Search Results (60)

Long- or post-COVID-19 syndrome, which is also designated by WHO as Post COVID-19 Condition (PCC), is characterized by the persistent symptoms that remain after recovery from SARS-CoV-2 infection. A worldwide consortium of Long COVID-19 Host Genetics Initiative (Long COVID-19 HGI) identified an SNP rs9367106 (G>C; chr6:41,515,652, GRCh38, p = 1.76 × 10⁻¹⁰, OR = 1.63, 95% CI: 1.40–1.89) that is associated with PCC. Unraveling the functional significance of this SNP is of prime importance to understanding the development of the PCC phenotypes and their therapy. Here, in Silico, I explored how the risk allele of this SNP alters the functional mechanisms and molecular pathways leading to the development of PCC phenotypes. Bioinformatic methods include physical interactions using HI-C and Chia-PET analysis, Transcription Factors (TFs) binding ability, RNA structure modeling, epigenetic, and pathway analysis. This SNP resides within two long RNA genes, LINC01276 and FOXP4-AS1, and is located at ~31 kb upstream of a transcription factor FOXP4. This DNA region, including this SNP, physically interacts with FOXP4-AS1 and FOXP4, implying that this regulatory SNP could alter the normal cellular function of FOXP4-AS1 and FOXP4. Furthermore, rs9367106 is in eQTL with the FOXP4 gene in lung tissue. rs9367106 carrying DNA sequences act as distant enhancers and bind with several transcription factors (TFs) including YY1, PPAR-α, IK-1, GR-α, and AP2αA. The G>C transition extensively modifies the RNA structure that may affect the TF bindings and enhancer functions to alter the interactions and functions of these RNA molecules. This SNP also includes an ALU/SINE sequence and alteration of which by the G>C transition may prevent IFIH1/MDA5 activation, leading to suppression of host innate immune responses. LINC01276 targets the MED20 gene that expresses mostly in brain tissues, associated with sleep disorders and basal ganglia abnormalities similar to some of the symptoms of PCC phenotypes. Taken together, G>C transition of rs9367601 may likely alter the function of all three genes to explain the molecular basis of developing the long-term symptomatic abnormalities in the lungs and brain observed after COVID-19 recovery. Full article

Background/Objectives: To investigate associations between Follistatin (FST) gene polymorphisms (SNPs) and baseline musculoskeletal traits, and their interactions with 16-week exercise interventions. Methods: A cohort of 470 untrained Northern Han Chinese adults (208 males, 262 females), sourced from the “Research on Key Technologies for an Exercise and Fitness Expert Guidance System” project, was analyzed. These participants were previously randomly assigned to one of four exercise groups (Hill, Running, Cycling, Combined) or a non-exercising Control group, and completed their respective 16-week protocols. Body composition, bone mineral content (BMC), bone mineral density (BMD), and serum follistatin levels were all assessed pre- and post-intervention. Dual-energy X-ray absorptiometry (DXA) was utilized for the body composition, BMC, and BMD measurements. FST SNPs (rs3797296, rs3797297) were genotyped using matrix assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS) or microarrays. To elucidate the biological mechanisms, we performed in silico functional analyses for rs3797296 and rs3797297. Results: Baseline: In females only, the rs3797297 T allele was associated with higher muscle mass (β = 1.159, 95% confidence interval (CI): 0.202–2.116, P_{_adj} = 0.034) and BMC (β = 0.127, 95% CI: 0.039–0.215, P_{_adj} = 0.009), with the BMC effect significantly mediated by muscle mass. Exercise Response: Interventions improved body composition, particularly in females. Gene-Exercise Interaction: A significant interaction occurred exclusively in women undertaking hill climbing: the rs3797296 G allele was associated with attenuated muscle mass gains (β = −1.126 kg, 95% CI: −1.767 to −0.485, P_{_adj} = 0.034). Baseline follistatin correlated with body composition (stronger in males) and increased post-exercise (primarily in males, Hill/Running groups) but did not mediate SNP effects on exercise adaptation. Functional annotation revealed that rs3797297 is a likely causal variant, acting as a skeletal muscle eQTL for the mitochondrial gene NDUFS4, suggesting a mechanism involving muscle bioenergetics. Conclusions: Findings indicate that FST polymorphisms associate with musculoskeletal traits in Northern Han Chinese. Mechanistic insights from functional annotation reveal potential pathways for these associations, highlighting the potential utility of these genetic markers for optimizing training program design. Full article

Plant height (PH) and ear height (EH) are closely related to dense planting characteristics and lodging resistance of maize (Zea mays L.). Increasing the planting density will lead to changes in the structural characteristics of maize plants, such as reduced stem length and stem strength, thereby influencing their yield and quality. Therefore, analyzing the genetic basis of PH and EH in maize can provide valuable information for cultivating ideal plant types with suitable PH and EH. This study aims to identify stable genomic regions and candidate genes associated with PH and EH in maize through Meta-QTL (MQTL) analysis. A total of 187 original QTLs were collected from 13 published articles on QTL localization related to maize PH and EH. A high-density consistency map with a total length of 6970.00 cM was constructed, and 152 original QTLs were successfully projected into the consistency map. The remaining 35 QTLs could not be projected onto the consistency map, which may be attributed to a lack of common markers between the original and consistency map or to the QTL exhibiting low phenotypic variance explained (PVE), resulting in large confidence intervals (CIs). Then, 29 MQTLs were identified on 10 chromosomes via meta-analysis. Among them, the three identified MQTLs, i.e., MQTL4-1, MQTL4-2, and MQTL6-1, were specifically controlled by maize EH. Further analysis achieved 188 candidate genes in all MQTL intervals, which were related to maize plant development and morphogenesis. Meanwhile, the gene ontology (GO) enrichment analysis revealed that these candidate genes were involved in 77 GO annotations. These findings thus will help us better understand the molecular genetic basis of maize PH and EH under various environments, and thereby achieve an increased yield with maize dense planting breeding. Full article

Single-cell RNA sequencing (scRNA-seq) enables expression quantitative trait locus (eQTL) analysis at cellular resolution, offering new opportunities to uncover regulatory variants with cell-type-specific effects. However, existing tools are often limited in functionality, input compatibility, or scalability for sparse single-cell data. To address these challenges, we developed scQTLtools, a comprehensive R/Bioconductor package that facilitates end-to-end single-cell eQTL analysis, from preprocessing to visualization. The toolkit supports flexible input formats, including Seurat and SingleCellExperiment objects, handles both binary and three-class genotype encodings, and provides dedicated functions for gene expression normalization, SNP and gene filtering, eQTL mapping, and versatile result visualization. To accommodate diverse data characteristics, scQTLtools implements three statistical models—linear regression, Poisson regression, and zero-inflated negative binomial regression. We applied scQTLtools to scRNA-seq data from human acute myeloid leukemia and identified eQTLs with regulatory effects that varied across cell types. Visualization of SNP–gene pairs revealed both positive and negative associations between genotype and gene expression. These results demonstrate the ability of scQTLtools to uncover cell-type-specific regulatory variation that is often missed by bulk eQTL analyses. Currently, scQTLtools supports cis-eQTL mapping; future development will extend to include trans-eQTL detection. Overall, scQTLtools offers a robust, flexible, and user-friendly framework for dissecting genotype–expression relationships in heterogeneous cellular populations. Full article

Background: Asthma is one of the most prevalent chronic diseases, affecting more than 300 million individuals globally. Inhaled corticosteroids (ICSs) are recommended as the primary therapy for managing and preventing asthma symptoms in current treatment guidelines. However, long-term use of ICSs could lead to multiple side effects, including skin changes. Methods: We identified ICS target genes using DrugBank and DGIdb databases and derived genetic instruments from cis-eQTL data in whole-blood samples (n = 31,684). GWAS data for facial aging traits (n = 423,999) and plasma metabolites (1400 metabolites, n = 8000) were analyzed. DNA methylation QTL (mQTL) data were used to explore epigenetic regulation. Mendelian randomization (MR) and colocalization analyses were performed to assess causality and shared genetic loci. Results: MR analysis suggested a significant link between genetically proxied ICSs (ORMDL3) and face aging in the European population. Further mediation analysis indicated that 5-Hydroxylysine partially mediates the relationship between ICSs and face aging. In addition, our analysis revealed the pleiotropic association of some novel DNA methylation sites of ORMDL3 with face aging, suggesting the possible regulatory mechanism that are involved in face aging. Conclusions: These findings, while exploratory, raise the hypothesis that ICSs may impact face aging through upregulation of ORMDL3 expression and 5-hydroxylysine metabolism and highlight the need for further pharmacological and clinical research to validate these potential effects. Full article

Background: Autism spectrum disorder (ASD) involves complex interactions between genetic and environmental factors. Recent studies suggest that dysregulation of β-arrestin2 (Arrb2) in the central nervous system is linked to ASD. However, its specific mechanisms remain unknown. Methods: This study employs a systems genetics approach to comprehensively investigate Arrb2 in multiple brain tissues, including the amygdala, cerebellum, hippocampus, and prefrontal cortex, using BXD recombinant inbred (RI) strains. In addition, genetic variance analysis, correlation analysis, expression quantitative trait loci (eQTL) mapping, and functional annotation were used to identify the key downstream targets of Arrb2, validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB). Results: Arrb2 exhibited expression variations across the four brain regions in BXD mice. eQTL mapping revealed that Arrb2 is cis-regulated, and increased Arrb2 expression levels were significantly correlated with ASD-like symptoms, such as impaired social interactions and abnormal learning and memory. Furthermore, protein–protein interaction (PPI) network analysis, tissue correlation, functional relevance to autism, and differential expression identified eight downstream candidate genes regulated by Arrb2. The experimental results demonstrated that deletion of Arrb2 led to the downregulation of Myh9, Dnmt1, and Brd4 expression, along with protein kinase A (PKA)-induced hyperactivation of Synapsin I. These findings suggest that Arrb2 may contribute to the pathogenesis of autism by modulating the expression of these genes. Conclusions: This study highlights the role of Arrb2 in ASD pathogenesis and identifies Myh9, Dnmt1, and Brd4 as key downstream regulators. These findings provide new insights into the molecular mechanisms of ASD and pave the way for novel therapeutic targets. Full article

Hubei indigenous cattle have adapted to diverse environmental conditions, exhibiting unique genetic traits associated with both economic and adaptive characteristics. Understanding their adaptive selection offers insight into their evolutionary history and genetic enhancements. In this study, we analyzed whole-genome sequencing (WGS) data from five Hubei indigenous cattle breeds to identify selection signals. Selective sweep analysis revealed the candidate genes (USH2A, TMTC2, ABCC12, and SUGT1) associated with sensory perception, backfat thickness, reproduction, and immune function. The further integration of cis-regulatory elements (CREs) and expression quantitative trait loci (eQTL) highlighted regulatory variants, influencing adaptive traits. Notably, positively selected genes such as RPS6KA2, CRLS1, MGST3, GPCPD1, and LDLRAP1 were associated with lipid metabolism, meat quality, and reproductive traits, influencing aldehyde volatile organic compounds (VOCs) and fat deposition. These findings highlight the understanding of the genetic basis of adaptation and production traits in Hubei indigenous cattle and provide valuable insights for their conservation and potential breeding strategies. Full article

Plant architecture is a crucial trait for ornamental plants. Chrysanthemum with prostrate growth habit is a novel cultivar group of ground-cover chrysanthemum, which have high ornamental value, strong lodging resistance, and outstanding landscape greening capability. To explore the genetic mechanism underlying the prostrate growth habit in chrysanthemum, we used tetraploid prostrate-type Chrysanthemum yantaiense as the female parent and erect-type Chrysanthemum indicum as the male parent to produce four generations (P₁, P₂, F₁, F₂). Five traits related to prostrate growth habit in chrysanthemum were investigated including plant height (PH), crown width of the plant (CP), creeping index (CI), gravitropic set-point angle (GSA), and growth habit (GH). The major gene plus polygene mixed inheritance analysis was conducted on five traits across four generations over two years. For the five traits, the coefficients of variation (CVs) were wide-ranging and high (16.64–42.75%), with the PH having the highest CV among them. Genetic analysis revealed that PH conformed to the additive-dominant-epistatic polygene model (C-0) and the model of two equally dominant major genes plus additive-dominant polygene (E-5). The most suitable genetic model for CI was an additive-dominant major gene plus additive-dominant-epistatic polygene model (D-0). The best-fit models for CP and GH were both C-0. For GSA, the best-fit models were E-4 and C-0. Additionally, it appeared that both genetic and environmental factors influenced the prostrate growth habit, as the heritability of major genes and polygenes was less than 50%. This study can serve as a theoretical foundation for the mapping of quantitative trait loci (QTLs) and further exploration of the genetic mechanisms underlying plant architecture in chrysanthemum. Full article

Understanding the genetic regulation of gene expression and splicing in muscle tissues is critical for elucidating the molecular mechanisms of meat quality traits. In this study, we integrated large-scale whole-genome sequencing and strand-specific RNA-seq data from 582 F2 hybrid pigs (White Duroc × Erhualian) to characterize the expression and splicing quantitative trait loci (eQTLs/sQTL) in longissimus dorsi muscle. We identified 11,058 cis-eQTL-associated genes (eGenes) and 5139 cis-sQTL-associated genes (sGenes), of which 29% of eGenes and 80% of sGenes were previously unreported in the PigGTEx database. Functional analyses revealed distinct genomic features: eQTLs were enriched near transcription start sites (TSSs) and associated with active TSS-proximal transcribed regions and enhancers, whereas sQTLs clustered at splice junctions, underscoring their distinct roles in gene expression and splicing regulation. Colocalization analysis of e/sQTLs with GWAS signals prioritized PHKG1 as a key candidate gene (PPH4 > 0.9) for glycogen metabolism. Notably, we confirmed that an sQTL-driven alternative splicing event in exon 10 of PHKG1 was significantly correlated with phenotypic variation (R = −0.39, p = 9.5 × 10⁻²¹). Collectively, this study provides novel insights into the genetic regulation of gene expression and alternative splicing in porcine muscle tissue, advancing our understanding of the molecular mechanisms underlying economically important meat quality traits. Full article

Expression quantitative trait locus (eQTL) mapping is an effective tool for identifying genetic variations that regulate gene expression. An increasing number of studies suggested that SNPs associated with complex traits in farm animals are considered as expression quantitative trait loci. Identifying eQTLs associated with gene expression levels in the endometrium helps to unravel the regulatory mechanisms of genes related to reproductive functions in this tissue and provides molecular markers for the genetic improvement of high-fertility sow breeding. In this study, 218 RNA-seq data from pig endometrial tissue were used for eQTL analysis to identify genetic variants regulating gene expression. Additionally, weighted gene co-expression network analysis (WGCNA) was performed to identify hub genes involved in reproductive functions. The eQTL analysis identified 34,876 significant cis-eQTLs regulating the expression of 5632 genes (FDR ≤ 0.05), and 90 hub genes were identified by WGCNA analysis. By integrating eQTL and WGCNA results, 14 candidate genes and 16 fine-mapped cis-eQTLs were identified, including FRK, ARMC3, SLC35F3, TMEM72, FFAR4, SOWAHA, PSPH, FMO5, HPN, FUT2, RAP1GAP, C6orf52, SEL1L3, and CLGN, which were involved in the physiological processes of reproduction in sows through hormone regulation, cell adhesion, and amino acid and lipid metabolism. These eQTLs regulate the high expression of candidate genes in the endometrium, thereby affecting reproductive-related physiological functions. These findings enhance our understanding of the genetic basis of reproductive traits and provide valuable genetic markers for marker-assisted selection (MAS), which can be applied to improve sow fecundity and optimize breeding strategies for high reproductive performance. Full article

Summary-data-based Mendelian randomization (SMR) analysis identified a novel cis-expression quantitative loci (cis-eQTL) associated with the upregulation of the expression of the early growth response factor 4 (EGR4) gene in animals with paratuberculosis (PTB)-associated multifocal lesions, which has been suggested to be modulating the NF-kβ-induced proinflammatory immune response to Mycobacterium avium subsp. paratuberculosis (Map) infection. To confirm these findings and to study the role of EGR4 expression in PTB resilience, the number of EGR4-expressing cells were analysed in paraffin-fixed gut tissues and regional lymph nodes of naturally Map-infected Holstein Friesian cows with focal, multifocal (subclinical and clinical), and diffuse lesions (intermediate and multibacillary), and in controls without lesions by quantitative anti-EGR4 immunohistochemistry. Subclinical animals with multifocal lesions showed a significantly higher number of EGR4-positive cells and were sacrificed at a significantly older average age than the remaining groups (p < 0.001 in all cases). We hypothesize that EGR4 could be mitigating the negative impact of Map infection on host clinical status through its involvement in three molecular mechanisms that promote resilience: (i) limiting NF-kβ-mediated proinflammatory responses, (ii) controlling tissue damage, acting as a brake on T-cell proliferation and cytokine production, and (iii) favouring tissue repair through interaction with epidermal growth factor receptor (EGFR). Full article

Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP1R) agonists may have potential benefits for mental illnesses. However, their exact effects remain unclear. This study investigated the causal relationship between glucagon-like peptide-1 receptor agonist (GLP1RA) and the risk of 10 common mental illnesses, including attention deficit and hyperactivity disorder, anorexia nervosa, anxiety disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, post-traumatic stress disorder, schizophrenia, cannabis use disorder, and alcohol use disorder. We selected GLP1RA as the exposure and conducted a Mendelian randomization (MR) analysis. The cis-eQTLs of the drug target gene GLP1R, provided by eQTLGen, were used to simulate the pharmacological effects of GLP1RA. Type 2 diabetes and BMI were included as positive controls. Using data from both the Psychiatric Genomic Consortium and FinnGen, we conducted separate MR analyses for the same disease across these two independent databases. Meta-analysis was used to pool the results. We found genetic evidence suggesting a causal relationship between GLP1RA and a reduced risk of schizophrenia [OR (95% CI) = 0.84 (0.71–0.98), I² = 0.0%, common effects model]. Further mediation analysis indicated that this effect might be unrelated to improvements in glycemic control but rather mediated by BMI. However, the findings of this study provide insufficient evidence to support a causal relationship between GLP1RA and other mental illnesses. Sensitivity analyses did not reveal any potential bias due to horizontal pleiotropy or heterogeneity in the above results (p > 0.05). This study suggests that genetically proxied activation of glucagon-like peptide-1 receptor is associated with a lower risk of schizophrenia. GLP1R is implicated in schizophrenia pathogenesis, and its agonists may exert potential benefits through weight management. Our study provides useful information for understanding the neuropsychiatric effects of GLP1RA, which may contribute to refining future research designs and guiding clinical management. Moreover, our findings could have significant implications for overweight individuals at high risk of schizophrenia when selecting weight-loss medications. Future research should further investigate the potential mechanisms underlying the relationship between GLP1RA and schizophrenia. Full article

DNA damage repair (DDR) plays a key role in maintaining genomic stability and developing inflammatory bowel disease (IBD). However, no report about the causal association between DDR and IBD exists. Whether DDR-related genes are the precise causal association to IBD in etiology remains unclear. Herein, we employed a multi-omics summary data-based Mendelian randomization (SMR) approach to ascertain the potential causal effects of DDR-related genes in IBD. Methods: Summary statistics from expression quantitative trait loci (eQTL), DNA methylation QTL (mQTL), and protein QTL (pQTL) on European descent were included. The GWAS summarized data for IBD and its two subtypes, Crohn’s disease (CD) and ulcerative colitis (UC), were acquired from the FinnGen study. We elected from genetic variants located within or near 2000 DDR-related genes in cis, which are closely associated with DDR-related gene changes. Variants were selected as instrumental variables (IVs) and assessed for causality with IBD and its subtypes using both SMR and two-sample MR (TSMR) approaches. Colocalization analysis was employed to evaluate whether a single genetic variant simultaneously influences two traits, thereby validating the pleiotropy hypothesis. Results: We identified seven DDR-related genes (Arid5b, Cox5a, Erbb2, Ube2l3, Gpx1, H2bcl2, and Mapk3), 33 DNA methylation genes, and two DDR-related proteins (CD274 and FCGR2A) which were all causally associated with IBD and its subtypes. Beyond causality, we integrated the multi-omics data between mQTL-eQTL and conducted druggability values. We found that DNA methylation of Erbb2 and Gpx1 significantly impacted their gene expression levels offering insights into the potential regulatory mechanisms of risk variants on IBD. Meanwhile, CD247 and FCGR2A could serve as targets for potential pharmacological interventions in IBD. Conclusions: Our study demonstrates the causal role of DDR in IBD based on the data-driven MR. Moreover, we found potential regulatory mechanisms of risk variants on IBD and potential pharmacological targets. Full article

Background: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for cardiovascular disease, and it plays a causal role in the development of atherosclerosis. Genome-wide association studies (GWASs) have successfully identified hundreds of genetic variants associated with LDL-C. Most of these risk loci fall in non-coding regions of the genome, and it is unclear how these non-coding variants affect circulating lipid levels. One hypothesis is that genetically mediated variation in transcript abundance, detected via the analysis of expressed quantitative trait loci (eQTLs), is key to the biologic function of causal variants. Here, we investigate the hypothesis that non-coding GWAS risk variants affect the homeostatic expression of a nearby putatively causal gene for serum LDL-C levels. Methods: We establish a set of twenty-one expert-curated and validated genes implicated in hypercholesterolemia via dose-dependent pharmacologic modulation in human adults, for which the relevant tissue type has been established. We show that the expression of these LDL-C genes is impacted by eQTLs in relevant tissues and that there are significant genomic-risk loci in LDL-GWAS near these causal genes. We evaluate, using statistical colocalization, whether a single variant or set of variants in each genetic locus is responsible for the GWAS and eQTL signals. Results: Genome-wide association study results for serum LDL-C levels demonstrate that the 402 identified genomic-risk loci for LDL-C are highly enriched for known causal genes for LDL-C (OR 527, 95% CI 126–5376, p < 2.2 × 10⁻¹⁶). However, we find limited evidence for colocalization between GWAS signals near validated hypercholesterolemia genes and eQTLs in relevant tissues (colocalization rate of 26% at a locus-level colocalization probability > 50%). Conclusions: Our results highlight the complexity of genetic regulatory effects for causal hypercholesterolemia genes; we suggest that context-responsive eQTLs may explain the effects of non-coding GWAS hits that do not overlap with standard eQTLs. Full article

Osteoarthritis (OA), particularly in the knee and hip, poses a significant global health challenge due to limited therapeutic options. To elucidate the molecular mechanisms of OA and identify potential biomarkers and therapeutic targets, we utilized genome-wide association studies (GWAS) and cis-miRNA expression quantitative trait loci (cis-miR-eQTL) datasets to identify miRNAs associated with OA, revealing 16 that were linked to knee OA and 21 to hip OA. Among these, hsa-miR-1303 was significantly upregulated in both knee and hip OA (IVW: p = $6.8164\times {10}^{-36}$ and $4.7919\times {10}^{-2}$ respectively, OR > 1) and identified as a key factor in disease progression. Hsa-miR-1303 potentially regulates 30 genes involved in critical signaling pathways, such as the neurotrophin signaling pathway, and interacts with competing endogenous RNAs (ceRNAs) like circ_0041843 and LINC01338, thereby influencing key regulatory proteins such as SUMO2 and PARP1. Pharmacologically, hsa-miR-1303 targets nine druggable genes, including NRAS, H2AZ1, and RPS3, which have implications for drugs like cantharidin and diindolylmethane, potentially critical for developing novel OA treatments. Conversely, hsa-miR-125a-5p and hsa-miR-125b-5p, which are downregulated in both knee and hip OA, are associated with pathways such as HIF-1 and JAK-STAT, which modulate apoptotic signaling and transcriptional regulation. These miRNAs also interact with ceRNAs such as circ_0000254 and SPACA6P-AS, impacting proteins like STAT3, MCL1, and TRAF6. A drug interaction analysis identified 47 potential treatments, including Resveratrol and Acetaminophen, suggesting new therapeutic possibilities for OA management. This study not only highlights the role of miRNAs like hsa-miR-1303 and hsa-miR-125 in OA but also opens avenues for miRNA-based therapeutic development. Full article