Search Results (572)

Schizophrenia is a challenging multifactorial neuropsychiatric disease that involves interactions between genetic susceptibility and environmental insults. Increasing evidence implicates viral infections as significant environmental contributors, particularly during sensitive neurodevelopmental periods. This review synthesises current findings on the viral hypothesis of schizophrenia, encompassing a wide array of neurotropic viruses, including influenza viruses, herpesviruses (HSV-1 and 2, CMV, VZV, EBV, HHV-6 and 8), hepatitis B and C viruses, HIV, HERVs, HTLV, Zika virus, BoDV, coronaviruses (including SARS-CoV-2), and others. These pathogens can contribute to schizophrenia through mechanisms such as direct microinvasion, persistent central nervous system infection, immune-mediated neuroinflammation, molecular mimicry, and the disturbance of the blood–brain barrier. Prenatal exposure to viral infections can trigger maternal immune activation, resulting in cytokine-mediated alterations in the neurological development of the foetus that persist into adulthood. Genetic studies highlight the role of immune-related loci, including major histocompatibility complex polymorphisms, in modulating susceptibility to infection and neurodevelopmental outcomes. Clinical data also support the “mild encephalitis” hypothesis, suggesting that a subset of schizophrenia cases involve low-grade chronic neuroinflammation. Although antipsychotics have some immunomodulatory effects, adjunctive anti-inflammatory therapies show promise, particularly in treatment-resistant cases. Despite compelling associations, pathogen-specific links remain inconsistent, emphasising the need for longitudinal studies and integrative approaches such as viromics to unravel causal relationships. This review supports a “multi-hit” model in which viral infections interfere with hereditary and immunological susceptibilities, enhancing schizophrenia risk. Elucidating these virus–immune–brain interactions may facilitate the discovery of biomarkers, targeted prevention, and novel therapeutic strategies for schizophrenia. Full article

Background: Rheumatoid arthritis (RA) is an autoimmune disease that remains incurable. An increasing number of proteomic genome-wide association studies (GWASs) are emerging, offering immense potential for identifying novel therapeutic targets for diseases. This study aims to identify potential therapeutic targets for RA based on human plasma proteome. Methods: Protein quantitative trait loci were extracted and integrated from eight large-scale proteomic GWASs. Proteome-wide Mendelian randomization (Pro-MR) was performed to prioritize proteins causally associated with RA. Further validation of the reliability and stratification of prioritized proteins was performed using MR meta-analysis, colocalization, and transcriptome-wide summary-data-based MR. Subsequently, prioritized proteins were characterized through protein–protein interaction and enrichment analyses, pleiotropy assessment, genetically engineered mouse models, cell-type-specific expression analysis, and druggability evaluation. Phenotypic expansion analyses were also conducted to explore the effects of the prioritized proteins on phenotypes such as endocrine disorders, cardiovascular diseases, and other immune-related diseases. Results: Pro-MR prioritized 32 unique proteins associated with RA risk. After validation, prioritized proteins were stratified into four reliability tiers. Prioritized proteins showed interactions with established RA drug targets and were enriched in an immune-related functional profile. Four trans-associated proteins exhibited vertical or horizontal pleiotropy with specific genes or proteins. Genetically engineered mouse models for 18 prioritized protein-coding genes displayed abnormal immune phenotypes. Single-cell RNA sequencing data were used to validate the enriched expression of several prioritized proteins in specific synovial cell types. Nine prioritized proteins were identified as targets of existing drugs in clinical trials or were already approved. Further phenome-wide MR and mediation analyses revealed the effects and potential mediating roles of some prioritized proteins on other phenotypes. Conclusions: This study identified 32 plasma proteins as potential therapeutic targets for RA, expanding the prospects for drug discovery and deepening insights into RA pathogenesis. Full article

Osteoporosis is a multifactorial, polygenic disease characterized by reduced bone mineral density (BMD) and increased fracture risk. Genome-wide association studies (GWASs) have identified numerous loci associated with BMD and/or bone fractures, but functional characterization of these target genes is essential to understand the biological mechanisms underlying osteoporosis. This review focuses on current methodologies and key examples of successful functional studies aimed at evaluating gene function in osteoporosis research. Functional evaluation typically follows a multi-step approach. In silico analyses using omics datasets expression quantitative trait loci (eQTLs), protein quantitative trait loci (pQTLs), and DNA methylation quantitative trait loci (mQTLs) help prioritize candidate genes and predict relevant biological pathways. In vitro models, including immortalized bone-derived cell lines and primary mesenchymal stem cells (MSCs), are used to explore gene function in osteogenesis. Advanced three-dimensional culture systems provide additional physiological relevance for studying bone-related cellular processes. In situ analyses of patient-derived bone and muscle tissues offer validation in a disease-relevant context, while in vivo studies using mouse and zebrafish models enable comprehensive assessment of gene function in skeletal development and maintenance. Integration of these complementary methodologies helps translate GWAS findings into biological insights and supports the identification of novel therapeutic targets for osteoporosis. Full article

Background/Objectives: Maternal exposures are known to influence the risk of isolated cleft lip with or without cleft palate (CL/P)—a common and highly heritable birth defect with a multifactorial etiology. Methods: To identify new risk loci, we conducted a genome-wide gene–environment interaction (GEI) analysis of CL/P with maternal smoking and vitamin use in Filipinos (N_cases = 540, N_controls = 260). Since GEI analyses are typically low in power and the results can be difficult to interpret, we applied multiple testing frameworks to evaluate potential GEI effects: a one degree-of-freedom (1df) GxE test, the 3df joint test, and the two-step EDGE approach. Results: While no genome-wide significant interactions were detected, we identified 11 suggestive GEIs with smoking and 24 with vitamin use. Several implicated loci contain biologically plausible genes. Notable interactions with smoking include loci near FEZF1, TWIST2, and NET1. While FEZF1 is involved in early neuronal development, TWIST2 and NET1 regulate epithelial–mesenchymal transition, which is required for proper lip and palate fusion. Interactions with vitamins encompass CECR2—a chromatin remodeling protein required for neural tube closure—and FURIN, a critical protease during early embryogenesis that activates various growth factors and extracellular matrix proteins. The activity of both proteins is influenced by folic acid. Conclusions: Our findings highlight the critical role of maternal exposures in identifying genes associated with structural birth defects such as CL/P and provide new paths to explore for CL/P genetics. Full article

The serrated pathway represents a significant route to colorectal cancer (CRC), accounting for approximately 15–30% of cases, yet the specific epithelial cell subpopulations driving this pathway remain poorly understood. This study explores the causal relationship between serrated epithelial cells and CRC risk using single-cell transcriptomics and Mendelian randomization (MR). Publicly available single-cell RNA sequencing data were utilized to analyze epithelial cell subpopulations in CRC, focusing on specific serrated cells (SSCs). By integrating genome-wide association study data, MR was employed to assess the causal relationship between gene expression patterns and CRC risk. The study found that an increase in SSCs is closely associated with CRC progression. MR analysis revealed a significant correlation between expression changes in specific genes, such as IER3 in SSCs, and CRC risk (p < 0.05). Functional analyses indicated that IER3 may promote malignancy by regulating cell proliferation, adhesion, and immune evasion. Several genetic loci related to SSC gene expression were identified and validated for CRC risk association. This study demonstrates the significant role of serrated epithelial cell subpopulations in CRC development, particularly through key genes such as IER3, providing new perspectives for understanding CRC pathogenesis and future therapeutic strategies. Full article

In recent decades, fishery stock enhancement has been increasingly utilized as a restoration tool to mitigate population declines and enhance the resilience of marine fisheries. Nevertheless, persistent enhancement efforts risk eroding the evolutionary potential of wild populations via genetic homogenization and maladaptive gene flow. Using long-term monitoring data (2017–2023), we quantified the effects of large-scale Penaeus penicillatus stock enhancement (~10⁸ juveniles/yr) on wild population dynamics and genetic integrity in the Beibu Gulf ecosystem. Temporal genetic changes were assessed using eight highly polymorphic microsatellite loci, comparing founder (2017) and enhanced (2024) populations to quantify stocking impacts. Insignificantly lower expected heterozygosity was observed in the stocked population (He = 0.60, 2024) relative to natural populations (He = 0.62–0.66; p > 0.1), indicating genetic dilution effects from enhancement activities. No significant erosion of genetic diversity was detected post-enhancement, suggesting current stocking practices maintain short-term population genetic integrity. Despite conserved heterozygosity, pairwise Fst analysis detected significant genetic shifts between temporal cohorts (pre-enhancement—2017 vs. post-enhancement—2024; Fst = 0.25, p < 0.05), demonstrating stocking-induced population restructuring. Genetic connectivity analysis revealed that while the enhanced Beihai population (A-BH) maintained predominant self-recruitment (>90%), it experienced substantial stocking-derived gene flow (17% SW → A-BH). The post-stocking period showed both reduced genetic exchange with adjacent populations and increased asymmetric dispersal from A-BH (e.g., 5% to YJ), indicating that hatchery releases simultaneously enhanced population isolation while altering regional genetic structure. Our findings revealed the paradoxical dual effects of stock enhancement and allelic diversity while disrupting natural genetic architecture. This underscores the need for evolutionary-impact assessments in marine resource management. Full article

Ischemic stroke is a complex, multifactorial disorder with a significant heritable component. Recent developments in genome-wide association studies (GWASs) have identified several common variants associated with clinical outcomes, stroke subtypes, and overall risk. Key loci implicated in biological pathways related to vascular integrity, lipid metabolism, inflammation, and atherogenesis include 9p21 (ANRIL), HDAC9, SORT1, and PITX2. Although polygenic risk scores (PRSs) hold promise for early risk prediction and stratification, their clinical utility remains limited by Eurocentric bias and missing heritability. Integrating multiomics approaches, such as functional genomics, transcriptomics, and epigenomics, enhances our understanding of stroke pathophysiology and paves the way for precision medicine. This review summarizes the current genetic landscape of ischemic stroke, emphasizing how evolving methodologies are shaping its prevention, diagnosis, and treatment. Full article

In this study we searched for correlations between polymorphic variants that determine sex hormone-binding globulin concentration (SHBG_con) and uterine fibroids (UFs). The work was performed on a sample of 1542 women (569 with UFs and 973 without UFs [control]), from whom we obtained experimental data on the distribution of nine single-nucleotide polymorphisms (SNPs) affecting the SHBG_con (data confirmed in genome-wide association studies [GWASs]). When searching for associations with UFs, both the independent effects of SNPs and the effects of their SNP–SNP interactions (SNP-SNP_ints) were taken into account during the “deep study” of the functionality of seven important UF loci and 115 strongly linked [r² ≥ 0.80] variants (an in silico methodology was used). As the results show, two SHBG_con-related SNPs correlated with UF risk: rs3779195 [T/A] BAIAP2L1 (OR_AA = 0.38; 95%CI_AA = 0.20–0.91; p_perm(AA) = 0.023) and rs440837 [A/G] ZBTB10 (OR_GG = 1.93; 95%CI_GG = 1.17–3.14; p_perm(GG) = 0.010). At the same time, seven SHBG_con-related SNPs interacting with each other (four models of such SNP-SNP_ints [p_perm ≤ 0.01)] were found to influence UF risk. These SHBG_con-related SNPs, determining susceptibility to UF, showed strong functional relevance and were involved in pathways of gene transcription regulation, interactions with hormone ligand-binding receptors, the content control of SHBG, testosterone, liver enzymes, lipids, etc. This study’s results demonstrate the effect of significant SHBG_con-related genetic determinants of UF risk. Full article

Apolipoprotein E (APOE) allele 4 (APOE4), one of the robust genetic risk factors for AD, has also been associated with cognitive decline in terms of memory, executive function, language, and global cognitive function. APOE genotype-stratified analysis can help to identify additional genetic loci which might be masked due to a strong effect of APOE4. We conducted a genome-wide meta-analysis in APOE2 carriers, APOE4 carriers, and APOE 3/3 homozygote groups among 2969 non-Hispanic Whites aged ≥ 65 years using slopes of decline over time across five cognitive domains (attention, language, executive function, memory, and visuospatial function) and global cognitive function. We identified novel genome-wide significant associations for decline in global cognitive function in the intergenic region between RNU7-66P/RNA5SP208 at rs116379916 (p = 1.44 × 10⁻⁹) in the APOE 3/3 group and for decline in language in the intergenic region between LINC0221/DTWD2 at rs13187183 (p = 3.79 × 10⁻⁸) in APOE4 carriers. A previously reported locus for decline in attention near RASEF at rs6559700 (p = 9.95 × 10⁻⁹) was found to be confined to the APOE 3/3 group. We also found two sub-threshold significant associations in the APOE 2 group for decline in attention (IL1RL2/rs77127114; p = 8.64 × 10⁻⁸) and decline in language (YTHDC2/KCNN2, rs116191836; p = 5.66 × 10⁻⁸). Our study points to potential biological pathways pertaining to specific domains within each APOE genotype group, and the findings suggest that immune-related pathways, plasma levels of polysaturated fatty acids, and bitter taste receptors may play roles in cognitive decline. Our findings enhance the understanding of cognitive aging and provide a framework for future studies. Full article

Background and Objectives: Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide. Genetic and epigenetic changes, especially DNA methylation alterations, are key in CRC development. LINE-1 hypomethylation marks global DNA methylation loss and genomic instability, making it a potential early CRC biomarker. This study investigates the methylation status of LINE-1 in colorectal adenocarcinoma, precancerous lesions (tubular and serrated adenomas), and the surrounding normal mucosa, aiming to elucidate its role as an epigenetic marker in early colorectal tumorigenesis. Materials and Methods: Paired lesion and normal tissue samples from 66 patients were analyzed for LINE-1 methylation at three CpG sites using bisulfite pyrosequencing. Results: Adenocarcinomas and tubular adenomas showed significant hypomethylation, especially at loci A and B, while serrated adenomas exhibited no significant differences. Conclusions: LINE-1 hypomethylation is associated with colorectal tumorigenesis, with distinct patterns observed between tubular and serrated adenomas, indicating distinct pathways forming and progressing specific adenomas. These findings support the potential of LINE-1 methylation as an early epigenetic biomarker for CRC risk stratification and highlight the need for further research into its clinical utility. Full article

Background: D-dimer determined in citrated plasma is a well-established and efficient biomarker, particularly for ruling out venous thromboembolism. In certain clinical settings, the availability of citrated plasma may pose challenges when not readily available. To address this issue, we investigated the feasibility of using ethylenediaminetetraacetic acid (EDTA) plasma as an alternative specimen for D-dimer measurement. Methods: Our study evaluated anonymized plasma samples (n = 99, for both citrate and EDTA) using the INNOVANCE^® D-dimer assay, an automated particle-enhanced immunoassay, and the INNOVANCE^® LOCI hs D-dimer assay, leveraging the luminescent oxygen channeling assay (LOCI) method. Results: The assays demonstrated a correlation of r ≥ 0.97 (95% CI 0.96 to 0.98) within citrated plasma and maintained a similar correlation r ≥ 0.96 (95% CI 0.94 to 0.97) between citrate and EDTA plasma upon correction for the dilution effect of the sodium citrate solution. Conclusions: These results indicate that the utilization of EDTA instead of citrate plasma is feasible and may provide similar diagnostic information. However, the observed variance could have an impact on clinical interpretation and risk assessment. Therefore, future studies are needed to confirm the results and, if necessary, determine cut-off values and clinical performance. Full article

The coronavirus disease 2019 (COVID-19) pandemic has led to substantial health and financial burdens worldwide, and vaccines provide hope for reducing the burden of this pandemic. However, vaccinated people remain at risk for SARS-CoV-2 infection. Genome-wide association studies (GWASs) may identify potential genetic factors involved in the development of COVID-19 breakthrough infections (BIs); however, very few or no GWASs have been conducted for COVID-19 BI thus far. We conducted a GWAS and detailed bioinformatics analysis on COVID-19 BIs in a European population via the UK Biobank (UKBB). We conducted a series of analyses at different levels, including SNP-based, gene-based, pathway, and transcriptome-wide association analyses, to investigate genetic factors associated with COVID-19 BIs and hospitalized infections. The polygenic risk score (PRS) and Hoeffding’s test were performed to reveal the genetic relationships between BIs and other medical conditions. Two independent loci (LD-clumped at r² = 0.01) reached genome-wide significance (p < 5 × 10⁻⁸), including rs36170929, which mapped to LOC102725191/VWDE, and rs28645263, which mapped to RETREG1. A pathway enrichment analysis highlighted pathways such as viral myocarditis, Rho-selective guanine exchange factor AKAP13 signaling, and lipid metabolism. The PRS analyses revealed significant genetic overlap between COVID-19 BIs and heart failure and between HbA1c and type 1 diabetes. Genetic dependence was also observed between COVID-19 BIs and asthma, lung abnormalities, schizophrenia, and type 1 diabetes on the basis of Hoeffding’s test. This GWAS revealed two significant loci that may be associated with COVID-19 BIs and a number of genes and pathways that may be involved in BIs. Genetic overlap with other diseases was identified. Further studies are warranted to replicate these findings and elucidate the mechanisms involved. Full article

Genome-wide association studies (GWASs) play a central role in precision medicine, powering a range of clinical applications from pharmacogenomics to disease risk prediction. A critical component of GWASs is genotype imputation, a computational method used to infer untyped genetic variants. While imputation increases variant coverage by estimating genotypes at untyped loci, this expanded coverage can enhance the ability to detect genetic associations in some cases. However, imputation also introduces biases, particularly for rare variants and underrepresented populations, which may compromise clinical accuracy. This review examines the challenges and clinical implications of genotype imputation errors, including their impact on therapeutic decisions and predictive models, like polygenic risk scores (PRSs). In particular, the sources of imputation errors have been deeply explored, emphasizing the disparities in performance across ancestral populations and downstream effects on healthcare equity and addressing ethical considerations surrounding the access to equitable genomic resources. Based on the above, we propose evidence-based best practices for clinical GWAS implementation, including the direct genotyping of clinically actionable variants, the cross-population validation of imputation models, the transparent reporting of imputation quality metrics, and the use of ancestry-matched reference panels. As genomic data becomes increasingly adopted in healthcare systems worldwide, ensuring the accuracy and inclusivity of GWAS-derived insights is paramount. Here, we suggest a framework for the responsible clinical integration of imputed genetic data, paving the way for more reliable and equitable personalized medicine. Full article

Background/Objectives: Bovine respiratory disease (BRD) is a common disease impacting cattle throughout the US. BRD is a multifactorial disease as disease risk varies with the genetic profile of the host, environmental conditions, and pathogen exposure. Selection for enhanced BRD resistant cattle can aid in reducing BRD. The objectives of this study were to identify loci, gene sets, and genes associated and enriched for BRD in pre- and post-weaned Holstein cattle. Methods: Cases consisted of 2147 and 5607 calves treated for BRD as pre-weaned (0–60 days old) and post-weaned (61–420 days old) calves, respectively. Controls consisted of calves untreated for BRD that remained in the herd for 61 (n = 14,219) days for pre-weaned or 421 (n = 12,242) days for post-weaned calves. A genome-wide association analysis (GWAA) identified loci and positional candidate genes associated with BRD (uncorrected P < 1 × 10⁻⁵) for additive, dominant, and recessive inheritance models. A gene set enrichment analysis (GSEA-SNP) identified gene sets and leading-edge genes enriched (NES ≥ 3) for BRD. Results: In pre-weaned calves, 62 loci and 123 positional candidate genes were associated (P < 1 × 10⁻⁵) in addition to the 12 gene sets and 126 leading-edge genes enriched (NES ≥ 3) for BRD. In post-weaned calves, 181 loci and 185 positional candidate genes were associated (P < 1 × 10⁻⁵), and 63 gene sets and 849 leading-edge genes were enriched (NES ≥ 3) for BRD. Conclusions: These results provide further insight and validation of genomic regions that enhance selection for BRD resistance and for healthier cattle. Full article

Insulin resistance (IR) is a key mechanism underlying type 2 diabetes mellitus and is closely associated with obesity. Although numerous genome-wide association studies (GWASs) have identified variants that influence IR-related traits, it remains unclear whether the genetic architecture of IR differs according to obesity status. We conducted a stratified GWAS of the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in 8906 Korean individuals from the Korean Genome and Epidemiology Study. Participants were categorized into a normal-weight group (Body Mass Index (BMI) ≤ 23 kg/m²) and an overweight or obese group (BMI > 23 kg/m²), and the GWAS was performed separately within each group. No significant genome-wide variants were identified in the normal-weight group; however, seven loci showed suggestive associations. In contrast, in the overweight and obese group, two loci, rs662799 in Apolipoprotein A5 (APOA5) and rs671 in Aldehyde Dehydrogenase 2 (ALDH2), showed genome-wide significance, with seven loci showing suggestive associations. The risk allele of rs662799 was associated with increased HOMA-IR values, with a stronger effect observed in the overweight and obese group. This finding aligns with the known role of APOA5 in triglyceride metabolism, suggesting that a higher BMI may exacerbate its effect on IR. These results highlight obesity-specific genetic susceptibility to IR and the need to consider obesity status in genetic studies of metabolic traits. Full article