Search Results (4,585)

Osteosarcopenia, which is the coexistence of sarcopenia and osteoporosis, is being increasingly recognized as a systemic musculoskeletal aging syndrome. However, shared molecular regulators of bone–muscle deterioration remain unclear. In this study, we integrated bulk transcriptomic datasets from sarcopenic skeletal muscle and osteoporosis peripheral blood mononuclear cells to identify shared differentially expressed genes, followed by two-sample Mendelian randomization using osteoporosis genome-wide association study summary statistics to prioritize genes with potential causal relevance. Furthermore, diagnostic performance, functional enrichment, immune infiltration, single-cell RNA sequencing, regulatory network reconstruction, compound prediction, and siRNA-mediated validation were conducted in C2C12 and MC3T3-E1 cells. Overall, 122 shared differentially expressed genes were preliminarily screened, and KAZN and SUPT3H were tentatively proposed as candidate genes genetically associated with osteoporosis risk. Both genes were upregulated in the disease groups and exhibited weak to modest diagnostic performance. Furthermore, Kazn or Supt3h knockdown promoted myogenic differentiation in C2C12 cells as well as osteogenic differentiation and mineralization in MC3T3-E1 cells, supporting their roles as negative regulators of lineage differentiation. Moreover, functional analyses linked KAZN mainly to mitochondrial-related programs and SUPT3H to immune signaling, whereas single-cell analyses localized these genes to stromal, progenitor, and immune-related compartments. These hypothesis-generating findings suggest that KAZN and SUPT3H participate in shared bone–muscle dysfunction and generate candidate genes and mechanistic hypotheses for subsequent functional validation and translational research. Full article

Hexi cattle are a local cattle population endemic to the Hexi Corridor in Gansu Province, China, and exhibit strong adaptability to the region’s arid continental environment. However, comprehensive genomic investigations of this population are still lacking. In the present study, we integrated population genomic analyses with a genome-wide association study (GWAS) to dissect the genetic architecture of Hexi cattle. Whole-genome resequencing data were generated for 264 Hexi cattle, and public genomic datasets from six representative cattle breeds were obtained from the NCBI database for comparative analysis. Multiple analytical approaches—including principal component analysis (PCA), linkage disequilibrium (LD) decay analysis, neighbor-joining (NJ) phylogenetic tree construction, and ADMIXTURE analysis—were adopted to evaluate population structure and evolutionary relationships. A mixed linear model was then used to identify significant SNPs associated with five major body conformation traits in six-month-old cattle: body weight (BW), withers height (WH), hip height (HH), heart girth (HG), and abdominal girth (AG). Our results confirm the admixed nature of Hexi cattle, whose genome is derived primarily from Simmental cattle and secondarily from Mongolian cattle. A total of 69 trait-associated significant SNPs were identified and functionally annotated. Specifically, TBC1D31, DERL1 and MCPH1 were linked to BW; FSCN3 and PLBD1 to WH; MCPH1 to HH; NPAS3, TBC1D31, DERL1 and MCPH1 to HG; and SOX5, NTAQ1, FAM83A, TBC1D31, DERL1, CDH11, CPLX4 and ADAM18 to AG. This study deepens our understanding of the genetic basis of growth traits in Hexi cattle and offers valuable molecular resources for future selective breeding, genetic improvement, and long-term conservation of this indigenous cattle population. Full article

Background: Drug repurposing offers a cost-effective strategy to accelerate therapeutic discovery, but most computational approaches do not model noncoding genetic variation. Because over 90% of genome-wide association study (GWAS) risk variants reside in noncoding regions, linking regulatory variation to therapeutic hypotheses remains a major challenge. Methods: We developed an integrative deep learning framework that links allele-specific enhancer prediction to candidate therapeutics through two complementary prioritization strategies, a transcription factor (TF)-based and a gene-based approach. We used MCF7-breast cancer context as a proof-of-concept system. Results: GWAS heritability was significantly enriched in MCF7 enhancers. Allele-specific variant scoring identified 1537 breast cancer risk variants with strong predicted regulatory effects, and attribution-based motif discovery revealed enrichment of FOXA1-associated motif features, consistent with FOXA1 upregulation in primary tumors. TF-based prioritization, integrating FOXA1 knockdown-induced and drug-induced gene expression profiles, identified 63 candidate compounds, including 18 approved drugs, and recovered fulvestrant, an established breast cancer therapy. Gene-based prioritization, mapping candidate regulatory variants to 347 target genes, identified 140 candidate compounds, including approved breast cancer drugs toremifene and raloxifene. Both strategies identified compounds with anti-correlated transcriptional signatures across core breast cancer hallmark pathways, and integration of pathway anti-correlation, drug-gene interactions, and supporting experimental or clinical evidence yielded 15 high-confidence repurposing candidates. Conclusions: Recovery of approved breast cancer therapeutics supports the biological relevance of deep learning-predicted regulatory variants. This study establishes a regulatory variant-guided drug repurposing framework that connects noncoding genetic variation to candidate therapeutics and provides a scalable strategy for generating pharmacologically relevant hypotheses from the noncoding genome. Full article

Soil salinity severely restricts grapevine growth and development. Here, we integrated whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) to investigate DNA methylation changes and their relationship with gene expression under salt stress in Vitis vinifera L. ‘Shine Muscat’ grapevine. Salt stress altered genome-wide DNA methylation patterns, reducing methylation levels in CG, CHG, and CHH contexts following NaCl treatment. We identified 8606 differentially methylated regions (DMRs) and 3106 DMR-associated genes (DMGs) under salt stress. RNA-seq analysis revealed 2691 differentially expressed genes (DEGs), including multiple stress-related transcription factors (e.g., MYB, NAC, WRKY) and hormone-related genes strongly induced by salinity. Integrative analysis identified 171 genes that were both differentially methylated and differentially expressed, primarily enriched in metabolic pathways, fructose and mannose metabolism, and fatty acid biosynthesis. Notably, several key stress-responsive genes (e.g., VvNAC72, VvBAK1, VvMYBS3) showed coordinated changes between methylation status and transcript abundance. Collectively, this study provides a comprehensive integrative analysis of DNA methylation and transcriptome reprogramming in ‘Shine Muscat’ grapevine under salt stress, revealing potential epigenetic mechanisms involved in transcriptional regulation and salt adaptation. The identified candidate genes provide valuable targets for further functional validation and genetic improvement of grapevine salt tolerance. Full article

Introduction: Genetic susceptibility shapes paediatric oral health, yet candidate variants remain scattered across phenotype-specific studies. Aim: To synthesise genetic association evidence for oral and craniofacial phenotypes with paediatric onset, and to propose a candidate single-nucleotide polymorphism (SNP) panel to inform future risk-stratification research supporting precision prevention in paediatric dentistry. Methodology: A PRISMA 2020-informed systematic search of PubMed, Web of Science, and Scopus (2015–2024) identified genome-wide association studies (GWASs), meta-analyses, and replicated candidate-gene studies reporting SNP-phenotype associations for paediatric oral traits. Variants were assigned to five trait clusters and graded Strong, Moderate, or Weak against pre-specified replication, study design, and effect-estimate criteria. Phenotypic, population, and methodological heterogeneity precluded quantitative pooling; narrative synthesis was performed. Results: The candidate panel comprises 22 SNPs across five trait clusters: eruption and number; morphology, agenesis, and craniofacial growth; enamel structure and caries; periodontal inflammation; and pain sensitivity. Twelve variants (Tier 1) meet genome-wide significance or meta-analytic replication thresholds; ten (Tier 2) have moderate or exploratory evidence, designated for research-grade use pending prospective paediatric validation. Conclusion: This evidence-graded 22-SNP panel offers a reproducible candidate framework for future genetic risk-stratification research in paediatric dentistry, not a validated clinical test. Prospective multicentre validation, population-level calibration, and implementation studies are required before clinical adoption. The article reports a systematic evidence synthesis and panel design rationale, not assay or clinical validation data. Full article

Background: Polymorphonuclear (PMN) leukocyte recruitment to activated pulmonary endothelium is a central mechanism in acute respiratory distress syndrome (ARDS). This process is mediated by selectins and their counter-ligand, P-selectin glycoprotein ligand-1 (PSGL-1), encoded by SELPLG. Genetic variation in SELPLG has been associated with ARDS susceptibility, while disruption of PSGL-1/P-selectin interactions attenuates lung injury in preclinical models. Because inflammatory stimuli increase both SELPLG expression and circulating PSGL-1 levels, PSGL-1 represents a promising biomarker and therapeutic target. We sought to define the genetic determinants of plasma PSGL-1 levels and evaluate their causal relationships with key inflammatory and endothelial biomarkers. Methods: Genome-wide association study (GWAS) summary statistics for plasma PSGL-1 levels were obtained from the UK Biobank Pharma Proteomics Project (n = 35,571) and the SCALLOP consortium (n = 21,758 across 13 cohorts). Associated variants underwent functional annotation and in silico analyses to identify potential effects on protein structure and gene regulation. Bidirectional Mendelian randomization (MR) was performed using GWAS summary statistics for C-reactive protein (CRP), E-selectin, GlycA, and soluble intercellular adhesion molecule-1 (sICAM-1) to assess potential causal relationships with PSGL-1 levels. Results: Multiple cis- and trans-acting loci were significantly associated with plasma PSGL-1 concentrations. Three coding SELPLG variants (rs201689859, rs74792300, and rs139943851) were predicted to alter PSGL-1 protein structure and were associated with lower circulating PSGL-1 levels. Four promoter variants (rs1420663, rs1833245, rs1420664, and rs8179110) were linked to altered transcriptional activity, including a potential effect of rs1420664 on hypoxia-inducible factor binding. Bidirectional MR demonstrated that genetically predicted CRP, E-selectin, GlycA, and sICAM-1 levels were associated with increased plasma PSGL-1 concentrations. Additional loci implicated pathways related to immune signaling, cell adhesion, and protein stability. Conclusions: Large-scale GWAS and Mendelian randomization analyses identified genetic variants that regulate plasma PSGL-1 levels and demonstrated causal links between inflammatory and endothelial biomarkers and PSGL-1 expression. These findings provide new insights into the genetic regulation of leukocyte trafficking pathways and support a role for PSGL-1 in inflammatory diseases, including ARDS, sepsis, and cardiovascular disorders. Full article

The phosphatidylethanolamine-binding protein (PEBP) gene family plays essential roles in flowering regulation, plant development, and stress responses. However, its characteristics in Osmanthus fragrans remains largely unexplored. Here, a genome-wide analysis was conducted to comprehensively investigate the OfPEBP gene family. A total of 11 OfPEBP genes were identified and classified into three subgroups: FT-, TFL1-, and MFT-like. Genes within the same subgroup exhibited similar motif compositions and exon–intron structures. Promoter analysis revealed abundant light- and hormone-responsive cis-elements. Population genetic analyses identified significant differentiation in OfPEBP3, OfPEBP7, and OfPEBP8, with their single nucleotide polymorphisms (SNPs) and haplotypes closely associated with seasonal flowering phenotypes. DNA methylation profiling indicated that CpG and CHG methylation predominated across the OfPEBP family and remained relatively stable during flower development, whereas OfPEBP6, OfPEBP9, and OfPEBP10 displayed higher methylation levels. Segmental duplication was identified as the primary driver of family expansion, and duplicated gene pairs experienced strong purifying selection. Expression analyses revealed tissue-specific expression patterns and differential responses to temperature, ethylene, and DNA methylation inhibitor (Aza) treatments. These findings provide useful insights into the potential involvement of OfPEBP genes in seasonal flowering and offer candidate genetic resources for future functional studies and molecular breeding in O. fragrans. Full article

We aimed to determine whether the genetically predicted triglyceride–glucose (TyG) index, a surrogate marker of insulin resistance, is associated with cardiovascular–kidney–metabolic (CKM) stage severity and whether these associations are consistent with a potential causal role of insulin resistance within the CKM staging framework. The associations between the TyG index and CKM stages were assessed among 107,161 Taiwan Biobank participants using multivariable regression. CKM stages 3 and 4 were combined as the advanced CKM stage group. A genome-wide association study (GWAS) in 104,778 participants identified genetic determinants of the TyG index, followed by Mendelian randomization (MR), weighted genetic risk score (wGRS) analyses, and sample-split MR analyses. CKM stage severity was evaluated using ordinal regression analysis, a sensitivity analysis (CKM stages ≥ 1 vs. stage 0), and a later-stage comparison analysis (CKM stages ≥ 2 vs. stages 0–1). The TyG index increased progressively across CKM stages. GWAS identified 61 genome-wide significant loci associated with the TyG index. MR analyses demonstrated that genetically predicted TyG index was associated with greater CKM stage severity across all models, with consistent findings in the sample-split analyses. Genetic associations were modest for CKM stage 1 versus stage 0 but became substantially stronger for CKM stage 2 and the advanced CKM stages. Genetically predicted TyG index was associated with higher CKM stage severity in a stage-dependent manner, with substantially stronger genetic associations from CKM stage 2 onward. These findings are consistent with a potential causal role of insulin resistance in CKM stage severity and highlight the TyG index as a complementary biomarker for metabolic risk stratification. Full article

Kazakhstan ruminant genomics is expanding through targeted diagnostic testing, SNP-array studies, whole-genome sequencing, runs of homozygosity, candidate-gene analyses, transcriptomic studies and pathogen molecular diagnostics. However, these evidence types differ substantially in their relevance for breeding decisions. This structured narrative review evaluates molecular evidence for inherited disorders, deleterious alleles, disease-resistance loci, reproductive genes and genomic-health indicators in Kazakhstan cattle, sheep and goats. We define actionable evidence as evidence that can directly inform breeding management because it involves a validated pathogenic variant, risk variant or fertility haplotype detected or excluded in breeding-relevant animals or germplasm. Under this definition, cattle currently provide the strongest immediately actionable evidence, mainly because targeted studies have screened validated defects and fertility-related loci in artificial-insemination bulls, imported germplasm or breed-relevant populations. Evidence includes Kazakhstan-associated screening for BLAD (Bovine leukocyte adhesion deficiency), DUMPS (Deficiency of uridine monophosphate synthase), hypotrichosis, OH1-associated achromatopsia, fertility haplotypes and several beef- or dairy-breed recessive defects. In sheep, evidence is broader but less directly actionable, consisting mainly of prion protein gene preparedness, MHC (Major histocompatibility complex)-related immune hypotheses, reproductive candidate loci, runs of homozygosity, genome wide associated data and pathogen-exposure context. In goats, current evidence is mostly population-genomic and adaptation-oriented, while hereditary-disease surveillance and phenotype-linked resistance studies remain sparse. We propose an author-defined staged genomic-health framework that separates validated carrier-screening evidence from candidate genomic signals and international evidence requiring local validation. Priority actions include carrier-aware management of high-impact cattle germplasm, representative prion protein gene and runs of homozygosity baselines in small ruminants, phenotype-first surveillance, biobanking and national genotype–phenotype databases. Full article

Understanding the genetic basis of adaptation traits including chilling requirements, flowering and fruiting is essential for developing apricot cultivars adapted to changing climatic conditions and for extending the apricot production calendar. The objective of this study is to detect and finely identify marker−trait associations linked to these adaptation traits including chilling requirements in apricot, using an R-based workflow developed with agroclimatic functions. In this study, high-density GBS-based linkage maps previously developed for two biparental populations (‘Bergeron’ × ‘Currot’ and ‘Goldrich’ × ‘Currot’) were used to analyze the genetic basis of key adaptation traits, including chilling requirement (CR), blooming date (BD), fruit development period (FDP), and ripening time (RT), through Genome-Wide Association (GWAS) and Quantitative Trait Locus (QTL) analyses. Phenotypic evaluation over eight years revealed wide variability across genotypes and strong correlations between CR and BD, particularly when using Chill Portions as a metric. Genome-wide association and QTL mapping consistently identified major loci on linkage group (LG) 1 for BD and CR, and on LG4 for FDP and RT, explaining up to 59% of phenotypic variance. The candidate gene (qMD4.1 ANAC072), upon analysis, revealed the involvement of epigenetic regulators, cold-responsive proteins, and transcription factors, offering plausible functional links between genotype and phenotype. These findings provide novel insights into the genetic control of dormancy and phenological traits in apricot and represent a valuable genomic resource for marker-assisted breeding programs aimed at improving climatic resilience and extending the harvest. Full article

Genome-wide association studies (GWAS) have identified thousands of loci associated with complex human diseases. However, the majority of the association signals reside in non-coding regions of the genome, and do not directly reveal the causal variant, effector gene, regulatory biomolecule, cell type, pathway, biomarker, or therapeutic target. Because many disease-associated variants act through non-coding regulatory mechanisms, post-GWAS interpretation increasingly depends on fine-mapping, expression quantitative trait loci, transcriptome-wide association studies, and functional evidence from single-cell multi-omics, network biology, and genetic target prioritization. Artificial intelligence can attempt to integrate these heterogeneous molecular evidence layers, but the resulting black-box prediction is insufficient when outputs cannot be biologically reproduced or experimentally tested. This review evaluates explainable artificial intelligence (XAI) as a framework for linking genetic association signals to molecular mechanisms and causal gene hypotheses. We argue that explainability is best treated as a biological requirement because useful models must expose evidence paths from significant disease-associated variants to regulatory elements, genes, transcripts, proteins, pathways, cell states, and therapeutic hypotheses. By emphasizing transparent evidence provenance, ancestry-aware interpretation, and functional validation, XAI can support the translation of GWAS signals into molecularly testable hypotheses for target prioritization and precision molecular medicine. The review focuses on the question of how to accomplish AI-accelerated functionalization of GWAS outputs across complex human diseases and traits. Full article

Astragalus mongholicus is one of the original plant species of the medicinal herb Astragali Radix as recorded in the Chinese Pharmacopoeia, possessing significant medicinal value and being widely utilized worldwide. TCP transcription factors constitute a plant-specific transcription factor superfamily that plays essential regulatory roles in vegetative growth, organ development, and abiotic stress responses. However, the TCP gene family in A. mongholicus has not yet been systematically investigated, and its functional characteristics remain largely unknown. In this study, based on genome-wide data, a total of 25 AmTCP genes containing complete TCP domains were identified in A. mongholicus, and their protein properties, sequence alignment, gene structures, and phylogenetic relationships were systematically characterized using comprehensive bioinformatics tools. Promoter cis-element analysis revealed that the AmTCP promoter regions are enriched in cis-elements associated with hormones, light, and abiotic stresses (drought and salinity), suggesting their potential involvement in multiple signaling cascades. Furthermore, transcriptomic profiling combined with qRT-PCR validation demonstrated that AmTCP genes exhibit tissue-specific expression patterns and differential responses to salt stress and polyethylene glycol (PEG)-simulated drought stress. Notably, AmTCP3, AmTCP8, AmTCP11, AmTCP17, and AmTCP19 displayed tissue- and time-dependent alterations in expression under stress conditions, with AmTCP17 and AmTCP19 showing the most pronounced responsiveness. Collectively, our findings systematically elucidate the fundamental molecular characteristics of TCP transcription factors in A. mongholicus, providing a valuable reference for future investigations into the biological functions of this gene family during growth, development, and abiotic stress responses in this medicinal plant. Full article

Reproductive characteristics in pigs exhibit low heritability levels. Performing genome-wide association studies (GWAS) to pinpoint candidate genes for these characteristics is crucial for enhancing swine fertility. In this research, hair samples were gathered from 689 French Large White sows within the primary breeding population for DNA extraction purposes. Genotyping was carried out using a 50K liquid-phase SNP chip. Four statistical approaches—MLM, CMLM, FarmCPU, and BLINK—were utilized to perform GWAS on nine reproductive characteristics: total number born (TNB), litter birth weight (LBW), number born alive (NBA), number of healthy births (NHB), number of weak piglets (NWP), number of stillbirths (NSB), number of mummies (MUM), number of deformed fetuses (NDF), and adjusted 21-day litter weight (ALW). siRNAs targeting significantly associated genes were designed, and viral transfection was employed to introduce them into the ovarian granulosa cells of Large White sows to explore gene functions; transcriptome sequencing of granulosa cells treated with DNAH6 siRNA was conducted to investigate the gene’s action mechanism. The analysis indicated that both MLM and CMLM models identified a significant locus linked to the total number of piglets born, with the SNP positioned at 3-60064515, associated with the DNAH6 gene. Disruption of the DNAH6 gene notably reduced the proliferation of ovarian granulosa cells (p < 0.05). Transcriptome sequencing results suggest that DNAH6 may support the normal transcriptional activity of the cAMP signaling pathway by maintaining EP300 and CREBBP expression in porcine ovarian granulosa cells, while potentially inhibiting the anti-proliferative effects of the FoxO pathway. This potential mechanism may help sustain the proliferative ability of granulosa cells and promote normal follicular development, which may ultimately contribute to an increase in the total number of piglets born in sows. These results offer a potential candidate marker for enhancing the total number born of French Large White sows. Full article

Eggshell quality is a critical trait in poultry production, as it directly influences economic outcomes. The genetic architecture underlying this trait remains poorly characterized. In this study, we conducted a genome-wide association study (GWAS) on Chinese Wenshang Barred chickens at 43 weeks of age to identify genomic loci and candidate genes associated with eggshell quality. This analysis revealed 87 significant SNPs and 14 candidate genes. Genes including MC2R, CDC73, LYSMD2, TNFAIP8L3, and CYP19A1 were associated with eggshell weight; PHEX, ATM, STXBP6, SLIT3, and RALY with eggshell thickness; and SOCS5 and ATG4C with eggshell strength. Notably, three SNPs emerged as the most promising markers for eggshell quality, though their functional roles in laying hens require further investigation. This study advances our understanding of the genetic basis of eggshell quality and holds significant practical implications for improving this trait through targeted breeding strategies. Full article

Plumage coloration in birds is a complex genetic trait involving both direct pigmentation genes and their modifiers. The Columbian pattern, characterized by black feathers restricted to the neck, wing tips, and tail, remains poorly understood at the genetic level. This study aimed to conduct a genome-wide association study of the Columbian pattern across 29 chicken breeds of diverse origins. Blood samples were collected from breeds with (n = 11) and without (n = 18) the Columbian pattern. Genotyping was performed using the Illumina Chicken 60K SNP chip, and GWAS was conducted using EMMAX with Bonferroni correction. A total of 10 significant and nine suggestive SNPs on chromosomes GGA1, 2, 5, 7, 10, and 11 were identified. Eight significant SNPs mapped to a ~0.7 Mb region on GGA11 containing MC1R and multiple functionally diverse genes involved in melanocyte adhesion (CDH1), signaling (WWP2, NFAT5), transcription (ZFHX3, TCF25), protein degradation (PSMD7, ATXN1L), and vesicular trafficking (AP1G1). On GGA2, a significant SNP within a lncRNA gene was located in a QTL for yellow plumage, with positional candidates (ROCK1, GREB1L, CABLES1, TMEM241, ANKRD29) suggesting links to pheomelanin deposition. A suggestive locus near DLK1 on GGA5 was also identified. This study refines the genetic architecture of the Columbian pattern, implicating a core region on GGA11 modulating melanocyte function and a distinct locus on GGA2 involved in pheomelanin synthesis. Full article