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PubMed2026

Integrative multi-omics identifies DOC2A as a novel pharmacological target for bipolar disorder.

BACKGROUND: Current bipolar disorder (BD) therapies suffer from limited efficacy and adverse effects, necessitating mechanistically grounded targets. METHODS: We integrated BD genome-wide association study data (158,036 cases; 2,796,499 controls) with brain proteomics (ROSMAP and Banner dorsolateral prefrontal cortex, n = 376 and 152) to perform proteome-wide association studies (PWAS). Bayesian colocalization and summary-data-based Mendelian randomization (SMR) prioritized causal genes. Cell-type-specific transcriptomics validated dysregulation in iPSC-derived neurons, astrocytes, and postmortem hippocampus/prefrontal cortex. Weighted gene co-expression networks (WGCNAs), functional enrichment, and molecular docking assessed functional pathways and druggability. RESULTS: PWAS identified eight BD-associated genes (false discovery rate < 0.05), with DOC2A emerging as the top candidate. Colocalization (H4 > 0.8) and SMR supported a causal association of DOC2A with BD, with no pleiotropy (heterogeneity in dependent instruments P > 0.01); DOC2A expression decreased in BD across neurons (P = 4.26 × 10-2), astrocytes (P = 2.09 × 10-2), hippocampus (P = 9.80 × 10-3, t = -2.738), and prefrontal cortex (P = 1.44 × 10-2, t = -2.580); WGCNA positioned DOC2A as a key regulator (module membership/gene significance P < 0.05) of co-expression networks enriched for BD-associated processes including neurotransmitter secretion and postsynaptic actin cytoskeleton organization (P < 0.05); molecular docking revealed favorable-affinity binding (ΔG < -4 kcal/mol) between DOC2A and BD-related drugs and neuroprotective compounds. CONCLUSIONS: Our convergent multi-omics framework highlights DOC2A dysregulation as a key contributor to synaptic dysfunction in BD and nominates it as a promising therapeutic target. The demonstrated interaction with existing neuroactive compounds provides immediate translational avenues.

Bipolar Disorder↗

PubMed2026

Deciphering novel targets in salivary gland pleomorphic adenoma by integrating plasma proteomics and parotid transcriptomics analyses.

BACKGROUND/PURPOSE: Pleomorphic adenoma (PA) is the most common salivary gland benign tumor, with its molecular drivers elusive due to a lack of experimental models. This study aimed to decipher novel targets in PA by systematically integrating plasma protein quantitative trait loci (pQTL)-based Mendelian randomization (MR) with multi-omics profiling of parotid gland tissues. MATERIALS AND METHODS: We performed two-sample MR using 5450 plasma pQTLs and genome-wide association study summary for benign or broader salivary gland diseases from FinnGen consortium. Bulk RNA-sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) comparing PA to normal tissue were used for transcriptomic validation. Immunohistochemistry (IHC) was applied for protein-level validation in human PA, adenoid cystic carcinoma (ACC), and murine inflammatory lesions. RESULTS: MR identified 12 plasma proteins associated with benign salivary gland tumor risk. Transmembrane serine protease 6 (TMPRSS6) was the only protein significantly risk-increasing for both benign and broader salivary gland diseases. Strikingly, mitogen-activated protein kinase kinase 4 (MAP2K4) showed opposite MR effects between benign and all-lesion outcomes. Bulk RNA-seq showed limited concordance with MR findings, while scRNA-seq revealed a unique plastic epithelium and partially validated candidates at cellular resolution. Critically, IHC confirmed MAP2K4 protein overexpression specifically in human PA, but not in ACC or inflammatory lesions, while TMPRSS6 was downregulated in established pathologies despite its genetic risk association. CONCLUSION: By integrating plasma proteome-based causal inference with parotid tissue multi-omics, this study unveils MAP2K4 as a potential PA-specific driver. This integrative framework provides novel, context-specific targets for further functional investigation in salivary gland tumorigenesis.

Gene expression profiling↗

PubMed2026

Unraveling causal links between chronic rhinosinusitis and peripheral artery diseases: insights from genetic correlations through genome-wide association studies.

OBJECTIVES: Chronic Rhinosinusitis (CRS) shares epidemiological links with Cardiovascular Diseases (CVDs), however, their shared genetic basis remains unclear. We hypothesized that pleiotropic genetic variants underlie CRS-CVDs links via distinct biological pathways. METHODS: Using large-scale GWAS data from European-ancestry individuals, we assessed global and local genetic correlations. We applied Genomic Structural Equation Modeling (Genomic SEM) to dissect shared genetic architecture, performed bidirectional Mendelian Randomization (MR) to infer causality, and conducted cis-eQTL colocalization to identify shared genetic signals. Finally, in vitro endothelial models (HUVECs) validated the functional dynamics of candidate genes under CRS-mimicking inflammatory stress. RESULTS: CRS showed significant genetic correlations with multiple CVDs. Genomic SEM revealed a latent factor structuring shared genetic risk through three pathways: artery diseases, myocardial diseases, and heart failure. Local genetic correlations identified significant local genetic correlations specifically between CRS and Peripheral Atherosclerosis (PAS)/Peripheral Artery Disease (PAD) specifically within the chr6: 31.57‒33.24 Mb locus. MR demonstrated causal effects of CRS on PAD (OR = 1.23, p = 0.022) and PAS (OR = 1.21, p = 0.011), but not vice versa. Genetically predicted HLA-DRB1, APOM, and COL11A2 expression conferred protection, while HLA-DQA2 increased risk. Crucially, in vitro validation corroborated these pathogenic trajectories, inflammatory stress significantly downregulated the protective APOM and upregulated the risk-associated HLA-DQA2 alongside pro-atherogenic VCAM-1, while HLA-DRB1 exhibited a compensatory upregulation (p < 0.05). CONCLUSION: CRS shares global genetic liability with CVDs, structured through three primary etiological pathways. Causal effects of CRS on peripheral artery diseases are mediated by immune and lipid-related genes within the chr6 locus, revealing divergent pleiotropic mechanisms. Our integrated genetic and in vitro evidence provides a mechanistic framework wherein chronic mucosal inflammation contributes to systemic endothelial vulnerability, thereby highlighting candidate targets for mechanism-directed therapy.

Humans↗

PubMed2026

Causal Relationship of Polyunsaturated Fatty Acids With Mental Disorders: A Systematic Review and Meta-analysis.

CONTEXT: Mental disorders (MDs) pose a important global health challenge, with a complex pathogenesis complicating treatment development. Nutritional interventions, particularly polyunsaturated fatty acids (PUFAs), have gained attention as potential therapeutic options. OBJECTIVE: This Mendelian randomization (MR) meta-analysis aimed to evaluate the potential causal relationship between PUFAs and MDs. DATA SOURCES: Genome-wide association study data were utilized to analyze the association between PUFAs (including omega-3, omega-3 percentage [omega-3%], omega-6, omega-6 percentage [omega-6%], and omega-6 to omega-3 ratio) and 12 major MDs. DATA EXTRACTION: Two-sample MR technology was used to assess the role of PUFAs in MDs. DATA ANALYSIS: The MR analysis revealed that genetically predicted omega-3 was causally linked to MDs, such as obsessive-compulsive disorder, bipolar disorder, schizophrenia, and major depressive disorder. Omega-3% exhibited protective effects against emotional personality disorder. Conversely, omega-6 was inversely correlated with attention-deficit/hyperactivity disorder risk, while a high omega-6 to omega-3 ratio was associated with an increased risk of depression and other mood disorders. CONCLUSION: High omega-3 levels and omega-3% may reduce the risk of MDs, whereas a high omega-6:omega-3 ratio may elevate the risk. These findings highlight the potential of PUFAs, particularly omega-3, in MD prevention and treatment, while underscoring the need for further research into the complex interactions between omega-3 and omega-6. The study provides a scientific foundation for future clinical trials and dietary intervention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no. CRD42024598472.

Humans↗

PubMed2026

Integrative genetic and transcriptomic analyses prioritize CDC16 as a candidate marker for gastric cancer.

BackgroundGastric cancer (GC) remains a major cause of cancer-related mortality, and biomarkers for early detection are needed.MethodsStomach and blood expression quantitative trait loci were integrated with two GC genome-wide association studies using Mendelian randomization (MR), Bayesian colocalization, and summary-data-based MR/heterogeneity in dependent instruments (SMR/HEIDI) testing. Bulk and single-cell transcriptomic analyses characterized candidate expression and lesion-associated patterns. CDC16 protein expression was evaluated by immunohistochemistry in 53 paired GC and non-neoplastic tissues, followed by paired and exploratory receiver operating characteristic analyses.ResultsMR prioritized PILRB, CDC16, and GABPB1-AS1; SMR/HEIDI provided complementary support, while colocalization for CDC16 and GABPB1-AS1 was suggestive and model-dependent. Bulk-tissue CDC16 abundance was higher in GC, but the modest TCGA-STAD tumor-normal difference (log2FC = 0.210, FDR = 0.019) was attenuated after proliferation adjustment (log2FC = -0.002, FDR = 0.987), indicating close coupling with proliferative activity. Single-cell analysis localized CDC16 predominantly to epithelial populations, and the proportion of CDC16-detectable epithelial cells increased across lesion categories (ρ = 0.735; permutation P = 0.031). CDC16 H-scores were higher in GC than in paired non-neoplastic tissues (161.15 ± 45.11 vs 102.15 ± 54.50; P < 0.001), with higher cancer-tissue scores in 41 of 53 cases. Exploratory AUC was 0.794 (95% CI, 0.704-0.874; sensitivity, 66.0%; specificity, 79.2%).ConclusionsConvergent genetic, transcriptomic, and protein-level evidence prioritizes CDC16 as a GC-associated candidate tissue marker whose expression is closely linked to proliferative activity. Prospective validation in independent cohorts, including appropriate disease controls and blood-based evaluation, is warranted.

Stomach Neoplasms↗

PubMed2026

A regulatory network underlying idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which genetic susceptibility interacts with epithelial, immune, and mesenchymal remodeling. Although the chromosome 11p15.5 locus contains established IPF susceptibility signals near MUC5B and TOLLIP, the broader regulatory architecture of this region remains incompletely resolved. METHODS: We integrated IPF genome-wide association study summary statistics with methylation, expression, and protein quantitative trait loci using summary-data-based Mendelian randomization (SMR). SMR-prioritized candidates were evaluated in independent transcriptomic and methylation cohorts and further contextualized using microRNA, transcription-factor, protein-interaction, machine-learning, single-cell, and spatial transcriptomic analyses. Fibrosis-associated expression patterns were assessed in a bleomycin-induced pulmonary fibrosis rat model. RESULTS: The analyses recovered the established MUC5B and TOLLIP signals and prioritized BRSK2 as a comparatively underexplored candidate supported by eQTL-based SMR and independent molecular evidence. The BRSK2 pQTL association did not pass the HEIDI test and was therefore not interpreted as convergent protein-level genetic evidence. Network analyses linked BRSK2 to cell-cycle, metabolic-stress, and senescence-related programs, while cross-cohort machine learning prioritized FOXA2, CDC25B, and NFE2 as informative network features. Single-cell and spatial analyses localized BRSK2 preferentially to fibroblast and myofibroblast compartments and to regions with greater histological fibrosis severity. In fibrotic rat lungs, BRSK2 expression increased, whereas FOXA2 and CDC25B decreased at the transcript and protein levels. CONCLUSIONS: These findings refine the molecular landscape of the chromosome 11p15.5 IPF susceptibility locus and prioritize BRSK2 as a candidate component of an IPF-associated profibrotic fibroblast state. Its causal contribution, direct regulatory relationships, and therapeutic tractability require targeted mechanistic validation.

Idiopathic Pulmonary Fibrosis↗

PubMed2026

Cell type resolved MR based on brain single cell eQTLs corroborated by single cell RNA sequencing uncovers neuroimmune and vascular programs in intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) lacks effective neuroprotective therapies. We integrated cell type–resolved genetic inference with single-cell profiling to map putative causal programs and multicellular circuitry relevant to ICH. METHODS: Cis-eQTLs from eight human brain cell types were used as instruments for two-sample Mendelian randomization (MR), with an ICH meta-analysis from large biobanks and a stroke consortium as the outcome. Instruments were LD-pruned and restricted to strong variants (F > 10). Inverse-variance weighting (IVW) was the primary estimator, supported by robustness methods, heterogeneity/pleiotropy diagnostics, and false discovery rate control. Experimental validation used mouse collagenase ICH single-cell RNA-seq at 24 h (n = 3 sham; n = 3 ICH) with Seurat integration, composition testing, Slingshot pseudotime, and CellChat. An independent mouse cohort underwent qRT–PCR for selected genes. RESULTS: The ICH meta-analysis showed acceptable genomic control, supporting downstream MR. We identified 524 nominal gene–cell type associations, with a glia-weighted signal landscape. Enrichment implicated autophagy/mitophagy, antigen processing, cytoskeletal and vesicular trafficking, endothelial matrix–adhesion programs, ferroptosis, and myelin stress pathways. In mouse scRNA-seq, disease-associated microglia expanded with reciprocal loss of homeostatic microglia and increased neutrophils and T cells. Prioritized genes showed directional concordance; qRT–PCR confirmed ARPC3 and EIF2AK2 upregulation and TBCK and SPECC1 downregulation in ICH versus sham. Pseudotime supported a shift toward disease-associated microglial states, and CellChat indicated increased network interaction strength with microglia and endothelium as hubs. CONCLUSIONS: Cell type–specific MR combined with single-cell validation highlights neuroimmune and neurovascular programs in ICH and links genetic signals to state transitions and inferred intercellular communication.

Animals↗

PubMed2026

Spatially Contextualized Integrative Genomics Highlights Neuronal and Glial Regulatory Programs in Low Back Pain.

PURPOSE: Low back pain (LBP) is a heterogeneous pain condition with a measurable genetic contribution, but the genes, brain cell types, and spatial tissue contexts through which inherited risk is expressed remain unclear. We aimed to define cell-type-specific and spatially contextualized genetic mechanisms underlying LBP. METHODS: FinnGen R12 LBP GWAS summary statistics (42,521 cases and 353,224 controls) were integrated with brain single-nuclei eQTL data across eight major brain cell classes. We evaluated genome-wide polygenic signal using LDSC, prioritized genes using MAGMA and PoPS, and performed brain cell-type-specific eQTL-anchored Mendelian randomization, primarily based on single-instrument Wald ratio estimates, followed by Bayesian colocalization. Spatial genetic mapping was conducted using gsMap in an E16.5 murine embryonic atlas and two adult human lumbar spinal cord Visium sections. Selected candidates were assessed by RT-qPCR in neuronal-like and astroglial-like inflammatory cell models. RESULTS: LDSC supported interpretable polygenic signal for LBP. MAGMA and PoPS showed partial gene-level convergence, with TCF4 and TMEFF2 supported by both approaches. Across 1641 tested gene-cell type exposures, significant eQTL-anchored MR associations were concentrated in excitatory neurons, oligodendrocytes, inhibitory neurons, and astrocytes. Integrated eQTL-anchored MR, colocalization, and gene-prioritization evidence highlighted CLEC18A, QPRT, and GMPPB as higher-priority non-MHC candidates with moderate, but not strong, colocalization support. gsMap localized LBP-associated enrichment to neuroaxis-related embryonic regions, including brain, spinal cord, sympathetic nerve, and dorsal root ganglion, and to neuronal-like niches in adult lumbar spinal cord. RT-qPCR showed model-dependent expression changes, with QPRT and LGI4 preferentially responsive in neuronal-like SH-SY5Y cells and GMPPB and DPYSL5 responsive in astroglial-like U251 cells. CONCLUSION: These findings support neuronal and glial regulatory programs as plausible contributors to LBP genetic susceptibility and highlight CLEC18A, QPRT, and GMPPB as higher-priority non-MHC candidates with moderate colocalization support. The results provide a spatially contextualized framework for candidate prioritization in LBP, while emphasizing the need for larger cell-type-specific eQTL resources and functional validation before therapeutic or mechanistic conclusions can be drawn.

Mendelian randomization↗

PubMed2024

MONOCYTES AND B CELLS MEDIATE ALTERATIONS IN THE GENETIC ASSOCIATION BETWEEN PLATELETS AND SEPSIS VIA CLEC SIGNALING PATHWAY.

Background: Sepsis is a life-threatening condition characterized by multiple organ dysfunction. Blood cells abnormalities play a significant role in the onset and progression of sepsis; however, the potential causal relationship between platelets and sepsis remains unclear, as does whether immune cells mediate the interaction between platelets and sepsis. This study aims to explore the potential causal relationship between platelets and sepsis and analyze the mediating effect of immune cells. In addition, cell-to-cell communication was analyzed to explore the interaction between blood cells and immune cells. Material and methods: In this study, genome-wide association study data were utilized to examine the association between blood cells and sepsis. Two-sample Mendelian randomization (MR) and reverse MR were performed to investigate the potential causal relationship between blood cells and sepsis, with a specific focus on the relationship between platelets and sepsis. Subsequently, two-step MR was employed to identify the immune cells that mediate the interaction between platelets and sepsis and to assess their potential mediating effects. Cellchat software was used to analyze cell-to-cell communication. Results: The results of two-sample MR indicated that platelets were negatively correlated with sepsis (OR = 0.976, 95% CI 0.959-0.993, P = 0.005), suggesting that platelets have a protective effect against sepsis. Additionally, reverse MR demonstrated that sepsis had no significant effect on platelets (OR = 0.909, 95% CI 0.156-5.296, P = 0.916). The mediating effect analysis revealed that monocytes and B cells were important mediators in the relationship between platelets and sepsis. Notably, the correlation between platelets and sepsis shifted from negative to positive with the involvement of monocytes and B cells. The number and strength of cell-cell interactions were decreased in sepsis. Monocytes and B cells primarily regulate platelets through the CLEC signaling pathway, contributing to the pathogenesis of sepsis. Conclusion: This study confirmed the protective role of platelets in sepsis. Monocytes and B cells mediate changes in the genetic association between platelets and sepsis. Monocytes and B cells primarily interact with platelets via the CLEC pathway, thereby modulating the genetic association between platelets and sepsis. These findings indicate that thrombocytopenia, especially when accompanied by elevated monocytes and B cells, may serve as a potential marker for sepsis.

Humans↗

PubMed2025

Genetic predisposition to systemic inflammatory proteins is causally associated with inflammatory bowel disease: Insights from multi-omics association study and single-cell RNA-sequencing analysis.

Systemic inflammatory proteins have been reported to be related to inflammatory bowel disease (IBD) in previous observational research. However, their causal links remain obscure. Herein, we performed a Mendelian randomization (MR) analysis to analyze the causality between systemic inflammatory proteins and IBD. Genetic variants related to systemic inflammatory proteins were extracted from a meta-analysis of genome-wide association study (GWAS) data of 8293 European participants. Summary statistics of IBD diverse subtypes were obtained from the international IBD genetic consortium (IIBDGC). We conducted multi-omics method and MR study to detect the causal links through integrating GWAS and protein quantity trait loci (pQTL) data. Inverse variance weighted (IVW) approach was utilized as the dominated analysis method. Moreover, complementary approaches such as MR-Egger intercept test, Cochran Q test and leave-one-out analysis were utilized to validate pleiotropy and heterogeneity. Finally, single-cell RNA-sequencing analysis was performed to detect the expression of significant genes. For IBD, IVW estimates suggested that genetically predicted IL-10 and IL-13 were suggestively associated with an elevated risk of IBD (IL-10: OR: 1.12, 95% CI: 1.00-1.24, P = .04; IL-13: OR: 1.09, 95% CI: 1.01-1.18, P = .023), while CXCL10 was suggestively linked to a lower risk of IBD (CXCL10: OR: 0.90, 95% CI: 0.82-0.99, P = .037). For Crohn disease (CD), the IVW approach provided evidence to sustain that genetically determined IL-13 and CCL3 had a suggestive association with a higher risk of CD (IL-13: OR: 1.13, 95% CI: 1.02-1.26, P = .023; CCL3: OR: 1.22, 95% CI: 1.03-1.45, P = .018). Sensitivity analysis did not explore any heterogeneity and pleiotropy. Our findings supported the causal relationships between 4 specific inflammatory proteins (IL-10, IL-13, CXCL10, and CCL3) and the risk of IBD and CD, thereby providing promising biomarkers of various subtypes stratification and new insights for the prevention and therapeutic target of IBD.

Humans↗

PubMed2026

Genetic Evidence Linking Circulating Epidermal Growth Factor to Sjögren's Syndrome Risk.

BACKGROUND: This study aimed to explore the potential causal correlations between circulating expression levels of six growth factors - epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and nerve growth factor (NGF) - and the risk of developing Sjögren's syndrome (SS), from the perspective of genetic variation, using a Mendelian Randomization (MR) approach. METHODS: Genetic data related to SS and the six growth factors were obtained from the IEU OpenGWAS project [GWAS IDs: "finn-b-M13_SJOGREN" (SS), "ebi-a-GCST90010212" (EGF), "ebi-a-GCST90011995" (VEGF), "ebi-a-GCST004459" (FGF), "ebi-a-GCST90000481" (TGF-β), "ebi-a-GCST004432" (PDGF), and "prot-b-40" (NGF)]. A two-sample MR analysis was conducted to estimate the causal effect of each growth factor on SS risk. Five complementary MR methods were employed to ensure robustness: Inverse Variance Weighted (IVW), MR-Egger, Weighted Median, Simple Mode, and MR-PRESSO. We further assessed heterogeneity and horizontal pleiotropy using Cochran's Q test and MR-Egger intercept, and performed leave-one-out analyses to test the sensitivity and reliability of the results. RESULTS: The MR analysis provided evidence supporting a causal association between elevated EGF levels and increased SS risk. Both IVW (p = 0.0485, OR [95%] = 1.0696 [1.0004 - 1.1436]) and MR-PRESSO (p = 0.0406, OR [95% CI] = 1.0684 [1.0080 - 1.1325]) yielded statistically significant results. No significant causal associations were observed between SS and the other five growth factors across all MR methods. Sensitivity analyses supported the robustness of the observed association between EGF and SS. CONCLUSIONS: The findings suggest that elevated circulating EGF levels may play a causal role in the development of Sjögren's syndrome, supporting EGF as a potential biomarker for early diagnosis and risk prediction. These results provide novel insights into the pathogenesis of SS and highlight EGF as a potential target for future diag-nostic and therapeutic strategies. Further research is needed to explore the clinical utility of growth factor-targeted approaches for SS prevention and treatment.

Humans↗

PubMed2025

Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits.

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with transcriptomic and proteomic measure using multi-omics data from a Hispanic/Latino population. Using this approach, we identify genes linked to type 2 diabetes and lipid/lipoprotein traits, including TMEM205 and NEDD9 for HDL cholesterol, TREH for triglycerides, and ANXA4 for type 2 diabetes.

Female↗

PubMed2022

Genetically predicted on-statin LDL response is associated with higher intracerebral haemorrhage risk.

Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75 973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (-3.47, -3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [-0.05 mg/dl per year, (-0.07, -0.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.

Cerebral Hemorrhage↗

PubMed2026

A Comprehensive Assessment of the Shared Genetic Architecture between Myopia and Open-Angle Glaucoma.

OBJECTIVE: Individuals with high myopia have an increased prevalence of open-angle glaucoma (OAG). We aim to clarify the possibly shared genetic architecture of myopia and OAG, in particular in high myopes with myopic macular degeneration (MMD), where OAG screening is highly challenging. DESIGN: Individual participant data meta-analysis of one-sample Mendelian randomization analyses and pleiotropic analysis under a composite null hypothesis. PARTICIPANTS: A total of 34 825 participants from 6 population-based cohort studies and 1 high myopia case-control study, including 708 OAG and 1953 high-myopia cases. METHODS: First, we calculated and validated genetic risk scores (GRSs) for OAG and myopia in each cohort. We subsequently meta-analyzed linear and logistic regression models for the association of a myopia GRS with OAG, intraocular pressure (IOP), and vertical cup-to-disc ratio (VCDR), and the association of an OAG-GRS with high myopia, axial length, and spherical equivalent. We stratified the analysis of OAG in different stages of axial elongation, and in high myopes with or without MMD. Pleiotropic analysis under a composite null hypothesis was applied to genome-wide association study summary statistics. MAIN OUTCOME MEASURES: Odds ratio (OR) of OAG and high myopia, and mean difference in IOP, VCDR, axial length, and spherical equivalent. RESULTS: One standard deviation (SD) increase in myopia GRS was associated with an OR (95% CI) of 1.18 (1.09, 1.28) for OAG, a beta (95% CI) of 0.04 (0.00, 0.08) mmHg in IOP, and of 0.005 (0.003, 0.007) in VCDR. The OAG-GRS was not significantly associated with high myopia compared to emmetropes, but a 1 SD increase was associated with a beta (95% CI) of 0.05 (0.01, 0.08) mm in axial length and of -0.05 (-0.10, -0.00) diopters in spherical equivalent. One SD increase in OAG-GRS had a substantially larger effect on OAG in high myopes with MMD, with an OR (95% CI) of 3.83 (1.89, 7.78) compared to 1.55 (1.24, 1.94) in emmetropes. Finally, we identified 95 independent pleiotropic single-nucleotide polymorphisms (SNPs). CONCLUSIONS: There is strong evidence for pleiotropy between myopia and OAG. Further research into the biological mechanisms of the identified pleiotropic SNPs is needed. An OAG-GRS might help to clinically estimate OAG risk, in particular in individuals with MMD. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Axial length↗

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↗

PubMed2025

A Multi-omics Exploration Revealing SLIT2 as a Prime Therapeutic Target for Peripheral Facial Paralysis: Integrating Single-Cell Transcriptomics and Plasma Proteome Data.

Peripheral facial paralysis (PFP) is a common neurological disorder characterized by facial-nerve dysfunction. Identifying therapeutic targets and understanding the molecular and cellular mechanisms underlying PFP are crucial for developing effective treatment strategies. This study combined Mendelian randomization (MR) analysis and single-cell RNA sequencing (scRNA-seq) to explore potential therapeutic candidates and their roles in PFP pathophysiology. The MR analysis included 1925 publicly available plasma protein cis-heritability instruments. Instrumental variables were selected for MR analysis to identify plasma proteins associated with PFP, followed by colocalization analysis to evaluate shared genetic variants between the identified proteins and PFP. After the initial identification of plasma proteins associated with Bell's palsy using MR analysis, a rat model of facial-nerve injury was established to further dissect underlying mechanisms at cellular and molecular levels. Using scRNA-seq technology, we delved deeply into cellular Heterogeneity and dynamic changes in gene expression in the facial-nerve nucleus tissues under both injured and control conditions, thereby achieving a systematic study ranging from macroscopic genetic associations to microscopic cellular functions. Finally, expression patterns were preliminarily validated by performing in vitro immunofluorescence analysis on the facial-nerve nucleus samples of SD rats. The MR analysis results identified 30 plasma proteins significantly associated with PFP, with nine target genes showing differential expression in the scRNA-seq data. Colocalization analysis demonstrated that slit guidance Ligand 2 (SLIT2), semaphorin 4D (SEMA4D), EGF containing fibulin extracellular matrix protein 1 (EFEMP1), and sprouty related EVH1 domain containing 2 (SPRED2) shared causal variants with PFP. SLIT2 was highly expressed in the microglia and inhibitory neurons in the experimental group, whereas SEMA4D showed elevated expression across multiple glial cell types in the same group. In contrast, EFEMP1 and SPRED2 showed distinct expression patterns in fibroblasts and oligodendrocytes. The role of SLIT2 has been previously well-documented in many central nervous system diseases. However, for the first time, this study detected SLIT2 alteration after facial-nerve injury. Altered intercellular signaling, particularly enhanced SLIT2-ROBO signaling between neurons and glial cells, was observed in the PFP group. Pseudotime analysis revealed dynamic SLIT2 expression during microglia and inhibitory neuron differentiation, mirroring changes in ROBO1 expression. Immunofluorescence analysis of rat facial-nerve nucleus samples verified that SLIT2 protein levels were significantly increased in the facial-nerve nuclei of injured samples. In conclusion, despite the fact that this study is primarily founded on animal models and despite notable differences existing between animals and humans in terms of the facial motor nucleus, this study successfully identified SLIT2 as potential therapeutic targets for PFP. The SLIT2-ROBO axis stands out as a particularly promising candidate. SLIT2 may play a role in modulating neuroimmune interactions and promoting nerve repair. These findings provide a foundation for future clinical studies and targeted interventions to enhance recovery from PFP. Future research should focus on human sample validation to enhance clinical translation.

Animals↗

PubMed2005

Obstacles and opportunities in meta-analysis of genetic association studies.

Genetic association studies have the potential to advance our understanding of genotype-phenotype relationships, especially for common, complex diseases where other approaches, such as linkage, are less powerful. Unfortunately, many reported studies are not replicated or corroborated. This lack of reproducibility has many potential causes, relating to study design, sample size, and power issues, and from sources of true variability among populations. Genetic association studies can be considered as more similar to randomized trials than other types of observational epidemiological studies because of "Mendelian randomization" (Mendel's second law). The rationale and methodology for synthesizing randomized trials is highly relevant to the meta-analysis of genetic association studies. Nevertheless, there are a number of obstacles to overcome when performing such meta-analyses. In this review, the impacts of Type I error, lack of power, and publication and reporting biases are explored, and the role of multiple testing is discussed. A number of special features of association studies are especially pertinent, because they may lead to true variability among study results. These include population dynamics and structure, linkage disequilibrium, conformity to Hardy-Weinberg Equilibrium, bias, population stratification, statistical heterogeneity, epistatic and environmental interactions, and the choice of statistical models used in the analysis. Approaches to dealing with these issues are outlined. The supreme importance of complete and consistent study reporting and of making data readily available is also highlighted as a prerequisite for sound meta-analysis. We believe that systematic review and meta-analysis has an important role to play in understanding genetic association studies and should help us to separate the wheat from the chaff.

Epistasis, Genetic↗

PubMed2022

Association of Vitamin D Polygenic Risk Scores and Disease Outcome in People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS. METHODS: We generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10-8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 × 10-5) and applying Mendelian randomization (MR) rather than using PGS. RESULTS: Initial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS: 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87-1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87-1.28), change in T25FW (per 1SD: 0.07%; 95% CI: -0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: -0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR. DISCUSSION: Genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.

Humans↗