Search Results (1,710)

This study aimed to explore the correlations of nuclear factor erythroid 2-related factor-2 (NRF2) gene polymorphisms, prepregnancy body mass index (BMI) and the interaction between them with the risk of preeclampsia (PE). A case–control study was conducted in which pregnant women with PE (n = 198) and normotensive pregnant women (n = 396) were recruited as the case group and control group, respectively, from two tertiary hospitals in Hunan Province. Data collection was achieved through face-to-face interviews utilizing a standardized questionnaire, along with perinatal health care records. Blood samples were also collected, and genotyping of nine single-nucleotide polymorphisms (SNPs) in the NRF2 gene was subsequently performed using the MassArray platform. Both univariate and multivariate logistic regression analyses were employed to assess the associations of NRF2 gene polymorphisms with prepregnancy BMI and their interactions with the risk of PE. Multivariate logistic regression analyses revealed a significant association between prepregnancy BMI and PE susceptibility. Specifically, prepregnancy overweight/obesity (BMI ≥ 24.0 kg/m²) was associated with an elevated risk of PE (adjusted OR = 4.59, 95% CI: 2.82–7.45), whereas underweight status (BMI < 18.5 kg/m²) was correlated with a reduced PE risk (adjusted OR = 0.38, 95% CI: 0.18–0.78). The NRF2 polymorphism rs13005431 exhibited a protective effect against PE under the additive genetic model (adjusted OR = 0.59, 95% CI: 0.37–0.93). Furthermore, logistic regression analyses revealed a significant effect of the multiplicative interaction between prepregnancy overweight/obesity and polymorphisms rs35652124 (adjusted OR = 0.24, 95% CI: 0.06–0.89) and rs2627765 (adjusted OR = 3.62, 95% CI: 1.07–12.23) on susceptibility to PE. These findings collectively underscore the critical and independent roles of prepregnancy BMI, NRF2 polymorphisms, and their interactions in modulating PE susceptibility, suggesting that the combined effects of metabolic profiles and genetic determinants may act synergistically to shape PE risk. Full article

Background/Objectives: The genes encoding HSPA1A, HSPA1B, and HSPA1L, located in the MHC class III region at 6p21.3–22.1, a region implicated in susceptibility to schizophrenia, are critical regulators of neurodevelopmental processes and contribute to synaptic neuroprotection. This study investigated whether the HSPA1A, HSPA1B, and HSPA1L genes are associated with schizophrenia. Methods: We sequenced the coding regions of HSPA1A, HSPA1B, and HSPA1L from 100 patients with schizophrenia to identify genetic variants. Further, we conducted a genetic association analysis of three SNPs (rs9469057, rs142416335, and rs2075800) in the HSPA1L gene in 519 patients with schizophrenia and 1492 healthy controls from the Taiwan Biobank. We analyzed the function of the HSPA1L protein via immunoblotting. Results: We identified 17 coding variants, including 8 missense and 9 synonymous mutations, in 100 patients with schizophrenia. Three variants (HSPA1L^p.Ala8Pro, HSPA1L^p.Ala8Thr, and HSPA1L^p.Glu602Lys) in the HSPA1L gene did not exhibit any significant differences in allele or genotype frequencies between patients and control subjects. Notably, one ultra-rare missense mutation, HSPA1L^p.Val262Met, was not documented in the control sample in Taiwan BioBank. Immunoblotting revealed HSPA1L^p.Val262Met mutant with decreased protein expression in SH-SY5Y cells compared with the wild type. Conclusions: While common variants in the HSPA1A, HSPA1B, and HSPA1L genes do not seem to be significant genetic risk factors for schizophrenia in this cohort, the ultra-rare mutation, HSPA1L^p.Val262Met, significantly reduces protein expression. These preliminary findings suggest that a potential loss-of-function or reduced expression of the HSPA1L gene may be a predisposing factor contributing to schizophrenia vulnerability in certain individuals. However, the finding should be replicated in other independent samples. The in vitro and in vivo impacts of the associated mutation at the HSPA1L gene on the pathophysiology of schizophrenia are worthy of future investigation. Full article

Objective: This umbrella review aimed to evaluate the strength and consistency of evidence linking genetic variants to dental caries susceptibility. Methods: An umbrella review was conducted, following PRISMA 2020 guidelines. A comprehensive literature search was performed across six databases. Eligibility criteria included systematic reviews and meta-analyses of human subjects. Study selection, data extraction, and methodological quality assessment were performed systematically, with quality evaluated using the AMSTAR-2 tool. Multilevel meta-analyses were conducted to assess variant-specific and grouped genetic effects. Results: The search identified 29 eligible systematic reviews and meta-analyses for inclusion. The multilevel meta-analysis showed statistically significant associations for polymorphisms in TAS2R38 rs713598 (OR = 0.26, 95% CI: 0.09–0.73) and VDR Cdx-2 rs11568820 (OR = 0.66, 95% CI: 0.46–0.95), both indicating lower odds of dental caries, while MBL2 rs1800450 was associated with increased odds (OR = 1.48, 95% CI: 1.03–2.14). However, pooled effects across the main gene categories, including tooth development and mineralization, salivary composition and function, immune and inflammatory response, taste perception, and signaling, were not statistically significant. Findings were heterogeneous across studies. Conclusions: Current evidence on the association between genetic variants and dental caries susceptibility remains limited and inconsistent, providing insufficient support for the use of genetic markers in risk assessment or personalized prevention. The significant single-nucleotide polymorphism (SNP) associations identified in this review are hypothesis-generating and require validation in larger and more diverse populations using standardized caries definitions and gene–environment approaches. Full article

High levels of low-density lipoprotein cholesterol (LDL-c) have been recognized as the main causal factor of atherosclerotic cardiovascular disease (ASCVD) and are influenced by both genetic and environmental factors. Among genetic determinants, Familial Hypercholesterolemia (FH) is the most common monogenic disorder, caused by rare high-impact variants in genes involved in LDL uptake. Other monogenic causes of hypercholesterolemia include sitosterolemia, cerebrotendinous xanthomatosis and lysosomal acid lipase deficiency (LALD). However, monogenic disorders only account for a small proportion of inherited hypercholesterolemia. In many individuals, increased LDL-c levels are caused by the contemporary presence of different single-nucleotide polymorphisms (SNPs) with a moderate/low impact. These SNPs could be summarized through polygenic risk scores (PRS) that attribute relative weight to each of these. Another genetic determinant of hypercholesterolemic phenotypes is high levels of lipoprotein(a)—Lp(a). Lp(a) is an LDL particle modified by the binding of apolipoprotein(a)—apo(a)—which represents an independent risk factor for ASCVD. Lp(a) levels are mainly genetically determined by variation in the number of kringle IV type 2 (K-IV₂) repeats, as well as by several SNPs, and remain stable throughout life. The aim of this narrative review is to report an updated overview of the genetic mechanisms underlying hypercholesterolemia, including monogenic disorders, PRS and Lp(a), focusing on their potential repercussion in clinical practice by the integration into cardiovascular risk stratification beyond traditional clinical assessment. This integration could lead to a more comprehensive and individualized approach to cardiovascular prevention, with emerging perspectives including the possible use of artificial intelligence (AI). Full article

Aim: The aim of this study was to correlate single-nucleotide polymorphisms (SNPs) in the FTO and MC4R genes with body composition (BC) in populations with various levels of physical activity, and to investigate associations of SREBF1 methylation with the level of physical activity (PA) and BC. Methods: Fifty-six participants aged 18–65 years old with no underlying medical conditions were included in the study and were classified into sedentary/light PA (SLPA), moderate PA (MPA) and vigorous PA (VPA) groups using the International PA questionnaire (IPAQ). Anthropometric measures such as age, gender, body mass index (BMI) and body fat percentage (BFP) were recorded at the time of recruitment. Venous blood samples were collected during participant recruitment and DNA was extracted. Genotyping assays were performed for SNPs in FTO (rs9939609) and MC4R (rs17782313) using Taqman^® RT qPCR and TaqMan Genotyper software 1.7.1. Methylation analysis assay for CpG sites in the SREBF1 gene was performed on 56 samples using PyroMark^® Q48 Autoprep (Qiagen, Venlo, The Netherlands). The results were statistically analysed to identify any associations between FTO/MC4R genotypes and the level of PA, and between SREBF1 methylation status and the level of PA. This is the first study to investigate links between PA and quantitative methylation of SREBF1. Results: According to IPAQ guidance, the 56 participants were classified into SLPA n = 14, MPA n = 11 and VPA n = 31. The correlation analysis revealed that the FTO rs9939609 ‘A’ risk allele had a significant negative association with BFP in the VPA group (p = 0.0387); the MC4R rs17782313 ‘C’ risk allele had a significant positive association with BMI in the VPA group (p = 0.0256). In the SREBF1 pyrosequencing analysis, higher levels of methylation were observed in the VPA group (p = 0.07). Conclusions: We concluded that SNPs associated with obesity identified in FTO rs9939609 and MC4R rs17782313 could help to predict the molecular effects of PA. A high frequency of FTO risk variants in the cohort was observed and the VPA group could help maintain a healthy BFP. Full article

Prostate cancer (PrC) is one of the most common malignancies among men worldwide. However, the contribution of genetic variation in microRNA (miRNA) biogenesis pathway genes to PrC susceptibility remains poorly characterized in many ethnically diverse populations. We conducted a case–control study involving 532 PrC patients and 550 controls from the Volga-Ural region of Eurasia to evaluate the association of twenty-one single nucleotide polymorphisms (SNPs) with PrC risk using single-variant and polygenic approaches. Association analyses identified rs595055 in the AGO1 gene as significantly associated with PrC risk after correction for multiple testing. To evaluate the cumulative effect of genetic variation, weighted and unweighted polygenic risk scores (PRSs) were constructed. The weighted PRS was significantly associated with PrC risk (odds ratio per standard deviation increase = 1.63, 95% CI [1.43–1.85], P = 1.37 × 10⁻¹³), and demonstrated moderate discriminatory performance (AUC = 63.1%), outperforming the unweighted model. Individuals in the highest PRS quartile had approximately threefold higher odds of PrC than those in the lowest quartile. Combining the weighted PRS with prostate-specific antigen improved discrimination (AUC = 68.1%). These findings support the contribution of miRNA biogenesis pathway genes to PrC susceptibility and highlight the potential value of pathway-based polygenic risk stratification in understudied populations. Full article

Objective: TNFSF13B, which encodes B-cell-activating factor (BAFF) and peptidylarginine deiminase 4 (PADI4), plays crucial roles in the pathogenesis of ANCA-associated vasculitis (AAV). This study investigated the associations of single-nucleotide polymorphisms (SNPs) in TNFSF13B/BAFF and PADI4 genes with AAV susceptibility, clinical phenotypes, and disease activity in a Guangxi Chinese population. Methods: A case–control study included 324 AAV patients and 324 healthy controls. After propensity score matching (201 pairs), genomic DNA was genotyped for TNFSF13B/BAFF rs3759467 (formerly rs386492354) and rs1041569, and PADI4 rs11203366 and rs874881 using multiplex PCR and high-throughput sequencing. Genetic associations were analyzed via logistic regression, subgroup, haplotype, and clinical correlation analyses. For each of the four SNPs separately, machine learning models (logistic regression, SVM, Random Forest, XGBoost) were built and evaluated via 5-fold cross-validation. No formal adjustment for multiple comparisons was applied due to the exploratory nature of this study. Results: For TNFSF13B/BAFF, the rs3759467 C allele was protective (dominant model OR = 0.60, p = 0.011; log-additive OR = 0.71, p = 0.020; CA haplotype OR = 0.71, p = 0.019), while the rs1041569 T allele was a risk factor (dominant model OR = 1.70, p = 0.016). Subgroup analysis revealed stronger protective effects of rs3759467 in females, Han ethnicity, and MPA patients, and stronger risk effects of rs1041569 in Han ethnicity and MPA patients. Haplotype CA was protective (OR = 0.71, p = 0.019), and TT was risk-associated (OR = 1.55, p = 0.017). Both TNFSF13B/BAFF SNPs were associated with rash and hemoptysis incidence (p < 0.05). rs1041569 was also associated with RBC (red blood cell) count and HB (hemoglobin) levels (p < 0.05). For PADI4, rs11203366 and rs874881 showed no association with AAV susceptibility (all p > 0.05). However, their genotypes were associated with disease activity (BVAS, Birmingham Vasculitis Activity Score), RBC count, and HB levels (p < 0.05). Although machine learning was applied to explore predictive patterns, its performance was suboptimal (AUC < 0.6), indicating limited clinical applicability. Accordingly, the primary findings rely on the genetic model analysis, and the machine learning results should not be overinterpreted as clinically actionable. SHAP analysis indicated that risk-associated genotypes contributed most to model predictions. Conclusions:TNFSF13B/BAFF gene polymorphisms rs3759467 and rs1041569 were associated with AAV susceptibility in this Guangxi cohort, influencing clinical manifestations like rash, hemoptysis, and anemia severity. PADI4 polymorphisms rs11203366 and rs874881 are not associated with susceptibility but may correlate with disease activity and hematological parameters. These findings highlight the ethnic and clinical subtype specificity of genetic influences in AAV. Due to the lack of external validation, these findings are exploratory and require replication. Full article

Background: Parenting stress is a known risk factor for children’s social anxiety, yet the mediating and moderating mechanisms underlying this relationship remain underexplored, particularly regarding gene–environment interactions. This quantitative, cross-sectional study, grounded in diathesis-stress and family process theories, examined whether maladaptive parenting mediates the link between parenting stress and children’s social anxiety, and whether FKBP5 gene variation moderates this mediation. Methods: A sample of 1774 fourth- to sixth-grade students (aged 10–14 years) and their parents participated. Parenting stress and maladaptive parenting were parent-reported, children’s social anxiety was self-reported, and children’s FKBP5-related cumulative genetic score was derived from four SNPs (rs4713916, rs1360780, rs3800373, rs9296158). Moderated mediation analyses were conducted. Results: Parenting stress was significantly and positively associated with children’s social anxiety. Maladaptive parenting partially mediated this relationship. The FKBP5 showed a marginally significant moderating effect, with simple slope analysis suggesting parenting stress was more strongly associated with child social anxiety among children with higher genetic risk. No moderating effect was found for the path from maladaptive parenting to social anxiety. Conclusions: Parenting stress is associated with children’s social anxiety both directly and indirectly through maladaptive parenting, with FKBP5-related cumulative genetic risk potentially moderating the direct effect. These findings offer preliminary evidence that may inform preventive interventions targeting parenting stress, although replication is needed. Full article

Background/Objectives: IL23R encodes a pivotal component of the IL-23/Th17 signaling axis and represents a validated genetic susceptibility locus for inflammatory bowel disease (IBD), psoriasis, and ankylosing spondylitis. Despite extensive GWAS data, the functional consequences of the full spectrum of IL23R missense single-nucleotide variants (SNVs) have not been systematically characterized. This study aimed to identify high-risk missense SNVs through a multi-tool in silico pipeline. Methods: A total of 723 missense SNVs from NCBI dbSNP were verified against transcript NM_144701.3/Q5VWK5-1 (629 aa) using Ensembl VEP (GRCh38). Sequential filtering was performed using applied SIFT, PolyPhen-2, PROVEAN, E-SNPs&GO, MutPred2, and ConSurf (grade ≥ 7); AlphaMissense and FATHMM-MKL were used as independent annotation layers. Protein stability was assessed with MuPro and DynaMut2 (AlphaFold2 AF-Q5VWK5-F1-v6; pLDDT = 68.19); structural characterization was performed with Project HOPE, and interaction networks were constructed using STRING and GeneMANIA. Results: Sequential filtering identified 37 high-risk missense variants. MuPro predicted destabilizing effects for 36/37 variants, with concordant DynaMut2 results for 35/37. Project HOPE identified disulfide bond disruption in 11 variants, charge-altering substitutions in 8, and glycine/proline backbone conformational changes in 11. STRING analysis identified IL12RB1 (0.999), IL23A (0.999), JAK2 (0.995), IL12B (0.986), and STAT3 (0.980) as the leading IL23R interactors. The protective variant R381Q was appropriately characterized as neutral by PROVEAN (−1.16) and AlphaMissense (likely_benign), supporting the specificity of the pipeline. Conclusions: Comprehensive in silico analysis identified 37 high-risk IL23R missense candidates with convergent computational evidence of predicted deleteriousness, predominantly involving cysteine bridge disruption, charge alteration, and glycine/proline backbone conformational changes. These variants are presented as prioritized candidates for future functional validation and may inform subsequent investigations of IBD susceptibility and IL-23 pathway pharmacogenomics. Full article

Host genetic susceptibility to urogenital Chlamydia trachomatis (Ct) reinfection remains poorly understood. Coding variants identified in prior genome-wide association studies (GWAS) explained only a small fraction of the risk of reinfection. Our goal in this study was to characterize whether more risk would be captured by sequence variation that traditional GWAS insufficiently captures. Specifically, we evaluated the risk attributable to SNPs present in regulatory, non-coding regions; post-transcriptional regulation by microRNAs (miRNAs) that may depend on sequence variation in either the miRNA or the target mRNA; and copy number variants (CNVs). We analyzed GWAS data from African American women with or without documented urogenital Ct reinfection. Fine mapping and independent association analyses identified 30 unique index single-nucleotide polymorphisms (iSNPs), which were expanded to variants in linkage disequilibrium. Regulatory annotation was performed using HaploReg, RegulomeDB, FORGEdb, rSNPBase, and GTEx. We examined whether genes identified in the Ct reinfection GWAS are targeted by known Ct infection–associated microRNAs using curated databases. Genome-wide CNV calling was conducted using SNP intensity data, followed by stringent quality control and gene-level association testing. Functional annotation prioritized 7 SNPs with strong regulatory evidence, with stringent criteria for regulatory relevance, using HaploReg, RegulomeDB, FORGEdb, and rSNPBase. The strongest signals were observed at the CHIT1 locus, where multiple intronic variants (including rs2486963 and rs2244385) overlapped regulatory chromatin, altered transcription factor binding motifs, and acted as cis-expression quantitative trait loci for CHIT1 in whole blood. Additional regulatory variants were identified near TDRP, ERICH1, and DLGAP1, showing tissue-specific regulatory effects. MicroRNA analysis revealed extensive post-transcriptional targeting of SOCS6 and SULF1, while CHIT1 showed no curated Ct-associated miRNA interactions. CNV analysis identified 5775 high-confidence events, with nominal gene-level associations observed for ATAD3A, CARD14, TMEM240, and ZNF140. These results indicate that a greater fraction of the susceptibility to urogenital Ct reinfection may be driven by genetic variation affecting immune and epithelial pathways rather than protein-coding changes. Full article

This study evaluates the vulnerability of Siberian larch (Larix sibirica L.) populations to future climate change using a genomic offset (GO) framework that integrates genome-wide SNP data with environmental variables. We analyzed 488 individuals from 37 populations across climatically diverse regions of Russia, genotyped by sequencing at over 20,000 SNP loci using the ddRADseq method. Gene–environment association (GEA) analyses (BayeScEnv, LFMM2, and RDA) identified candidate adaptive loci linked to six key bioclimatic variables. Based on these loci, GO was estimated using three approaches implemented in RONA–RDA, RDA, and Gradient Forest frameworks under multiple climate models (MIROC6, BCC-CSM2-MR, MRI-ESM2-0), scenarios (SSP2-4.5, SSP3-7.0, SSP5-8.5), and time periods (2041–2060, 2061–2080, and 2081–2100). Results revealed consistent spatial patterns of vulnerability, with northern and high-altitude populations, as well as populations from more continental and moisture-limited regions, exhibiting the highest GO and thus the greatest risk of maladaptation. In contrast, several central and southern populations showed relatively low vulnerability. The importance of temperature stability (isothermality) and precipitation of the driest month as key drivers of adaptive variation was highlighted. Despite differences in SNP datasets, population rankings remained highly consistent, supporting the robustness of predictions. Overall, our findings demonstrate substantial heterogeneity in climate vulnerability across the species range and provide a genomic basis for conservation strategies, including assisted gene exchange and climate-adaptive forest management. Full article

Background/Objectives: Obesity remains a global health concern, and personalized prevention strategies that consider genetic predispositions can enhance existing strategies. Research suggests that variation in circadian rhythm-related genes, or clock genes, may influence obesity risk, in part through effects on dietary behaviour. However, associations between single-nucleotide polymorphisms (SNPs) in clock genes and dietary outcomes remain understudied, particularly in children. Therefore, we investigated cross-sectional associations between clock gene SNPs and dietary outcomes using baseline data from 226 adults (138 females, 88 males) aged 26–50 y and 168 children (90 females, 78 males) aged 2–6 y from the Guelph Family Health Study. Methods: DNA was extracted from saliva and genotyped using the Illumina Global Diversity Array, and dietary intake was assessed using the Automated Self-Administered 24 h Dietary Assessment Tool. Nine SNPs representing 8 clock genes were selected based on prior associations with dietary and obesity-related outcomes. Generalized Estimating Equations were used to test associations, adjusted for multiple comparisons with the Benjamini–Hochberg false discovery rate (FDR) procedure. Results: Ten nominal associations were identified (p < 0.05), and 2 remained significant after FDR correction (P_adj < 0.05); among children, rs2314339-T (NR1D1) was associated with a lower percentage of energy from protein (β = −2.4%, P_adj = 0.003) and rs11605924-A (CRY2) with higher energy intake (β = 118.0 kcal, P_adj = 0.044). Conclusions: Findings suggest that clock gene SNPs may influence dietary habits from early childhood. Future longitudinal and functional studies are needed to clarify whether these variants can inform precision nutrition strategies for obesity prevention. Full article

Background: Gastrointestinal (GI) cancers, particularly colorectal, gastric, and liver cancers, account for a major global burden of incidence and mortality and remain important targets for genetic susceptibility research. Long non-coding RNAs (lncRNAs) can regulate gene expression and are increasingly studied in carcinogenesis. Numerous case–control studies have investigated associations between lncRNA polymorphisms and cancer risk, but findings are inconsistent. This study systematically evaluated the association between lncRNA single nucleotide polymorphisms (SNPs) and GI cancer susceptibility. Methods: A systematic literature search from Embase, Medline, Scopus, and Web of Science databases identified 174 potentially extractable studies. Eligible studies were case–control or cross-sectional studies published up to 8 May 2026; case reports, reviews, and meta-analyses were excluded. After screening for identical cancer type, identical SNP, and sufficient statistical data, only variants supported by at least three independent case–control studies were eligible for meta-analysis. Seven SNPs across six lncRNAs, comprising 23 studies (15,131 cases and 20,969 controls), were selected. Because of the limited number of eligible studies, subgroup analyses could not be performed consistently. Odds ratios (ORs) with 95% confidence intervals (CIs) were assessed under allelic, dominant, and recessive genetic models using fixed- or random-effects models according to heterogeneity. Results: In the primary analyses restricted to homogenous Chinese populations, H19 rs3024270 was significantly associated with hepatocellular carcinoma under allelic (OR = 1.22, 95% CI: 1.05–1.42, p = 0.01) and dominant models (OR = 1.22, 95% CI: 1.03–1.45, p = 0.02). Exploratory analyses including mixed populations identified additional associations, with the strongest observed for MEG3 rs7158663 and colorectal cancer, showing significant risk elevation under allelic (OR = 1.42, 95% CI: 1.25–1.63, p < 0.00001), dominant (OR = 1.42, 95% CI: 1.20–1.68, p < 0.0001), and recessive models (OR = 1.98, 95% CI: 1.46–2.68, p < 0.0001). PRNCR1 rs16901946 showed a significant association with gastric cancer under the dominant model (OR = 1.20, 95% CI: 1.02–1.41, p = 0.03), while GAS5 rs145204276 demonstrated a recessive-model association with gastric cancer (OR = 1.30, 95% CI: 1.16–1.46, p < 0.0001). In contrast, GAS5 rs145204276 in colorectal cancer; H19 rs2839698 and MALAT1 rs619586 in hepatocellular carcinoma yielded heterogeneous or unstable pooled estimates. Findings should be interpreted cautiously due to the limited number of studies, heterogeneity, and potential publication bias. Conclusions: Among the primary analyses, H19 rs3024270 showed the most consistent association with HCC susceptibility. Exploratory analyses identified candidate variants, including MEG3 rs7158663, PRNCR1 rs16901946, and GAS5 rs145204276. Population-specific effects and study heterogeneity remain important limitations. PROSPERO registration number for this study: CRD42023389742. Full article

Background: Persistent high-risk human papillomavirus (hrHPV) infection causes over 99% of cervical precancers and cancers worldwide, with HPV genotype 16 (HPV16) responsible for 50% of the cases. Latvia ranks among the top EU countries for cervical cancer incidence and mortality. In the general Latvian population, 4.2% of women are hrHPV-infected, mostly with HPV16. However, information on the circulating HPV16 isolates is missing. Objectives: To study the genomic variability of the Latvian HPV16 isolates, compare them with HPV16 in Europe and across the globe, reveal features associated with the severity of cervical disease and uncover eventual sequence changes due to the national HPV vaccination. Methods: DNA was extracted from the formalin-fixed paraffin-embedded cervical tissues of women diagnosed with cervical intraepithelial neoplasia (CIN) stages I-III and squamous cell carcinoma (SCC) grades 1–3, collected between 2012 and 2024. Samples positive for HPV16 were subjected to whole genome sequencing (WGS) on the Illumina platform (n = 16) or Sanger sequencing of the E6/E7 coding region (n = 31). A consensus HPV16 sequence was generated, and single nucleotide polymorphisms (SNPs) and eventual amino acid substitutions (AAS) were analysed. Results: Complete genomes of 16 HPV16 variants were reconstructed, with 13 related to the European sublineage A1 and 3 to the sublineage A2 references. Sequences showed high conservation; still 93 non-redundant variants were identified. The highest variability was observed for the capsid protein L2, and the lowest, for oncoprotein E7. The prevalence of SNPs and AAS in the Latvian HPV16 variants, specifically in capsid protein L1, did not increase with time, showing no effect of HPV vaccination. Associations between HPV16 sequence features and severity of cervical disease were limited to AAS E6:L90V, which was significantly more common in SCC grade 2/3 than in CINII/III cases (p = 0.015). Conclusions: Highly conserved HPV16 genomes circulating in Latvia harbour a series of unique as well as common nonsynonymous SNPs with respective AAS, with one, AAS E6:L90V, associating with disease severity. No HPV vaccine escape variants were detected. Deciphering complete genomes of HPV16 from CIN and SCC cases in Latvia informs public authorities performing HPV vaccination and is useful for the management of HPV-associated cervical diseases. Full article

Common forms of migraine are complex disorders characterized by significant clinical diversity. Their genetic basis has been extensively studied but remains unclear. This study represents the first pilot genome-wide association study (GWAS) integrating a polygenic risk score (PRS) in the Portuguese population, designed to identify migraine susceptibility loci through a case–control study and unravel population-specific variants. Genotyping data was acquired with Applied Biosystems Axiom™ PMDA array, producing 12,035,248 single-nucleotide polymorphisms (SNPs) post-imputation, providing a comprehensive scope for GWAS analysis. PRS models were created and tested using a k-folds cross-validation framework and the optimal significance threshold was assessed. We detected 12 potential risk loci corresponding to 12 lead SNPs (RP11-204N11.2, CTA-481E9.4/CTA-481E9.3, RAP1A, TIGD4, CADPS2, RP11-46E17.6, RP4-569D19.5, RP11-398K14.1, PCBP1-AS1, TCF15, IL6R and UNC13A). The top three variants (RP11-204N11.2, CTA-481E9.4/CTA-481E9.3 and RAP1A) were also supported by the PRS model. We highlight that several variants present putative biological relevance to migraine pathophysiology, reinforcing the importance of neurotransmitter release, synaptic transmission and the involvement of vascular components in migraine pathophysiology. Full article