SLAMF4 (CD244), Enolase 3 (ENO3) and Thioredoxin domain-containing protein 12 (TXNDC12) were identified as significant contributors to OHSS. Pathway enrichment and interaction analyses further supported their involvement in metabolic, immune and structural pathways related to OHSS. Drug availability for colocalized proteins reveled potential drug targets for ENO3 (2-deoxy-D-glucose), CD244 (lenalidomide) and TXNDC12 (Auranofin), while no potential drug targets were identified for SBSN. Over all, our study identified15 plasma proteins, including SBSN, CD244, ENO3, and TXNDC12, as key contributors to the risk of OHSS through MR and colocalization analysis. These proteins were involved in metabolic regulation, immune response and antioxidant pathways, highlighting potential therapeutic targets and suggesting new directions for treatment strategies.

Humans↗

PubMed2026

Mapping the Immune cell-specific gene regulatory network in bipolar disorder: A framework from scTWMR to exploratory drug-target annotation.

BACKGROUND: Although the involvement of the immune system in the genetic susceptibility of bipolar disorder (BD) is widely acknowledged, the causal relationship between gene expression in specific immune cell subtypes and BD requires systematic elucidation. METHODS: We implemented an analytical framework integrating single-cell transcriptome-wide Mendelian randomization (scTWMR) with colocalization analysis. This approach utilized cis-expression quantitative trait loci (cis-eQTLs) derived from 14 distinct immune cell types as instrumental variables to interrogate BD genome-wide association study (GWAS) summary statistics (comprising 41,917 cases and 371,549 controls). Subsequent investigations encompassed functional enrichment analysis, protein-protein interaction (PPI) network construction, phenome-wide association study (PheWAS), and performed an exploratory drug-target annotation. RESULTS: Our analysis identified 33 gene-immune cell associations. Colocalization analysis provided robust evidence (PPH4 > 90%) for shared causal variants implicating the MAD1L1, APOM, and NFKBIL1 loci. Significantly enriched biological pathways included cell cycle regulation, circadian rhythm entrainment, and neuroinflammation. The PPI network revealed a core regulatory module centered on histone-encoding and immune-related genes. Exploratory drug-target annotation nominated compounds for further investigation for compounds targeting APOM, TMEM258, and NFKBIL1. CONCLUSION: This study systematically delineates a genetically supported regulatory network of immune cell-specific gene expression in BD, predominantly implicating CD8⁺ effector T cells, plasma cells, and B cells. The findings corroborate established pathological pathways while uncovering novel cell type-specific therapeutic targets, thereby providing a genetic framework for prioritizing candidate targets for future investigation.

Bipolar disorder↗

PubMed2026

Immune cell-specific genetic architecture of Alzheimer's disease revealed by multi-omics analysis for therapeutic target discovery and prioritization.

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition in which accumulating genetic and molecular evidence implicates dysregulation of peripheral immune processes in disease pathogenesis. Nevertheless, the contribution of distinct peripheral immune cell subsets and associated gene regulatory landscapes to AD risk remains incompletely defined. To address this gap, we integrated single-cell expression quantitative trait loci (sc‑eQTL) data from the OneK1K cohort with AD GWAS summary statistics. We systematically interrogated immune cell-specific genes for their contributions to AD risk by integrating genetic causal inference with Bayesian colocalization analyses, and identified 24 eGenes that passed both the MR significance threshold (P < 0.05) and the criterion for strong shared genetic signals (PP.H4 > 0.8). Notable candidates included GATS, HLA-DOB, HLA-DQA1, PM20D1, and others, with each gene demonstrating a cell-type-specific association restricted to its corresponding immune cell type, such as monocytes, CD8 + T cells, or B cells. Independent peripheral blood single-cell transcriptomic data further supported disease-associated shifts in cell-type-specific expression patterns in AD. Phenome-wide association studies (PheWAS) indicated limited associations with off-target traits, indicating a favorable safety profile for therapeutic intervention, with the exceptions of B4GALNT3, PM20D1, and CNN2. Integration of immune gene targets with pharmacological databases yielded three candidate compound, including NSC321521 (targeting HLA-DQA1), phenoxybenzamine (targeting GSTP1), and rimexolone (targeting BIN1). Among these compounds, Predicted blood-brain barrier permeability was observed only for phenoxybenzamine and rimexolone, with docking studies indicating stable interactions, such as those between NSC321521 and HLA-DQA1, phenoxybenzamine and GSTP1, and rimexolone and BIN1. This integrative approach highlights key immune‑cell‑specific genes involved in AD and proposes repurposable drugs with central nervous system potential, paving the way for more targeted immunomodulatory strategies in AD.

Humans↗