Biology subjects

Zhang, N.

Publications and source records attributed to Zhang, N..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

VASP Promotes Aortic Valve Calcification by Interacting with FBLIM1 to Activate the Focal Adhesion Pathway

BackgroundCalcific aortic valve disease (CAVD) is the most prevalent valvular heart disease, yet there is no effective pharmacological therapy to halt or reverse its progression. Focal adhesions (FAs) are dynamic structures that connect cells to the extracellular matrix (ECM), serving not only as mechanical anchors but also as critical signalling hubs that regulate cell adhesion, spreading, migration, differentiation, and mechanotransduction. However, their specific role in CAVD pathogenesis remains largely unknown. MethodsTo identify upregulated hub genes, an integrated analysis of proteomics and RNA sequencing was performed on calcified aortic valves. To investigate functional roles in vitro, we utilized genetic knockdown and overexpression of VASP in valvular interstitial cells (VICs), followed by phenotypic evaluations of osteogenic differentiation, calcification, and elastin (ELN) secretion. Downstream mechanisms were explored using RNA-seq in VASP-overexpressing VICs, alongside pharmacological inhibition of the FA pathway. Finally, protein-protein interaction assays were conducted to map and analyze the physical binding between VASP and the structural domains of FBLIM1. ResultsIntegrated omics analysis identified VASP as a significantly upregulated gene in human calcified aortic valve tissues. Functionally, VASP knockdown inhibited, whereas its overexpression promoted, the osteogenic differentiation of VICs. RNA-seq revealed that VASP overexpression activated the FA pathway, and the pharmacological blockade of this pathway successfully suppressed calcification both in vitro and vivo. Mechanistically, we demonstrated a direct physical interaction between VASP and the third LIM zinc-binding domain of FBLIM1, and knockdown of FBLIM1 effectively reversed the pro-calcific effects of VASP. Finally, VASP overexpression was found to promote the secretion of ELN, which subsequently contributed to the calcification process. ConclusionOur study reveals that the interaction between VASP and FBLIM1 drives CAVD progression by activating the FA pathway, which subsequently leads to excessive ELN secretion. These findings reveal a novel mechanistic pathway and may provide a potential therapeutic target for CAVD intervention. What are the Clinical Implications?We have identified the VASP-FBLIM1-FA-ELN axis as a novel molecular pathway involved in CAVD pathogenesis, greatly enriching our understanding of the complex process of aortic valve calcification. This pathway intricately links cytoskeletal dynamics, cell adhesion signalling, and ECM remodelling, providing a new theoretical framework for pathophysiological research in CAVD. In clinical practice, VASP and its downstream pathway components, particularly FBLIM1 and the FA pathway, may serve as potential biomarkers and therapeutic targets for the early diagnosis and treatment of CAVD. For example, the FA pathway inhibitors PF-573228 and Y15 demonstrated significant anti-calcification effects both in vitro and in vivo, suggesting that targeting this pathway may offer a new nonsurgical intervention strategy for patients with CAVD.

cell biology↗

bioRxiv2026

AlfaDAX-Derived ActRIIA/B Antibody with Semaglutide Enhances Fat Loss and Improves Weight-Loss Quality in DIO Mice

GLP-1 receptor agonists achieve weight loss but are associated with clinically significant reductions in lean mass. Activin type II receptors (ActRIIA and ActRIIB) mediate signaling of myostatin and activin A, both of which negatively regulate muscle growth, suggesting that dual blockade of these receptors may preserve or increase lean mass while promoting fat loss. In this study, we developed anti-ActRIIA/B antibodies using AI-driven platforms (AlfaDAX) and selected the lead candidate AB130-165 based on in vitro binding, functional blocking, and developability assessments. Compared with a laboratory-prepared bimagrumab analog, AB130-165 exhibited potent dual inhibition of ActRIIA/B signaling, with a 9.5-fold higher functional blocking activity against activin A-induced SMAD signaling and 1054-fold improvements in binding affinity for ActRIIA (KD = 0.204 pM), 10-fold for ActRIIB (KD = 0.243 pM), respectively. In diet-induced obese mice, combination therapy with AB130-165 and semaglutide resulted in a 33.4% body weight reduction, which was superior to semaglutide monotherapy (-24.3%) and the bimagrumab combination group (-25.5%). Moreover, the combination significantly improved body composition, reducing fat mass percentage by 77.8% (vs. 65.0% in the bimagrumab combination group) and increasing the lean-to-body weight ratio to 67.3% (vs. 62.3%), demonstrating superior fat loss with better preservation of lean mass. Collectively, these findings establish AB130-165 as a differentiated anti-ActRII antibody that enables high-quality weight loss, and its combination with semaglutide shows superior efficacy over bimagrumab-based regimens. With favorable developability and potential for long-acting subcutaneous administration, AB130-165 represents a promising next-generation therapeutic candidate for obesity and muscle-sparing weight management.

pharmacology and toxicology↗

bioRxiv2026

Development and Analytical Validation of a Smartphone-Based Quantitative Lateral Flow Immunoassay for Serum Cystatin-C

Cystatin-C is an important renal function biomarker, and conventional quantification requires centralized laboratory analyzers, which limits timely testing in primary care and resource-limited settings. To address this need, we developed and validated a simple, rapid, and quantitative smartphone-based (SP) lateral flow immunoassay (LFIA) for measuring serum Cystatin-C. The SP-LFIA platform consists of a colorimetric LFIA strip and a custom SP reader with uniform LED illumination and macro lens for image capture. Quantitative image analysis of the colorimetric signal is performed by a dedicated application using a pre-defined third order polynomial calibration model. Following systematic optimization, the assay demonstrated a wide quantitative range of 0.32-8.00 mg/L, with a limit of detection of 0.15 mg/L. Analytical validation conducted according to CLSI guidelines showed excellent precision, with intra- and inter-assay coefficients of variation below 10%, and no significant interference from bilirubin, triglycerides, hemoglobin, or rheumatoid factor. Accelerated stability testing confirmed robust strip performance after storage at 50 {degrees}C for 28 days. Method comparison using 100 clinical serum samples showed high agreement with a commercial PETIA reference method (R{superscript 2} = 0.993) and minimal bias. These results indicate that the developed smartphone-based LFIA provides a reliable, cost-effective, and practical tool for point-of-care Cystatin-C monitoring.

biochemistry↗

bioRxiv2026

A missense mutation in FBXL3 links circadian regulation to out-of-season estrus in sheep

Seasonal breeding is a remarkable adaptive trait, but it constrains efficient production in the sheep industry. Recent studies have shown that seasonal breeding is associated with endogenous circannual rhythms, which are regulated in part by the circadian clock system. FBXL3, a pivotal component of the SCF (SKP1 - CUL1 - F-box) E3 ubiquitin ligase complex, is a known determinant of the mammalian circadian period. In this study, we identified a missense mutation, T183M, in FBXL3 through selective sweep analysis. The allele frequency of this mutation differed significantly between sheep breeds exhibiting year-round estrus and those showing seasonal breeding patterns. The association between the T183M mutation and seasonal breeding was further validated using an ovariectomized, estradiol-implanted sheep model. We then generated mice carrying the homologous T183M mutation and found that they exhibited significantly lengthened circadian periods, accompanied by reduced CRY1 expression and increased CLOCK expression. Co-immunoprecipitation assays confirmed that the mutation reduced the interaction between FBXL3 and CRY1. These findings demonstrate an evolutionarily conserved role of FBXL3 in the circadian clock system. We propose that the T183M mutation disrupts day-length recognition, thereby influencing seasonal estrus in sheep. Author summarySeasonal breeding limits sheep productivity and is regulated by circadian rhythms, yet the key genetic determinants remain poorly understood. Here, we identified an FBXL3 T183M missense mutation whose allele frequency differed markedly between year-round-estrous and seasonally breeding sheep, and validated its association with seasonal reproduction in a sheep population. Functional analyses in mutant mice showed that this variant lengthened the circadian period, disrupted the expression of core clock genes, and weakened the interaction between FBXL3 and CRY1. These findings suggest that the FBXL3 T183M variant impairs day-length perception, thereby modulating seasonal estrus in sheep. Our study reveals a conserved circadian mechanism underlying seasonal breeding and highlights FBXL3 T183M as a promising genetic target for improving reproductive performance in sheep.

genetics↗

bioRxiv2026

Multitrophic interaction networks mediate biodiversity effects on ecosystem multifunctionality

Biodiversity loss threatens the multifunctionality of ecosystems on which human well-being ultimately depends. Changes in multitrophic species interactions may be key to explaining the ecological consequences of biodiversity loss, but research explicitly linking species interactions and ecosystem multifunctionality remains rare. To assess interaction-mediated biodiversity effects and underlying mechanisms, characterizing the structure of species interaction networks is invaluable. Using comprehensive species interaction and ecosystem functioning data from a large-scale tree biodiversity experiment, we find consistent effects of the structure of species interaction networks on ecosystem multifunctionality across multiple types of antagonistic and mutualistic interactions. While positive effects of network size align with expected positive effects of multitrophic species diversity, positive effects of niche overlap among interacting species and negative effects of highly connected species (i.e. high linkage density) reveal additional, interaction-mediated drivers of multifunctionality. Specifically, the effects of niche overlap suggest benefits of functionally similar species, and the effects of linkage density underscore the importance of specialized interactions in promoting ecosystem multifunctionality. These findings emphasize that to effectively safeguard ecosystem service provisioning, ecosystem management and biodiversity conservation not only need to account for biodiversity changes at multiple trophic levels, but also explicitly for how species interact among each other.

ecology↗

bioRxiv2026

A dish-to-biobank framework links β-cell nutrient-stress programs to genetic and dietary risk for Type 2 Diabetes

Type 2 diabetes (T2D) arises from genetic susceptibility and chronic metabolic stress, but whether these converge on shared molecular programs in human populations remains unclear. Here, we develop a dish-to-biobank framework linking controlled {beta}-cell perturbation to population-scale disease genetics through the circulating plasma proteome, and apply it to T2D. scRNA-seq of human stem cell-derived islets under factorial glucose and palmitate exposure identifies their combination (glucolipotoxicity) as the condition eliciting the strongest SC-{beta} cell transcriptional response, with glucolipotoxicity-upregulated genes uniquely enriched for T2D heritability, monogenic diabetes genes, and rare-variant burden signals. CRISPR knockout of {beta}-cell identity regulators PAX6 and PDX1 aligns with this program, establishing convergence of environmental and genetic perturbations on a shared disease-relevant state. We then used the plasma proteome as an accessible population-scale readout of these experimentally defined {beta}-cell stress programs, scoring 45,956 UK Biobank White British participants. We define heritable stress signatures that associate with refined carbohydrate and saturated fat intake, and undergo trans-tissue genetic regulation, with a subset of variants showing diet-dependent effects. Together, these findings establish glucolipotoxicity as a genetically anchored model of {beta}-cell dysfunction and provide a generalizable framework for linking controlled cellular perturbations to human disease genetics at population scale.

genetics↗

bioRxiv2026

Integrating longitudinal hyperspectral phenotyping with AI and GWAS to dissect barley waterlogging responses

Waterlogging is a major constraint on barley productivity, yet its dynamic, multi-phase nature makes it challenging to dissect using traditional phenotyping approaches. High-throughput phenotyping (HTP) platforms address this by enabling temporal, multi-sensor imaging of large populations, but generate complex datasets that demand new analytical frameworks. Here, we imaged 230 barley accessions over 14 days of waterlogging stress and seven days of recovery using visible, chlorophyll fluorescence, and hyperspectral sensors. Explainable AI was applied to classify stress responses into early stress, late stress, and recovery phases, achieving 86% classification accuracy, and to identify the hyperspectral indices most informative for each phase. Water index (WATER1) and structure insensitive pigment index (SIPI) emerged as primary predictors of stress response. Longitudinal genome-wide association studies (GWAS), using a treatment-by-marker interaction model, identified 236 significant loci across 12 linkage disequilibrium blocks, implicating candidate genes involved in oxidative stress regulation, transcriptional control, and auxin transport. MYB transcription factors were consistently identified across all stress phases, underscoring their central role in waterlogging adaptation. To support interpretation of longitudinal GWAS results, we developed 3D-QTLVis, an interactive visualisation tool that extends Manhattan plots across time, enabling clearer identification of dynamic genomic regions underlying stress tolerance.

plant biology↗

bioRxiv2026

Loss of the Y chromosome drives epigenetic and transcriptomic plasticity in lung adenocarcinoma

Loss of the Y chromosome (LOY) is associated with poor survival across multiple solid tumors, yet the underlying molecular mechanisms remain poorly understood. Here, we identify LOY as a central driver of lineage plasticity and epigenetic heterogeneity in lung adenocarcinoma. Integrating multi-omic profiling of primary samples with isogenic cellular models, we show that LOY triggers epithelial-to-mesenchymal transition (EMT). Mechanistically, LOY causes haploinsufficiency of dosage-sensitive regulators, leading to widespread DNA hypomethylation at EMT gene promoters, including THY1 and LOX. Single-cell multi-omic analyses demonstrate that LOY induces epigenetic heterogeneity, destabilizes the chromatin landscape, and increases lineage plasticity, enabling rapid cellular adaptation to metabolic and genotoxic stress. Moreover, LOY-induced plasticity facilitates tumor engraftment and metastatic dissemination in vivo. These findings establish Y-linked gene dosage as a critical guardian of epigenetic stability, providing a mechanistic rationale for how its loss amplifies phenotypic diversity and lineage plasticity, ultimately driving adverse clinical outcomes in LOY patients.

cancer biology↗

bioRxiv2026

A genetic tool targeting brain GPR75

G-protein-coupled receptor 75 (GPR75) has emerged as an important mediator in diet-induced obesity (DIO) and a promising therapeutic target for anti-obesity drugs. However, the anatomical location of GPR75 in the brain remains unclear, hindering the understanding of GPR75 biology in DIO. Here, we generated a new GPR75-GFP-Ires-Cre knockin mouse strain, in which the Cre expression is driven by the endogenous GPR75 promoter and the GFP is fused with the C-terminal of the GPR75 protein. Both Cre and GFP were confirmed to be colocalized with the endogenous GPR75 expression. In addition, the GPR75-GFP fusion protein remains functionally normal with unaltered susceptibility to DIO. Moreover, using this mouse strain, we found that GPR75 is broadly expressed throughout the brain and mainly localized to the cytoplasm of brain neurons. This new genetic tool can therefore be used to study the neural basis for GPR75 in mediating DIO.

neuroscience↗

bioRxiv2026

Circadian misalignment underlies immune escape in breast cancer

Circadian regulation shapes tissue physiology, yet how it organizes cellular and molecular dynamics within the tumor microenvironment (TME) and influences tumor immunity remains unclear. Using temporal single-nucleus multiomic profiling of mouse breast tumors, we uncovered extensive circadian programs that are both cell-type-specific and shared across the TME, governing proliferation and immune responses. Notably, cancer epithelial cells exhibited global acrophase misalignment relative to immune populations. This intercellular desynchrony manifests as temporal decoupling between tumor proliferation and immune activation, discordant antigen presentation and T cell recognition with intrinsic activation-exhaustion overlap in T cells, and asynchronous PD-1/PD-L1 oscillations that sustain checkpoint-mediated suppression. Similar patterns were observed in human triple-negative breast cancer (TNBC). Together, these findings establish intercellular circadian misalignment as a mechanism of tumor immune evasion and position the circadian architecture of the tumor-immune ecosystem as a previously underappreciated determinant of tumor development and therapeutic response. HIGHLIGHTSO_LISingle-cell multiomics maps circadian regulation of tumor-immune programs. C_LIO_LICircadian regulation in cancer epithelial cells is misaligned with immune cell populations. C_LIO_LITumor-immune temporal misalignment undermines antitumor immunity. C_LIO_LICircadian misalignment in human TNBC suggests relevance for immunotherapy timing. C_LI

cancer biology↗

bioRxiv2026

Prediction of Transcription Factor DNA Binding Affinity with High-Throughput Kd Measurements and Deep Learning

Transcription factors (TFs) regulate gene expression through specific interactions with genomic DNA. While TF binding motifs from public databases describe sequence preferences, quantifying genome-wide affinity (Kd) is highly desirable for a more accurate thermodynamic description. Here, we report ivtFOODIE (in vitro FOOtprinting with DeamInasE), an assay that leverages deaminase-mediated cytosine-to-uracil conversion to measure Kd values for a given TF across accessible genomic regions from human cells. By pre-training on TF binding sites from JASPAR and fine-tuning with our ivtFOODIE data from 46 TFs representing 13 different DNA-binding domains (DBDs), we developed Seq2Kd, a deep learning model capable of predicting a TFs absolute binding affinity on DNA sequences. Seq2Kd enables de novo motif discovery of [~]500 previously uncharacterized human TFs and reveals the effects of genetic variation both in TF-coding regions and DNA-binding sites on gene expression and disease susceptibility. By correlating predicted affinity changes with the sign and magnitude of expression quantitative trait locus (eQTL) effects, we stratified TFs into activator-like and repressor-like groups. Compared to clinically benign variants, pathogenic single-nucleotide variants (SNVs) within regulatory and protein-coding regions show significantly larger predicted shifts in Kd. We provide an interactive web portal, the ENcyclopedia of Transcription-factor Interactions with Regulatory Elements (ENTIRE), which integrates the Seq2Kd model with the ivtFOODIE dataset. This resource offers thermodynamic prediction for TF-DNA interactions for functional genomics and human disease.

biophysics↗

bioRxiv2026

Nascent protein retention at polysomes reduces kinetic barriers to self-assembly

Living proteomes are necessarily far from equilibrium. It is paradoxical, then, that reducing the translation of new proteins -- which should promote equilibration -- instead prolongs life. We investigated the impact of translational flux to nucleation barriers that preserve the solubility of proteins destined to form amyloids or other assemblies. By manipulating translation initiation rates directly or indirectly, across yeast and human cells, and across a variety of supersaturable proteins, we find that accelerating translation initiation broadly accelerates nucleation irrespective of their global concentrations. We showed that this effect was confined to polysomes and was enhanced by N-terminal placement or other features that retained the nascent aggregating domain at polysomes. Finally, we show that intrinsically disordered regions with high tendencies to self-associate are specifically positioned to do so co-translationally, providing evidence that cotranslational nucleation has shaped proteome evolution.

cell biology↗

bioRxiv2026

Tree diversity intensifies soil microorganism-tree interactions

O_LIA productivity-driven higher nutrient demand of trees in diverse mixtures is frequently reported. Yet, it remains unclear how tree diversity influences microorganisms-plants interactions, in which microbes facilitate tree nutrient acquisition in exchange for carbon (C) to meet the resource demand of both. C_LIO_LIUsing a long-term tree diversity experiment in the subtropics, we assessed microbial investment in C-, nitrogen (N)-, and phosphorus (P)-acquiring enzymes in litter and mineral soil, testing the effects of tree species richness and mycorrhizal type (arbuscular (AM)- vs. ectomycorrhizal (EcM)-associated tree species). C_LIO_LIWith increasing tree species richness, microbial investment in C acquisition decreased, while investment in N and/or P acquisition increased in litter and in mineral soil. In mineral soil of AM-associated tree mixtures, ecoenzymatic stoichiometry revealed a shift from microbial investment in C toward P acquisition as tree species richness increased. C_LIO_LIOur findings suggest that tree diversity strengthens microbe-tree interactions in terms of C-for-nutrient exchange. This highlights the key role of soil microorganisms, particularly in AM symbiosis, shaping tree diversity-biogeochemical feedbacks. C_LI

ecology↗

bioRxiv2026

Eleven deep-sea coral genome assemblies unveil insights into evolution, adaptation, and coral biodiversity

Deep-sea corals are vital in maintaining coral ecosystem biodiversity, yet their genetic characteristics remain largely unexplored. Here, we present 11 deep-sea coral genome assemblies, including four Hexacorallia and seven Octocorallia species, significantly contributing new genomic information across two orders. Our analysis reveals the historical dynamics of coral speciation and the influence of environmental factors on the evolution of coral reef ecosystems.Total of 126 horizontal gene transfer (HGT) events were detected, among which genes from the ancestor of symbiodiniaceae indicate that the ancestors of deep-sea corals may have inhabited shallow-sea environments. Notably, several of these HGTs are involved in phosphorus (PhnX/PhnW) and cholesterol (DHCR7) metabolisms within corals, indicating that HGTs may serve as an adaptive survival strategy for the coral holobionts. Deep-sea corals also rely on symbiotic bacteria to synthesize 10 essential amino acids (such as valine and tyrosine), retaining only partial amino acid synthesis capacity. In addition, we investigated the evolution of key biological rhythm genes and temperature adaptation in corals. The loss of key rhythm genes (e.g., clock and cry) in deep-sea corals and copy number difference of genes related to heat stress (e.g., Cbl-b and Rchy) revealed genetic difference between deep-sea and shallow-sea corals. Our new genome assemblies enhance the understanding of deep-sea coral evolution, biodiversity, and adaptation, providing a genetic foundation for coral conservation.

genomics↗

bioRxiv2026

ExMODE: A Multi-Omics Repository for Extremophile Adaptation and Bioprospecting

Extreme environments, though hostile to most life forms, host specialized extremophile communities that have redefined biological cognition and emerged as vital biotechnological resources, with their unique adaptive traits and bioactive molecules driving advances in multiple scientific and industrial fields. However, research on extremophiles is hindered by limitations in culture-based methods, fragmented multi-omics data with non-uniform annotation standards across repositories, the lack of cross-extreme comparative research in existing resources, and the singularity of data dimensionality that neglects key structural information, all of which restrict the functional interpretation of extremophile microbes and the exploitation of their bioprospecting potential. To tackle these challenges, we developed ExMODE (https://db.genomics.cn/exmode/), a comprehensive multi-omics database platform dedicated to extremophiles. It centrally integrates multi-omics data from diverse extreme habitats with a standardized annotation framework, resolving data fragmentation and enabling systematic cross-environment comparative analyses to elucidate extremophile adaptive mechanisms. Moreover, ExMODE aggregates multi-dimensional datasets including genes, genomes, secondary metabolite sequences and protein structures, overcoming the constraints of single-dimensional data and significantly improving the efficiency of biotechnological resource discovery from extreme microorganisms.

microbiology↗

bioRxiv2026

Generation of High-Affinity Anti-GIPR Antagonist Antibodies with Sustained and Non-rebound Weight Loss in DIO Mice by AlfaBodY

The glucose-dependent insulinotropic polypeptide receptor (GIPR) is an attractive therapeutic target for metabolic disorders, with GIPR antagonism emerging as a promising strategy for obesity and type 2 diabetes. However, developing functional antibodies against GPCRs remains challenging due to their complex architecture and conformational dynamics. Here, we employed AlfaBodY, an iterative active learning platform integrating structural and sequence information, to in silico design human anti-GIPR antibodies. Through four rounds of optimization, we generated antibodies with high binding affinities. Lead candidates AB106-131 (KD 1.2 nM) and AB106-156 (KD 1.7 nM) exhibited 7 to 10-fold higher affinity than 2G10 (KD 12 nM) while maintaining comparable antagonistic activity in a cAMP reporter assay (IC50 4[~]5 nM). In diet-induced obese mice, AB106-156 alone induced weight loss comparable to that of semaglutide ([~] -15%), while preserving lean mass and achieving sustained weight control after treatment withdrawal. Co-administration with the GLP-1 receptor agonist semaglutide produced synergistic weight reduction (-25.4%) and markedly attenuated the fat-mass rebound observed with semaglutide alone. Our results demonstrate that AI-driven design can generate potent anti-GIPR antibodies with favourable in vivo efficacy, supporting further development of GIPR antagonist for obesity and related metabolic disorders. The AlfaBodY platform enables faster development of more efficacious biologic drugs.

pharmacology and toxicology↗

bioRxiv2026

Dissecting the coordinated progression of cell states in spatial transcriptomics with CoPro

Spatial transcriptomics enables the study of how cells coordinate their molecular states within tissue, providing insight into both normal function and disease processes. A key challenge is to identify gene expression programs that vary continuously across space and are coordinated between cell types. We present CoPro, a computational framework for detecting the spatially coordinated progression of cellular states. CoPro can operate in both supervised and unsupervised modes to identify gene programs that co-vary within or between cell types, and to disentangle multiple overlapping spatial patterns. CoPro can be applied to single-cell-level spatial transcriptomics datasets, including MERFISH, SeqFISH+, Xenium, and histology-imputed transcriptomic data. We demonstrate the utility of CoPro with data collected from colon, brain, liver, and kidney tissues. In the colon, CoPro separates epithelial differentiation along the crypt axis from spatially localized inflammatory signals. In the aging liver, it identifies multiple aging-associated cellular programs superimposed on anatomical zonation. In the brain, the flexible kernel design enables the decoupling of the gene expression gradient along the dorsal-ventral and medial-lateral axes. In the kidney, CoPro identifies tubule-vasculature coordination that is essential in nephron function. These results demonstrate CoPros utility for analyzing spatial coordination of gene expression in complex tissues and disentangling overlapping biological processes, such as anatomical organization and disease-associated variation.

bioinformatics↗

bioRxiv2026

Sex stratified analyses enable new genetic insights into brain imaging phenotypes

Sex differences are commonly observed in neuroimaging phenotypes and in the risk of brain diseases, yet the underlying genetic mechanisms remain poorly understood. We investigated sex differences in the genetic architecture of 805 neuroimaging phenotypes in 22,950 males and 22,950 females matched for sample size and covariates, and systematically compared sex-stratified with sex-combined genetic analyses. We found eight variant-trait associations with significant sex differences, 235 fine-mapped sex-dominant causal associations, 457 sex-dominant colocalizations with sex hormones, and 96 sex-dominant colocalizations with schizophrenia. Compared with sex-combined analysis, sex-stratified analysis identified 47 new genetic associations, 170 new fine-mapped causal associations, 1,019 new colocalizations with sex hormones, and 191 new colocalizations with schizophrenia. Additionally, sex-stratified analysis improved global heritability and genetic-correlation estimates and enhanced polygenic prediction for certain phenotypes. This work highlights the need to routinely perform sex-stratified genetic association analyses to elucidate sex-specific and sex-shared genetic control of neuroimaging phenotypes and related disorders.

genetics↗