Biomedical subjects

Yun Li

Publications and source records attributed to Yun Li.

15 recordsLinked to original sources

PubMed2026

Genetically Predicted Muscle Mass and Function in Relation to Deep Vein Thrombosis: A Two-step Mendelian Randomization Study Highlighting the Mediating Role of BMI.

BackgroundSarcopenia is observationally linked to venous thromboembolism, but the causal architecture and underlying biological pathways remain largely unclear. This study investigated the causal effects of sarcopenia-related traits on lower extremity deep vein thrombosis (DVT) and quantified potential mediating mechanisms.MethodsWe performed two-sample bidirectional Mendelian randomization (MR) and two-step mediation MR using large-scale GWAS data from UK Biobank, EMBL-EBI, and FinnGen. Exposures included appendicular lean mass (ALM), leg fat-free mass (LFM), hand grip strength, and walking pace. Eighteen candidate mediators were screened for indirect pathways.ResultsGenetically predicted higher ALM was significantly associated with increased DVT risk (FinnGen: OR = 1.288, 95% CI: 1.215-1.365, P < 0.001). Similar positive associations were observed for LFM (OR = 1.920-1.954, P < 0.001). By contrast, muscle functional traits - grip strength and walking pace - demonstrated no consistent causal effects. Reverse MR confirmed a unidirectional relationship. Body mass index (BMI) emerged as a pivotal mediator, accounting for 7.58% - 10.50% of the ALM-DVT effect and 52.74% - 62.73% of the LFM-DVT effect. Notably, the independent effect of ALM was largely attenuated after adjusting for metabolic confounders in multivariable MR.ConclusionGenetic predisposition to high muscle mass, rather than functional strength, increases DVT risk. This relationship appears to be significantly driven by metabolic adiposity, suggesting that the "muscle-vascular-coagulation" interaction is partly explained by body-size-related metabolic burden. Risk stratification should integrate muscle mass evaluation with comprehensive metabolic health assessments.

Humans↗

PubMed2026

Inherited Predisposition to Increased Systemic Inflammation Predicts a Broad Class of Disease Phenotypes.

Chronic, low-grade systemic inflammation is a polygenic trait captured with the INFLA-score, a composite of C-reactive protein, platelet count, leukocyte count, and granulocyte-to-lymphocyte ratio. We derived a polygenic risk score from the INFLA-score (iPRS) in a multi-ancestry population from the UK Biobank (n=421,368), then evaluated and used it in a phenome-wide association study among participants in the All of Us Research Program (AoU). The multi-ancestry iPRS was tested for association with the INFLA-score in AoU (N=4,833 with biomarker data) via linear regression, adjusting for age, sex, and genetically-determined principal components (PCs) and with 2,821 phecodeX-defined phenotypes in AoU (N=265,068) via logistic regression, adjusting for sex, age, EHR length, race, ethnicity and PCs. The iPRS predicted the INFLA-score (R-squared=0.026, beta=0.980, p<2x10-16) and was associated with 47 phenotypes (Bonferroni-corrected p<0.05). The strongest associations were with blood-related phenotypes: elevated white blood cell count (OR=1.19, p=3.85x10-66), thrombocytopenia (OR=0.86, p=5.70x10-44), platelet defects (OR=0.86, p=2.47x10-43), neutropenia (OR= 0.86, p=5.52x10-18), myeloproliferative disorder (OR= 1.2, p=2.77x10-15). Others included celiac disease (OR=0.713, p=2.98x10-46), ankylosing spondylitis (OR=1.4, p=1.33 x 10-17), hypertension (OR=1.04, p=4.56x10-15), rheumatoid arthritis (OR=1.09, p=1.02x10-13), hematuria (OR=1.05, p=1.96x10-10). Removing major-histocompatibility-complex SNPs abolished associations with known autoimmune diseases, while all other associations remained. We replicated 17 (42.5%) of 40 significant phenotypes available in the Vanderbilt University Medical Center's BioVU. Our findings demonstrate that systemic inflammation can be predicted using the iPRS across multiple ancestries, and the iPRS is associated with numerous clinical endpoints. This multi-ancestry iPRS may have future utility in stratifying risk for inflammation-driven conditions across diverse populations.

Journal Article↗

PubMed2026

3D epigenome of glial cell types in developing human cortex.

The human cortex is complex and heterogeneous, undergoing extensive expansion during development1,2. Our prior study of neurogenesis, including radial glia (RG), intermediate progenitor cells, excitatory neurons and interneurons demonstrated that chromatin looping underlies transcriptional regulation for lineage-specific genes, shedding light on how non-coding genetic variants contribute to neuropsychiatric disorders by means of cell-type-specific gene regulation3. RG have a crucial role in generating cellular diversity through both neurogenesis and gliogenesis and can be further classified into ventricular RG (vRG) and outer RG (oRG)4,5. Given their significance in cortical development, we conducted a comprehensive three-dimensional (3D) epigenomic analysis of four main glial populations, including vRG, oRG, oligodendrocyte precursor cells and microglia, from the mid-gestational human neocortex. By integrating gene expression, chromatin accessibility, DNA methylation and 3D chromatin interactions, we identified cell-type-specific candidate cis-regulatory elements (cCREs) and validated their regulatory function using transgenic mouse embryos. Using machine learning, we prioritized 112 schizophrenia risk variants within glia cCREs and further confirmed the predicted vRG enhancer disruption by the rs4449074 risk allele in vivo. Finally, oRG cCREs are enriched for human accelerated regions compared with other cCREs and a subset of human accelerated regions show activity differences from their chimpanzee orthologues that interact with genes involved in neuronal development. Our findings advance the understanding of human-specific gene regulation during corticogenesis.

Journal Article↗

PubMed2026

Transcriptomic and RNAi analyses reveal chloride channel 3-associated osmoregulation in Litopenaeus vannamei under low-salinity stress.

Chloride channels and transporters are important for cellular volume regulation and salinity adaptation in euryhaline crustaceans, yet the intestinal transcriptional relationship between plasma-membrane and intracellular chloride pathways remains unclear in Litopenaeus vannamei. In this study, RNA interference of anoctamin 1 (ANO1) was combined with intestinal transcriptome sequencing under the production-relevant low-salinity condition of salinity 3. ANO1 silencing produced a focused transcriptional response, with 16 differentially expressed genes (DEGs) identified (11 upregulated and 5 downregulated). Functional enrichment indicated that these genes were associated with transporter activity, cytoskeletal organization, extracellular matrix-receptor interaction, membrane lipid metabolism, and vesicular processes. Notably, a transcript encoding chloride channel protein 3 (CLC-3) was significantly upregulated following ANO1 knockdown, suggesting a potential transcriptional relationship between ANO1 and CLC-3 in chloride homeostasis. Based on this finding, CLC-3 was selected for full-length cDNA cloning, sequence characterization, salinity-gradient expression analysis, and RNAi-based functional assessment. The cloned CLC-3 cDNA was 2883 bp in length and encoded an 850 amino acid protein containing a conserved voltage-gated chloride channel (Voltage-CLC) domain and two cystathionine β-synthase domains. Phylogenetic analysis placed LvCLC-3 within the intracellular CLC-c clade, and tissue distribution analysis showed the highest CLC-3 expression in the intestine. Intestinal CLC-3 expression responded nonlinearly to salinity variation, peaking at salinity 20. Under salinity 3, CLC-3 knockdown reduced ANO1, Na+/K+-ATPase alpha subunit, and Na+-K+-2Cl- cotransporter transcript levels, whereas glutamate-gated chloride channel expression increased. Mild hepatopancreatic structural alterations were also observed after CLC-3 knockdown. These findings suggest that CLC-3 is a salinity-responsive intracellular chloride-transporter candidate associated with intestinal ion-transport-related transcriptional responses after ANO1 suppression in L. vannamei, although the underlying physiological mechanism requires further validation.

Animals↗

PubMed2026

Multi-omics identification and functional validation of signal regulatory protein gamma as a prognostic biomarker and immune regulator in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) comprises biologically diverse tumors, and durable responses to immune-checkpoint blockade are achieved by only a subset of patients. There remains a need for markers that connect clinical outcome with malignant-cell phenotypes and tissue-level immune organization. METHODS: We integrated The Cancer Genome Atlas HNSCC cohort (TCGA-HNSC), five Gene Expression Omnibus (GEO) validation cohorts, single-cell RNA sequencing, Visium spatial transcriptomics, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq)-informed protein-potential inference, pharmacogenomic screening, genetic-risk analysis and experimental validation. A reconstructed 296-pipeline survival modelling framework was used to prioritize prognostic hub genes across validation-cohort-specific analyses. RESULTS: SIRPG was repeatedly ranked among the top ten selected genes in all five validation cohorts. At single-cell resolution, SIRPG-high tumor cells showed stronger malignant-cell features, immune-inhibitory and metabolic programs, Scissor-positive risk association, CLCA2/P53-related perturbation signals and inferred SIRPG-CD47/signal regulatory protein (SIRP) communication. Spatial analyses placed this axis within an immune-checkpoint-coupled niche, supported by Maxspin/multiview intercellular spatial modelling (MISTy) spatial coupling, communication analysis by optimal transport (COMMOT)-inferred CD47-SIRPG communication and scProTrans-inferred CD47/SIRPG protein-potential overlap. Functionally, SIRPG knockdown reduced HNSCC cell viability and increased apoptosis, whereas re-expression of short hairpin RNA (shRNA)-resistant SIRPG restored the CLCA2-BAX/BCL2 protein response. CONCLUSION: Together, these findings identify SIRPG as an immune-related prognostic hub and context-dependent tumor-cell regulator associated with apoptosis, immune communication and spatial microenvironmental organization in HNSCC.

Humans↗

PubMed2026

Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.

RNA splicing shapes neuronal identity and disease risk, yet current maps lack the developmental resolution and depth to resolve this complexity. Here, we integrate deep long-read RNA sequencing and proteomics in induced pluripotent stem cell-derived cortical neurons to generate a high-resolution proteogenomic atlas of human neuron development. We identify 182,371 mRNA isoforms (over half previously unknown) and provide direct peptide evidence for the translation of hundreds of novel protein-coding sequences. Population genetics demonstrates that variants affecting novel exons and splice sites are under negative selection, underscoring the potential significance of these isoforms. During neuronal maturation, we observe that autism risk genes undergo dynamic isoform switching, including microexon inclusion and intron retention, that remodel key protein domains and regulatory regions. Furthermore, we uncover widespread, long-range coordination between alternative transcript processing events, including transcription start sites, exon splicing, and polyadenylation. Finally, our atlas enables variant reinterpretation in autism, highlighting the value of an isoform-centric view for interpreting pathogenic variation in neurodevelopment.

Humans↗

PubMed2026

Distinct spatial immune microenvironment features of different EGFR mutation subtypes in early-stage lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinoma (LUAD), yet their influence on the spatial tumor immune microenvironment (TIME) in early-stage disease remains unclear. We characterized the spatial TIME in 144 treatment-naïve, early-stage LUADs using integrated genomic sequencing and multiplex immunohistochemistry (mIHC). Although EGFR-mutant tumors overall displayed reduced CD8 + T-cell infiltration compared with EGFR-wild-type tumors, substantial heterogeneity was observed among EGFR subtypes. Specifically, L858R and rare-variant subtypes exhibited higher tumor mutational burden, greater CD8 + T-cell density, and enrichment of T-cell-dominant cellular neighborhoods relative to 19del subtype, consistent with a comparatively immune-infiltrated phenotype. In contrast, 19del tumors showed lower T-cell infiltration. TP53 co-mutation was also associated with enhanced CD8 + T-cell infiltration. These cross-sectional findings identify hypothesis-generating spatial immune phenotypes across EGFR-mutant LUAD subtypes; their potential relevance to perioperative treatment selection requires prospective validation in outcome-annotated treatment cohorts.

Humans↗

PubMed2026

A spatially resolved genomic-molecular atlas of human white-matter microstructure.

Human white matter has been linked to inherited variation, circulating molecular state and brain disease, but these layers have rarely been mapped onto the same tract anatomy. Here we measured genetic effects along 6,090 atlas-aligned fiber pathways sampled at 609,000 locations in 72,185 UK Biobank participants, and integrated proteomic and metabolomic profiles within the same anatomical frame. Genetic effects were not whole-tract properties: each locus formed a spatial footprint along fiber trajectories, ranging from single locations to broad multi-tract patterns and reflecting regional polygenicity rather than tract heritability. This map identified 258, 186 and 298 previously unreported loci for fractional anisotropy, mean diffusivity and axial diffusivity; spatial patterns replicated in adults and 157 of 315 FA loci replicated in adolescence in ABCD. Mendelian randomization linked localized genetic effects to neurodegenerative and psychiatric traits, with Alzheimer's disease showing directional effects across 12 of 17 tracts. Multi-omic analyses identified 97 proteomic and 161 metabolomic associations, with the broadest signals from lipid metabolites including linoleic acid and phosphatidylcholines. The strongest lipid-metabolite and genetic signals converged in the corpus callosum, placing inherited variation, disease risk and systemic lipid metabolism on the same localized tract segments.

Journal Article↗

PubMed2026

Retinal Transcriptome-Wide Association Study Identifies Novel Alzheimer's Disease Risk Genes.

INTRODUCTION: Alzheimer's disease (AD) is the leading cause of dementia worldwide. The retina shares molecular pathways with the brain, yet no study has systematically linked retinal gene expression to AD risk. METHODS: We performed transcriptome-wide association studies (TWAS) using two independent retinal eQTL panels (Strunz et al., n = 311; EyeGEx, n = 406) and a large meta-analyzed AD genome-wide association study (GWAS) (Bellenguez et al., 111,326 cases, 677,663 controls). Genes were further validated with GWAS in the independent Alzheimer's Disease Sequencing Project (ADSP) using a matched eQTL-panel strategy. RESULTS: We identified 62 AD-associated genes across the two eQTL panels using Bellenguez et al. as the discovery cohort. Of these, 31 were replicated in the ADSP cohort. The findings highlight shared complement-mediated immune dysregulation (CD55, CD46, TREM2) and provide functional transcriptomic evidence to prioritize novel causal drivers of AD pathogenesis, including STYX and the LRRC37 gene family. DISCUSSION: Retinal data capture core AD genetic architecture and reveal novel risk genes, highlighting the retina as a molecularly informative tissue for dementia research.

Alzheimer’s disease↗

PubMed2026

ScRNA-seq analysis reveals the effects of nitrite stress on the endocrine system of the eyestalk in Litopenaeus vannamei.

Nitrite is a harmful substance generated in Litopenaeus vannamei farming systems, largely originating from the inadequate breakdown of surplus feed and shrimp feces. Its accumulation in the water can affect the growth and physiological functions of shrimp, damage the immune system, and even cause mass mortality, thus becoming a key environmental factor restricting the green development of the industry. Under nitrite stress, the eyestalk, as an important neuroendocrine regulatory center in crustaceans, participates in the stress adaptation of the organism and exerts a protective effect by regulating energy metabolism and immune function. However, the molecular regulatory mechanism of the eyestalk in response to nitrite stress remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) technology was used to analyze the heterogeneity of eyestalk cells in L. vannamei under nitrite stress. A total of 18, 394 high-quality cells were obtained, and six major cell subpopulations, including Neurosecretory cell, Motor neuron, Sensory neuron, Interneuron, Neurogliocyte, and Support cell, were identified. Differential expression analysis identified 839 differentially expressed genes, and different cell types showed distinct specific responses to nitrite stress. Functional enrichment analysis indicated that pathways such as glycolysis, oxidative phosphorylation, ribosome function, and endoplasmic reticulum protein processing were significantly activated, while signal transduction and DNA repair-related pathways were inhibited. Further analysis revealed that nitrite stress could induce mitochondrial function changes and trigger oxidative stress, thereby affecting the neuroendocrine system function of the eyestalk. This study provided insights into transcriptomic responses of the eyestalk to nitrite stress at the single-cell level, laying a theoretical foundation for the management of aquaculture environments.

Animals↗

PubMed2026

Functional Annotation of the Major Histocompatibility Complex Locus.

The human major histocompatibility complex (MHC) locus has the greatest density of disease-associations in the human genome, including links to over 100 polygenic disorders. Its complex haplotype structure, rich gene density, and high degree of linkage disequilibrium combine to make deciphering the gene regulatory logic of the MHC locus extremely challenging. Employing complementary high-throughput CRISPR interference (CRISPRi) and activation (CRISPRa) epigenetic screens coupled with single-cell transcriptome profiling across three distinct human cell types, we identified hundreds of new connections between cis -regulatory elements (CREs) and their target genes in this locus. These CRE-gene links are largely cell type-specific and act as enhancers. Additionally, some CREs have complex features, including harboring both active and repressive histone marks, lacking chromatin accessibility, targeting multiple genes, or acting as silencers. Computational methods fail to predict a majority of these CRE-gene connections. These findings emphasize the potential for functional perturbation experiments to dissect complex loci and reveal shared and cell type-specific regulatory mechanisms relevant to genomics of complex diseases. Collectively, this study provides a unique resource for understanding the complex regulatory landscape within the MHC locus and supports the need for creating new models that encompass CRE-gene interactions, cell type-specific gene expression, and disease genetics in the noncoding genome.

Journal Article↗

PubMed2025

Genomic loci and molecular genetic mechanisms for hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a common, chronic and debilitating inflammatory disease that most commonly affects intertriginous skin. Despite its high heritability, the genetic underpinnings of HS remain poorly understood. OBJECTIVES: To identify genetic signals associated with HS, determine genetic relationships with other diseases and investigate potential molecular genetic mechanisms. METHODS: We performed a genome-wide association meta-analysis of six studies, totalling 4540 patients with HS and > 1 million control participants, and identified genetic correlations with other common diseases. We integrated the HS data with expression quantitative trait loci from 10 trait-relevant tissues, epigenomic and transcriptomic data from human scalp, differential expression data from HS lesions vs. adjacent skin and mesenchymal Hi-C chromatin looping data. To identify functional noncoding variants, we performed transcriptional reporter assays for signals near KLF5 and SOX9. RESULTS: We identified 11 significant HS signals across 7 loci: 4 corresponded to previously reported associations, 4 represented novel signals within known loci and 3 were signals in newly implicated loci. We identified significant genetic correlations between HS and other inflammatory conditions, particularly inflammatory bowel disease, rheumatoid arthritis, type 2 diabetes mellitus and asthma. We prioritized candidate genes for the 11 signals. The risk allele at KLF5 exhibited 10-fold greater transcriptional activity than the nonrisk allele, while risk alleles at SOX9 showed significantly reduced transcriptional activity. CONCLUSIONS: Our results provide insights into potential genetic mechanisms underlying HS and suggest potential therapeutic targets for this challenging condition.

Humans↗

PubMed2025

Human gut Bifidobacterium longum subsp. suillum is enriched in vitro by a pectic polysaccharide isolated from the flowers of Lilium lancifolium.

Although pectins have been explored widely, knowledge of their effects on the gut microbiota is lacking owing their complex structure. The aim of this study was to investigate whether pectin enriched gut microbes in vitro. To address this, a homogeneous RG-I like pectin, L01-B1, with a molecular weight of 43.9 kDa was extracted from the flowers of Lilium lancifolium. Structural analysis revealed that L01-B1 contained rhamnose, glucuronic acid, galacturonic acid, galactose, and arabinose in a molar ratio of 13.4: 1.8: 11.1: 37.2: 36.5. The backbone of L01-B1 was composed of 1, 6-β-Galp, 1, 4-α-GalpA, and 1, 2-α-Rhap, whereas the branches included 1, 5-α-Araf, 1, 4-β-Galp, and T-β-GlcpA attached to C-4 of rhamnose, and 1, 3-β-Galp and T-β-Galp linked to C-3 of galactose. L01-B1 altered the composition of human gut microbiota in vitro and increased the abundance of Bifidobacterium longum. Furthermore, Bifidobacterium longum subsp. suillum strain DK001 was isolated and identified from human feces. The DK001 genome was found to be circular with a genome size of approximately 2.4 M. Notably, L01-B1 might possibly be degraded by two kinds of enzymes and change the metabolism of human gut microbiota. Overall, these findings provide insights into intervention strategies that target Bifidobacterium longum.

Humans↗

PubMed2025

Exploring the shared genetic basis of attention-deficit/hyperactivity disorder and obstructive sleep apnea: A multi-omics analysis.

BACKGROUND: Observational studies have suggested an association between attention-deficit/hyperactivity disorder (ADHD) and obstructive sleep apnea (OSA), but these findings are often inconsistent due to potential biases from medication use, and varying diagnostic criteria. Genetic analyses can help mitigate these confounding factors, providing additional evidence. METHODS: This study evaluated the genetic correlations between ADHD and OSA using Genome-wide association study (GWAS) summary data, applying linkage disequilibrium score regression (LDSC) and SUPER GeNetic cOVariance Analyzer (SUPERGNOVA). Cross-trait association and colocalization analysis identify potential pleiotropic loci. Tissue enrichment analysis and gene-level analysis of shared genes between OSA and ADHD was conducted. Additionally, bidirectional Mendelian randomization was used to assess potential causal relationships. RESULTS: We found significant genetic correlations between ADHD and OSA (rg = 0.309, p = 3.252E-27), and identified 8 novel pleiotropic loci through cross-trait association analysis. Tissue enrichment analysis showed that these shared genes were primarily concentrated in brain tissues, particularly in deep gray matter regions, and were associated with immune and inflammatory pathways. Forward Mendelian Randomization analysis showed that ADHD was significantly associated with the risk of OSA (OR 1.070, 95 % CI 1.013-1.130, p = 0.016), and reverse analysis showed that OSA was significantly associated with the risk of ADHD (OR 1.240, 95 % CI 1.106-1.390, p = 2.213E-4). CONCLUSION: The findings of this study show a significant positive genetic correlation between ADHD and OSA and each is a risk factor for the other. Inflammation in specific brain regions may be the underlying mechanism for their comorbidity.

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↗