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Background: Human leukocyte antigen-G (HLA-G) is a pivotal protein involved in immune regulation and tolerance, while systemic lupus erythematosus (SLE) is a multifaceted autoimmune condition influenced by genetic and environmental factors. Research indicates that variations and mutations in HLA-G may impact SLE development. Objective: This study aimed to explore the relationship between polymorphisms in the 3'-untranslated region (UTR) of the HLA-G gene and SLE. Methods: DNA from 100 SLE patients and 100 controls was analyzed using polymerase chain reaction to amplify the target sequence. Allele and genotype frequencies were determined, and haplotypes were assessed using Haploview v.4.2 software, with linkage disequilibrium calculated. Results: Findings revealed that the +2960 Ins allele was significantly linked to SLE as a risk factor, with the Del allele showing a protective effect. In addition, the +3010C allele and +3187A allele were significantly associated with SLE at both allele and genotype levels. The +3142 GG homozygote was notably linked to SLE at the genotype level. Haplotype analysis identified UTR-2 haplotypes as risk factors for SLE, whereas the UTR-1 haplotype was protective, shedding light on genetic factors influencing SLE risk. Conclusion: This study underscores the importance of HLA-G gene 3'-UTR polymorphisms in SLE susceptibility, suggesting their potential as diagnostic or therapeutic targets.
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Regiones no Traducidas 3' , Alelos , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Antígenos HLA-G , Haplotipos , Desequilibrio de Ligamiento , Lupus Eritematoso Sistémico , Polimorfismo de Nucleótido Simple , Humanos , Lupus Eritematoso Sistémico/genética , Antígenos HLA-G/genética , Haplotipos/genética , Regiones no Traducidas 3'/genética , Femenino , Masculino , Adulto , Frecuencia de los Genes/genética , Estudios de Casos y Controles , Polimorfismo de Nucleótido Simple/genética , Persona de Mediana Edad , Genotipo , Estudios de Asociación Genética , Factores de RiesgoRESUMEN
OBJECTIVE: To investigate the causal association between immune cell and different types of sepsis by using Mendelian randomization (MR) method, and to find the immune cell phenotypes causally associated with sepsis. METHODS: Summary data for various circulating immune cell phenotypes were obtained from the GWAS catalog (GCST90001391-GCST90002121). Sepsis data were sourced from the UK Biobank database. Single nucleotide polymorphisms (SNP) were used as instrumental variables. The correlation threshold of P < 5×10-6 was used to identify the strongly correlated instrumental variables, and the code was used to remove the linkage disequilibrium and the instrumental variables with F-value < 10. Inverse variance weighting (IVW) was used as the main research method to evaluate the stability and reliability of the results, including Cochran's Q test, MR-Egger regression and Leave one out. Reverse MR analysis was performed based on the immunophenotypic results of the removal of horizontal pleiotropy, and the immune cell phenotype with one-way causal association was obtained. Odds ratio (OR) and 95% confidence interval (95%CI) were used to represent the effect value of the results. RESULTS: CD16 on CD14-CD16+; monocyte had horizontal pleiotropy in sepsis (OR = 0.965 4, 95%CI was 0.933 5-0.998 3, P = 0.039 6). There were five immunophenotypes that had reverse causal associations with the types associated with sepsis. After excluding immune cell phenotypes with horizontal pleiotropy and reverse causation, a total of 42 immune cell phenotypes with sepsis, 36 immune cell phenotypes with sepsis (28-day death in critical care), 32 immune cell phenotypes with sepsis (critical care), 44 immune cell phenotypes with sepsis (28-day death), and 30 immune cell phenotypes had potential causal associations with sepsis (under 75 years old). After false discovery rate (FDR) correction, the correlations between BAFF-R on IgD- CD38br and sepsis (28-day death) were negative and strong (OR = 0.737 8, 95%CI was 0.635 9-0.856 0, P = 6.05×10-5, PFDR = 0.044 2). CONCLUSIONS: A variety of immune cell phenotypes may have a protective effect on sepsis, especially BAFF-R on IgD- CD38br expression is negatively correlated with sepsis (28-day death), which provides a new idea for immune modulation therapy in sepsis.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Sepsis , Humanos , Sepsis/genética , Fenotipo , Desequilibrio de Ligamiento , Oportunidad RelativaRESUMEN
OBJECTIVE: Sarcopenia and cognitive impairment often coexist in the elderly. In this study, we investigated the causal relationship between sarcopenia-related muscle characteristics and cognitive performance. METHODS: We used linkage disequilibrium score regression (LDSC) and Mendelian Randomization (MR) analyses to estimate genetic correlations and causal relationships between genetically predicted sarcopenia-related muscle traits and cognitive function, as well as cognitive function-based discovery samples and replicated samples. Estimated effect sizes were derived from a fixed-effects meta-analysis. RESULTS: Our univariate genome-wide association study (GWAS) meta-analysis indicated a causal relationship between appendicular lean mass (ALM) (ß = 0.049; 95% confidence interval (CI): 0.032-0.066, P < 0.001) and walking pace (ß = 0.349; 95% CI: 0.210-0.487, P < 0.001) with cognitive function, where a causal relationship existed between ALM in both male and female (ßALM-Male(M) = 0.060; 95% CI: 0.031-0.089, PALM-M < 0.001; ßALM-Female(F) = 0.045; 95% CI: 0.020-0.069, PALM-F < 0.001) with cognitive function. Low grip strength was not causally associated with cognitive function (ß = -0.045; 95% CI: -0.092 - -0.002, P = 0.062). A reverse causality GWAS meta-analysis showed a causal relationship between cognitive function and ALM (ß = 0.033; 95% CI: 0.018-0.048, P < 0.001) and walking pace (ß = 0.039; 95% CI: 0.033-0.051, P < 0.001), where ALM in both male and female showed a causality (ßALM-M = 0.041; 95% CI: 0.019-0.063, PALM-M < 0.001; ßALM-F = 0.034; 95% CI: 0.010-0.058, PALM-F = 0.005). Cognitive function was not causally related to low grip strength (ß = -0.024; 95% CI: -0.073-0.025, P = 0.344). Multivariable MR1 (MVMR1) analyses showed a significant causal relationship for ALM (ß = 0.077; 95% CI: 0.044-0.109, P = 0.000) and walking pace (ß = 0.579; 95% CI: 0.383-0.775, P = 0.000) and cognitive function. Multivariable MR2 (MVMR2) multivariate analysis showed that ALM causality remained (ß = 0.069; 95% CI: 0.033-0.106, P = 0.000), and walking pace (ß = 0.589; 95% CI: 0.372-0.806, P = 0.000). CONCLUSIONS: Bidirectional two-sample MR demonstrated that sarcopenia-related muscle characteristics and cognitive performance were positive causal genetic risk factors for each other, while a multivariable MR study demonstrated that low ALM and a slow walking pace were causally involved in reduced cognitive performance. This study suggests a causal relationship between sarcopenia and cognitive impairment in older adults and provide new ideas for prevention and treatment.
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Disfunción Cognitiva , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Sarcopenia , Humanos , Sarcopenia/genética , Masculino , Femenino , Disfunción Cognitiva/genética , Anciano , Polimorfismo de Nucleótido Simple , Desequilibrio de LigamientoRESUMEN
The aim is to investigate the evidence for shared genetic architecture between each of asthma, allergic rhinitis and eczema with gastro-esophageal reflux disease (GERD). Structural equation models (SEM) and polygenic risk score (PRS) analyses are applied to three Swedish twin cohorts (n = 46,582) and reveal a modest genetic correlation between GERD and asthma of 0.18 and bidirectional PRS and phenotypic associations ranging between OR 1.09-1.14 and no correlations for eczema and allergic rhinitis. Linkage disequilibrium score regression is applied to summary statistics of recently published GERD and asthma/allergic disease genome wide association studies and reveals a genetic correlation of 0.48 for asthma and GERD, and Genomic SEM supports a single latent factor. A gene-/gene-set analysis using MAGMA reveals six pleiotropic genes (two at 12q13.2) associated with asthma and GERD. This study provides evidence that there is a common genetic architecture unique to asthma and GERD that may explain comorbidity and requires further investigation.
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Asma , Reflujo Gastroesofágico , Estudio de Asociación del Genoma Completo , Humanos , Reflujo Gastroesofágico/genética , Asma/genética , Femenino , Masculino , Predisposición Genética a la Enfermedad , Suecia/epidemiología , Adulto , Persona de Mediana Edad , Herencia Multifactorial , Hipersensibilidad/genética , Desequilibrio de LigamientoRESUMEN
To investigate the association between single nucleotide polymorphism (SNP) at the rs3918188, rs1799983 and rs1007311 loci of the endothelial nitric oxide synthase (eNOS) gene and genetic susceptibility to systemic lupus erythematosus (SLE) in northeastern China. The base distribution of eNOS gene rs3918188, rs1799983 and rs1007311 in 1712 human peripheral blood samples from Northeast China was detected by SNaPshot sequencing technology. The correlation between genotype, allele and gene model of these loci of the eNOS gene and the genetic susceptibility to SLE was investigated by logistic regression analysis. The results of the differences in the frequency distribution of their gene models were visualised using R 4.3.2 software. Finally, HaploView 4.2 software was used to analyse the relationship between the haplotypes of the three loci mentioned above and the genetic susceptibility to SLE. A multifactor dimensionality reduction (MDR) analysis was used to determine the best SNP-SNP interaction model. The CC genotype and C allele at the rs3918188 locus may be a risk factor for SLE (CC vs AA: OR = 1.827, P < 0.05; C vs A: OR = 1.558, P < 0.001), and this locus increased the risk of SLE in the dominant model and the recessive model (AC + CC vs AA: OR = 1.542, P < 0.05; CC vs AA + AC: OR = 1.707, P < 0.001), while the risk of SLE was reduced in the overdominant model (AC vs AA + CC: OR = 0.628, P < 0.001). The GT genotype and T allele at locus rs1799983 may be a protective factor for SLE (GT vs GG: OR = 0.328, P < 0.001; T vs G: OR = 0.438, P < 0.001) and this locus reduced the risk of SLE in the overdominant model (GT vs GG + TT: OR = 0.385, P < 0.001). There is a strong linkage disequilibrium between the rs1007311 and rs1799983 loci of the eNOS gene. Among them, the formed haplotype AG increased the risk of SLE compared to GG. AT and GT decreased the risk of SLE compared to GG. In this study, the eNOS gene rs3918188 and rs1799983 loci were found to be associated with susceptibility to SLE. This helps to deeply explore the mechanism of eNOS gene and genetic susceptibility to SLE. It provides a certain research basis for the subsequent exploration of the molecular mechanism of these loci and SLE, as well as the early diagnosis, treatment and prognosis of SLE.
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Predisposición Genética a la Enfermedad , Haplotipos , Lupus Eritematoso Sistémico , Óxido Nítrico Sintasa de Tipo III , Polimorfismo de Nucleótido Simple , Lupus Eritematoso Sistémico/genética , Humanos , China/epidemiología , Óxido Nítrico Sintasa de Tipo III/genética , Femenino , Masculino , Adulto , Persona de Mediana Edad , Genotipo , Alelos , Frecuencia de los Genes , Estudios de Casos y Controles , Desequilibrio de Ligamiento , Estudios de Asociación GenéticaRESUMEN
KEY MESSAGE: A GWAS in an elite diversity panel, evaluated across 10 environments, identified genomic regions regulating six fiber quality traits, facilitating genomics-assisted breeding and gene discovery in upland cotton. In this study, an elite diversity panel of 348 upland cotton accessions was evaluated in 10 environments across the US Cotton Belt and genotyped with the cottonSNP63K array, for a genome-wide association study of six fiber quality traits. All fiber quality traits, upper half mean length (UHML: mm), fiber strength (FS: g tex-1), fiber uniformity (FU: %), fiber elongation (FE: %), micronaire (MIC) and short fiber content (SFC: %), showed high broad-sense heritability (> 60%). All traits except FE showed high genomic heritability. UHML, FS and FU were all positively correlated with each other and negatively correlated with FE, MIC and SFC. GWAS of these six traits identified 380 significant marker-trait associations (MTAs) including 143 MTAs on 30 genomic regions. These 30 genomic regions included MTAs identified in at least three environments, and 23 of them were novel associations. Phenotypic variation explained for the MTAs in these 30 genomic regions ranged from 6.68 to 11.42%. Most of the fiber quality-associated genomic regions were mapped in the D-subgenome. Further, this study confirmed the pleiotropic region on chromosome D11 (UHML, FS and FU) and identified novel co-localized regions on D04 (FU, SFC), D05 (UHML, FU, and D06 UHML, FU). Marker haplotype analysis identified superior combinations of fiber quality-associated genomic regions with high trait values (UHML = 32.34 mm; FS = 32.73 g tex-1; FE = 6.75%). Genomic analyses of traits, haplotype combinations and candidate gene information described in the current study could help leverage genetic diversity for targeted genetic improvement and gene discovery for fiber quality traits in cotton.
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Fibra de Algodón , Genotipo , Gossypium , Fenotipo , Sitios de Carácter Cuantitativo , Gossypium/genética , Gossypium/crecimiento & desarrollo , Fibra de Algodón/análisis , Polimorfismo de Nucleótido Simple , Estudio de Asociación del Genoma Completo , Estudios de Asociación Genética , Desequilibrio de Ligamiento , Mapeo Cromosómico/métodos , Genoma de Planta , FitomejoramientoRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) are autoimmune diseases that often coexist clinically. This phenomenon might be due to shared genetic components. METHODS: Genome-wide association study (GWAS) data for IBD and SLE were analyzed to determine both global and local genetic correlations using three methodologies: linkage disequilibrium score regression (LDSC), genetic covariance analyzer (GNOVA), and SUPERGNOVA. The genetic overlap and risk loci were subsequently examined using the conditional/conjunctional false discovery rate (cond/conjFDR) statistical framework. Furthermore, a multi-trait analysis of MTAG was employed to validate the loci, followed by an LDSC analysis focusing on tissue-specific gene expression. RESULTS: GWAS findings demonstrated a marked global genetic correlation between IBD (including Crohn's disease and ulcerative colitis) and SLE. Locally, SLE showed a strong association with IBD and Crohn's disease on chromosomes 10, 19, and 22. ConjFDR analysis confirmed the genetic overlap and identified relevant genetic risk loci. MTAG further validated several shared susceptibility genes. Additionally, the LDSC-SEG analysis results indicate that IBD (including CD and UC) and SLE are jointly enriched in the tissues of Spleen and Whole Blood. CONCLUSION: This study confirms a genetic overlap between IBD and SLE, identifying marked comorbid genes and offering new insights for treating these diseases.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedades Inflamatorias del Intestino , Desequilibrio de Ligamiento , Lupus Eritematoso Sistémico , Lupus Eritematoso Sistémico/genética , Humanos , Enfermedades Inflamatorias del Intestino/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter CuantitativoRESUMEN
This study offers insights into the genetic and biological connections between nine common metabolic diseases using data from genome-wide association studies. Our goal is to unravel the genetic interactions and biological pathways of these complex diseases, enhancing our understanding of their genetic architecture. We employed a range of advanced analytical techniques to explore the genetic correlations and shared genetic variants of these diseases. These methods include Linked Disequilibrium Score Regression, High-Definition Likelihood (HDL), genetic analysis combining multiplicity and annotation (GPA), two-sample Mendelian randomization analyses, analysis under the multiplicity-complex null hypothesis (PLACO), and Functional mapping and annotation of genetic associations (FUMA). Additionally, Bayesian co-localization analyses were used to examine associations of specific loci across traits. Our study discovered significant genomic correlations and shared loci, indicating complex genetic interactions among these metabolic diseases. We found several shared single nucleotide variants and risk loci, notably highlighting the role of the immune system and endocrine pathways in these diseases. Particularly, rs2476601 and its associated gene PTPN22 appear to play a crucial role in the connection between type 2 diabetes mellitus, hypothyroidism/mucous oedema and hypoglycaemia. These findings enhance our understanding of the genetic underpinnings of these diseases and open new potential avenues for targeted therapeutic and preventive strategies. The results underscore the importance of considering pleiotropic effects in deciphering the genetic architecture of complex diseases, especially metabolic ones.
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Pleiotropía Genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Desequilibrio de Ligamiento , Enfermedades Metabólicas , Polimorfismo de Nucleótido Simple , Humanos , Enfermedades Metabólicas/genética , Polimorfismo de Nucleótido Simple/genética , Desequilibrio de Ligamiento/genética , Teorema de Bayes , Análisis de la Aleatorización Mendeliana , Diabetes Mellitus Tipo 2/genética , Epistasis GenéticaRESUMEN
Family-based genome-wide association studies (GWASs) are often claimed to provide an unbiased estimate of the average causal effects (or average treatment effects; ATEs) of alleles, on the basis of an analogy between the random transmission of alleles from parents to children and a randomized controlled trial. We show that this claim does not hold in general. Because Mendelian segregation only randomizes alleles among children of heterozygotes, the effects of alleles in the children of homozygotes are not observable. This feature will matter if an allele has different average effects in the children of homozygotes and heterozygotes, as can arise in the presence of gene-by-environment interactions, gene-by-gene interactions, or differences in linkage disequilibrium patterns. At a single locus, family-based GWAS can be thought of as providing an unbiased estimate of the average effect in the children of heterozygotes (i.e., a local average treatment effect; LATE). This interpretation does not extend to polygenic scores (PGSs), however, because different sets of SNPs are heterozygous in each family. Therefore, other than under specific conditions, the within-family regression slope of a PGS cannot be assumed to provide an unbiased estimate of the LATE for any subset or weighted average of families. In practice, the potential biases of a family-based GWAS are likely smaller than those that can arise from confounding in a standard, population-based GWAS, and so family studies remain important for the dissection of genetic contributions to phenotypic variation. Nonetheless, their causal interpretation is less straightforward than has been widely appreciated.
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Estudio de Asociación del Genoma Completo , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Humanos , Estudio de Asociación del Genoma Completo/métodos , Herencia Multifactorial/genética , Modelos Genéticos , Heterocigoto , Alelos , Homocigoto , Familia , Interacción Gen-AmbienteRESUMEN
Studies of bacterial adaptation and evolution are hampered by the difficulty of measuring traits such as virulence, drug resistance, and transmissibility in large populations. In contrast, it is now feasible to obtain high-quality complete assemblies of many bacterial genomes thanks to scalable high-accuracy long-read sequencing technologies. To exploit this opportunity, we introduce a phenotype- and alignment-free method for discovering coselected and epistatically interacting genomic variation from genome assemblies covering both core and accessory parts of genomes. Our approach uses a compact colored de Bruijn graph to approximate the intragenome distances between pairs of loci for a collection of bacterial genomes to account for the impacts of linkage disequilibrium (LD). We demonstrate the versatility of our approach to efficiently identify associations between loci linked with drug resistance and adaptation to the hospital niche in the major human bacterial pathogens Streptococcus pneumoniae and Enterococcus faecalis.
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Enterococcus faecalis , Epistasis Genética , Genoma Bacteriano , Streptococcus pneumoniae , Streptococcus pneumoniae/genética , Enterococcus faecalis/genética , Desequilibrio de Ligamiento , Humanos , Genómica/métodosRESUMEN
Background: Temporomandibular joint disorders (TMD) are highly prevalent among people. Numerous investigations have revealed the impact of gut microbiota in many diseases. However, the causal relationship between Temporomandibular joint disorders and gut microbiota remains unclear. Methods: Genome-Wide Association Studies (GWAS) refer to the identification of sequence variations, namely single nucleotide polymorphisms (SNPs), existing across the entire human genome. GWAS data were collected on gut microbiota and TMD. Then, instrumental variables were screened through F-values and removal of linkage disequilibrium. These SNPs underwent mendelian analysis using five mathematical models. Sensitivity analysis was conducted to further verify the stability of the results. Pathogenic factors of TMD mediate the causal relationship between gut microbiota and TMD were explored through a two-step Mendelian randomization analysis. Finally, reverse mendelian analysis was conducted to account for potential reverse effects. Results: The analysis of the data in this article suggests that some gut microbiota, including Coprobacter, Ruminococcus torques group, Catenibacterium, Lachnospiraceae, Turicibacter, Victivallis, MollicutesRF9, Methanobacteriales, Methanobacteriaceae, FamilyXI, Methanobacteria were identified as risk factors, while Peptococcaceae provides protection for TMD. Conclusion: The research reveals the relation of gut microbiota in TMD. These findings provide insights into the underlying mechanisms and suggest potential therapeutic strategy.
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Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Trastornos de la Articulación Temporomandibular , Humanos , Microbioma Gastrointestinal/genética , Trastornos de la Articulación Temporomandibular/microbiología , Trastornos de la Articulación Temporomandibular/genética , Desequilibrio de Ligamiento , Bacterias/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación , Predisposición Genética a la EnfermedadRESUMEN
Genome-wide association studies (GWAS) implicate broad genomic loci containing clusters of highly correlated genetic variants. Finemapping techniques can select and prioritize variants within each GWAS locus which are more likely to have a functional influence on the trait. Here, we present a novel method, Finemap-MiXeR, for finemapping causal variants from GWAS summary statistics, controlling for correlation among variants due to linkage disequilibrium. Our method is based on a variational Bayesian approach and direct optimization of the Evidence Lower Bound (ELBO) of the likelihood function derived from the MiXeR model. After obtaining the analytical expression for ELBO's gradient, we apply Adaptive Moment Estimation (ADAM) algorithm for optimization, allowing us to obtain the posterior causal probability of each variant. Using these posterior causal probabilities, we validated Finemap-MiXeR across a wide range of scenarios using both synthetic data, and real data on height from the UK Biobank. Comparison of Finemap-MiXeR with two existing methods, FINEMAP and SuSiE RSS, demonstrated similar or improved accuracy. Furthermore, our method is computationally efficient in several aspects. For example, unlike many other methods in the literature, its computational complexity does not increase with the number of true causal variants in a locus and it does not require any matrix inversion operation. The mathematical framework of Finemap-MiXeR is flexible and may also be applied to other problems including cross-trait and cross-ancestry finemapping.
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Algoritmos , Teorema de Bayes , Estudio de Asociación del Genoma Completo , Desequilibrio de Ligamiento , Estudio de Asociación del Genoma Completo/métodos , Humanos , Polimorfismo de Nucleótido Simple/genética , Modelos Genéticos , Sitios de Carácter CuantitativoRESUMEN
BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is a complex autoimmune disease and the most common chronic rheumatological disease affecting children under the age of 16. The etiology of JIA remains poorly understood, but evidence suggests a significant genetic predisposition. METHODS: We analyzed a Swedish cohort of 329 JIA patients and 728 healthy adult controls using the Illumina OmniExpress array for genotyping. HLA alleles were imputed from GWAS data using the SNP2HLA algorithm. RESULTS: Case-control analysis yielded 12 SNPs with genome-wide significant association to JIA, all located on chromosome 6 within the MHC class II gene region. Notably, the top SNP (rs28421666) was located adjacent to HLA-DQA1 and HLA-DRB1. HLA-DRB1*08:01, HLA-DQA1*04:01, and HLA-DQB1*04:02 were the haplotypes most strongly associated with an increased risk of JIA in the overall cohort. When analyzing disease specific subtypes, these alleles were associated with oligoarthritis and RF-negative polyarthritis. Within the complex linkage disequilibrium of the HLA-DRB1-DQA1-DQB1 haplotype, our analysis suggests that HLA-DRB1*08 might be the primary allele linked to JIA susceptibility. The HLA-DRB1*11 allele group was also independently associated with JIA and specifically enriched in the oligoarthritis patient group. Additionally, our study revealed a significant correlation between antinuclear antibody (ANA) positivity and specific HLA alleles. The ANA-positive JIA group showed stronger associations with the HLA-DRB1-DQA1-DQB1 haplotype, HLA-DRB1*11, and HLA-DPB1*02, suggesting a potential connection between genetic factors and ANA production in JIA. Furthermore, logistic regression analysis reaffirmed the effects of HLA alleles, female sex, and lower age at onset on ANA positivity. CONCLUSIONS: This study identified distinct genetic associations between HLA alleles and JIA subtypes, particularly in ANA-positive patients. These findings contribute to a better understanding of the genetic basis of JIA and provide insights into the genetic control of autoantibody production in ANA-positive JIA patients. This may inform future classification and personalized treatment approaches for JIA, ultimately improving patient outcomes and management of this disease.
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Anticuerpos Antinucleares , Artritis Juvenil , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Humanos , Artritis Juvenil/genética , Artritis Juvenil/inmunología , Suecia , Masculino , Femenino , Anticuerpos Antinucleares/sangre , Adolescente , Niño , Estudios de Casos y Controles , Estudios de Cohortes , Alelos , Haplotipos , Adulto , Estudio de Asociación del Genoma Completo , Genotipo , Cadenas alfa de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Preescolar , Desequilibrio de LigamientoRESUMEN
B cells are adaptive immune cells in the tumor microenvironment and play an important role in tumor development and metastasis. However, the roles of genetic variants of the immunity B cell-related genes in the survival of patients with non-small cell lung cancer (NSCLC) remain unknown. In the present study, we first evaluated associations between 10,776 single nucleotide polymorphisms (SNPs) in 220 immunity B cell-related genes and survival of NSCLC in a discovery dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that 369 SNPs were significantly associated with overall survival (OS) of NSCLC in multivariable Cox proportional hazards regression analysis (P ≤ 0.05, Bayesian false discovery probability ≤ 0.80), of which 18 SNPs were validated in another independent genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. We then performed linkage disequilibrium (LD) analysis, followed by stepwise analysis with a multivariable Cox regression model. Finally, two independent SNPs, inositol polyphosphate-5-phosphatase D (INPP5D) rs13385922 C>T and exosome component 3 (EXOSC3) rs3208406 A>G, remained significantly associated withNSCLC OS with a combined hazards ratio (HR) of 1.14 (95% confidence interval = 1.06-1.23, P = 2.41×10-4) and 1.20 (95% confidence interval = 1.14-1.28, P = 3.41×10-9), respectively. Furthermore, NSCLC patients with the combination of unfavorable genotypes for these two SNPs were associated with a poor OS (P trend = 0.0002) and disease-specific survival (DSS, P trend < 0.0001) in the PLCO dataset. Expression quantitative trait loci (eQTL) analysis suggested that the INPP5D rs6782875 T allele was significantly correlated with elevated INPP5D mRNA expression levels in normal lung tissues and whole blood samples, while the EXOSC3 rs3208406 G allele was significantly correlated with increased EXOSC3 mRNA expression levels in normal lung tissues. Our data indicated that genetic variants in these immunity B cell-related genes may predict NSCLC survival possibly by influencing the gene expression.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Polimorfismo de Nucleótido Simple , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/inmunología , Masculino , Femenino , Persona de Mediana Edad , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/genética , Anciano , Linfocitos B/inmunología , Predisposición Genética a la Enfermedad , Desequilibrio de Ligamiento , Pronóstico , Genotipo , Monoéster Fosfórico Hidrolasas/genéticaRESUMEN
Carcinogenesis is closely related to the expression, maintenance, and stability of DNA. These processes are regulated by one-carbon metabolism (1CM), which involves several vitamins of the complex B (folate, B2, B6, and B12), whereas alcohol disrupts the cycle due to the inhibition of folate activity. The relationship between nutrients related to 1CM (all aforementioned vitamins and alcohol) in breast cancer has been reviewed. The interplay of genes related to 1CM was also analyzed. Single nucleotide polymorphisms located in those genes were selected by considering the minor allele frequency in the Caucasian population and the linkage disequilibrium. These genes were used to perform several in silico functional analyses (considering corrected p-values < 0.05 as statistically significant) using various tools (FUMA, ShinyGO, and REVIGO) and databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneOntology (GO). The results of this study showed that intake of 1CM-related B-complex vitamins is key to preventing breast cancer development and survival. Also, the genes involved in 1CM are overexpressed in mammary breast tissue and participate in a wide variety of biological phenomena related to cancer. Moreover, these genes are involved in alterations that give rise to several types of neoplasms, including breast cancer. Thus, this study supports the role of one-carbon metabolism B-complex vitamins and genes in breast cancer; the interaction between both should be addressed in future studies.
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Neoplasias de la Mama , Carbono , Polimorfismo de Nucleótido Simple , Complejo Vitamínico B , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Complejo Vitamínico B/metabolismo , Carbono/metabolismo , Ácido Fólico/metabolismo , Bases de Datos Genéticas , Simulación por Computador , Regulación Neoplásica de la Expresión Génica , Vitamina B 6/metabolismo , Desequilibrio de LigamientoRESUMEN
Methyltransferase-like 23 (METTL23) is a kind of RNA methyltransferase that catalyzes the methylation transfer to the N6-adenosine of RNA, serving as one of the key mediators in this process. However, the METTL23 gene has been poorly researched in pigs. In this study, we investigated the genetic effects of METTL23 single-nucleotide polymorphism(SNPs) on reproductive traits in Kele pigs. The DNA was extracted from 228 healthy multiparous Kele sows, and Sanger sequencing revealed three SNPs, g.4804958 G > T (intron 2), g.4805082 C > T (exon 2), and g.4806821 A > G (exon 3). The polymorphism information content (PIC) for each SNP was 0.264, 0.25, and 0.354, indicating moderate polymorphism (0.25 < PIC < 0.5) and providing genetic information. Linkage disequilibrium analysis showed no strong linkage disequilibrium between the three SNPs. The association analysis revealed that in the SNP g.4804958 G > T individuals with the GG genotype had a significantly higher number of piglets born alive, litter birth weight, number of weaned piglets, and weaning litter weight compared to those with the TT genotype (p < 0.05). Individuals with the GG genotype in the SNP g.4806821 A > G group had significantly higher litter birth weight and average birth weight than those with the AA genotype (p < 0.05). The H4H4 diplotype showed significant effects on the number of piglets born alive, litter birth weight, number of weaned piglets, weaning litter weight, and weaning weight (p < 0.05). Together, the METTL23 gene could be used as a candidate gene for the selection of reproductive traits in Kele pigs.
Asunto(s)
Metiltransferasas , Polimorfismo de Nucleótido Simple , Reproducción , Animales , Metiltransferasas/genética , Porcinos/genética , Reproducción/genética , Femenino , Desequilibrio de Ligamiento , Tamaño de la Camada/genética , Genotipo , Peso al Nacer/genética , Estudios de Asociación GenéticaRESUMEN
Portability of trans-ancestral polygenic risk scores is often confounded by differences in linkage disequilibrium and genetic architecture between ancestries. Recent literature has shown that prioritizing GWAS SNPs with functional genomic evidence over strong association signals can improve model portability. We leveraged three RegulomeDB-derived functional regulatory annotations-SURF, TURF, and TLand-to construct polygenic risk models across a set of quantitative and binary traits highlighting functional mutations tagged by trait-associated tissue annotations. Tissue-specific prioritization by TURF and TLand provide a significant improvement in model accuracy over standard polygenic risk score (PRS) models across all traits. We developed the Trans-ancestral Iterative Tissue Refinement (TITR) algorithm to construct PRS models that prioritize functional mutations across multiple trait-implicated tissues. TITR-constructed PRS models show increased predictive accuracy over single tissue prioritization. This indicates our TITR approach captures a more comprehensive view of regulatory systems across implicated tissues that contribute to variance in trait expression.
Asunto(s)
Algoritmos , Puntuación de Riesgo Genético , Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Humanos , Estudio de Asociación del Genoma Completo/métodos , Genómica/métodos , Desequilibrio de Ligamiento , Modelos Genéticos , Herencia Multifactorial/genética , Especificidad de Órganos/genética , Fenotipo , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Fusarium head blight (FHB) is a major disease of wheat and barley worldwide and is caused by different species in the genus Fusarium, Fusarium graminearum being the most important. We conducted population genomics analyses using SNPs obtained through genotyping by sequencing of over 500 isolates of F. graminearum from the US Upper Midwest, New York, Louisiana, and Uruguay. PCA and STRUCTURE analyses group our isolates into four previously described populations: NA1, NA2, Southern Louisiana (SLA) and Gulf Coast (GC). Some isolates were not assigned to populations because of mixed ancestry. Population structure was associated with toxin genotype and geographic origin. The NA1, NA2, and SLA populations are differentiated (FST 0.385 - 0.551) but the presence of admixed isolates indicates that the populations are not reproductively isolated. Patterns of linkage disequilibrium (LD) decay suggest frequent recombination within populations. Fusarium graminearum populations from the US have great evolutionary potential given the high recombination rate and a large proportion of admixed isolates. The NA1, NA2, and Southern Louisiana (SLA) populations separated from their common ancestral population roughly at the same time in the past and are evolving with moderate levels of subsequent gene flow between them. Genome-wide selection scans in all three populations revealed outlier regions with the strongest signatures of recent positive natural selection. These outlier regions include many genes with unknown function and some genes with known roles in plant-microbe interaction, fungicide/drug resistance, cellular transport and genes that are related to cellular organelles. Only a very small proportion of outlier regions are shared as outliers among the three populations, suggesting unique host-pathogen interactions and environmental adaptation.
Asunto(s)
Fusarium , Desequilibrio de Ligamiento , Enfermedades de las Plantas , Polimorfismo de Nucleótido Simple , Fusarium/genética , Fusarium/clasificación , Fusarium/aislamiento & purificación , Enfermedades de las Plantas/microbiología , Polimorfismo de Nucleótido Simple/genética , Triticum/microbiología , Genoma Fúngico/genética , Américas , Genotipo , Genómica , Metagenómica , Hordeum/microbiología , UruguayRESUMEN
This study describes a compact method for determining joint probabilities of identity-by-state (IBS) within and between loci in populations evolving under genetic drift, crossing-over, mutation, and regular inbreeding (partial self-fertilization). Analogues of classical indices of associations among loci arise as functions of these joint identities. This coalescence-based analysis indicates that multi-locus associations reflect simultaneous coalescence events across loci. Measures of association depend on genetic diversity rather than allelic frequencies, as do linkage disequilibrium and its relatives. Scaled indices designed to show monotonic dependence on rates of crossing-over, inbreeding, and mutation may prove useful for interpreting patterns of genome-scale variation.
Asunto(s)
Endogamia , Mutación , Desequilibrio de Ligamiento , Modelos Genéticos , Frecuencia de los Genes , Genética de Población , Flujo Genético , Variación Genética , Sitios Genéticos , HumanosRESUMEN
Genome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European ancestry has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries. Here we present SuSiEx, an accurate and computationally efficient method for cross-population fine-mapping. SuSiEx integrates data from an arbitrary number of ancestries, explicitly models population-specific allele frequencies and linkage disequilibrium patterns, accounts for multiple causal variants in a genomic region and can be applied to GWAS summary statistics. We comprehensively assessed the performance of SuSiEx using simulations. We further showed that SuSiEx improves the fine-mapping of a range of quantitative traits available in both the UK Biobank and Taiwan Biobank, and improves the fine-mapping of schizophrenia-associated loci by integrating GWAS across East Asian and European ancestries.