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1.
Med Sci Monit ; 26: e921133, 2020 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-32199022

RESUMEN

BACKGROUND Alternative splicing (AS), the mechanism underlying the occurrence of protein diversity, may result in cancer genesis and development when it becomes out of control, as suggested by a growing number of studies. However, systemically analyze of AS events at the genome-wide level for skin cutaneous melanoma (SKCM) is still in a preliminary phase. This study aimed to systemically analyze the bioinformatics of the AS events at a genome-wide level using The Cancer Genome Atlas (TCGA) SKCM data. MATERIAL AND METHODS The SpliceSeq tool was used to analyze the AS profiles for SKCM clinical specimens from the TCGA database. The association between AS events and overall survival was analyzed by Cox regression analysis. AS event intersections and a gene interaction network were established by UpSet plot. A multivariate survival model was used to establish a feature genes prognosis model. RESULTS A total of 103 SKCM patients with full clinical parameters available were included in this study. We established an AS network that investigated the relationship between AS events and clinical prognosis information. Furthermore, 4 underlying feature genes of SKCM (MCF2L, HARS, TFR2, and RALGPS1) were found in the AS network. We performed function analysis as well as correlation analysis of AS events with gene expression. Using the multivariate survival model, we further confirmed the 4 genes that impacted the classifying SKCM prognosis at the level of AS events as well as gene expression, especially in wild-type SKCM. CONCLUSIONS AS events could be ideal indicators for SKCM prognosis. The key feature gene MCF2L played an important role in wild-type SKCM.


Asunto(s)
Empalme Alternativo , Melanoma/genética , Neoplasias Cutáneas/genética , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias , Estudio de Asociación del Genoma Completo , Humanos , Melanoma/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Secuencia de ARN , Neoplasias Cutáneas/mortalidad
2.
Science ; 367(6484)2020 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-32193296

RESUMEN

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.


Asunto(s)
Corteza Cerebral/anatomía & histología , Variación Genética , Trastorno por Déficit de Atención con Hiperactividad/genética , Mapeo Encefálico , Cognición , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Imagen por Resonancia Magnética , Tamaño de los Órganos/genética , Enfermedad de Parkinson/genética
3.
Community Dent Health ; 37(1): 102-106, 2020 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-32031351

RESUMEN

Evidence regarding the genomic basis of oral/dental traits and diseases is a fundamental pillar of the emerging notion of precision health. During the last decade, technological advances have improved the feasibility and affordability of conducting genome-wide association studies (GWAS) and studying the associations of emanating data with both common and rare oral conditions. Most evidence thus far emanates from GWAS of dental caries and periodontal disease that have tested the associations of several million single nucleotide polymorphisms (SNPs) with typically binary, health vs. disease phenotypes. GWAS offer advantages over the previous candidate-gene studies, mainly owing to their agnostic (i.e., unbiased, or hypothesis-free) nature. Nevertheless, GWAS are prone to virtually all sources of random and systematic error. Here, we review common sources of bias in genomics research with focus on GWAS including: type I and II errors, population stratification and heterogeneity, selection bias, adjustment for heritable covariates, appropriate reference panels for imputation, and gene annotation. We argue that valid and precise phenotype measurement is a key requirement, as GWAS sample sizes and thus statistical power increase. Finally, we stress that the lack of diversity of populations with phenotypes and genotypes is a major limitation for the generalizability and ultimate translation of the emerging genomics evidence-base into oral health promotion for all.


Asunto(s)
Sesgo , Caries Dental , Estudio de Asociación del Genoma Completo , Interpretación Estadística de Datos , Genómica , Genotipo , Humanos , Fenotipo
4.
Medicine (Baltimore) ; 99(3): e18398, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32011434

RESUMEN

BACKGROUND: Recently, several genome-wide association studies have demonstrated a cumulative association of 17q24 rs1859962 gene variants with prostate cancer (PCa) risk, but conflicting results on this issue have been reported. Hence, we performed a systematic literature review and meta-analysis to assess the association between 17q24 rs1859962 gene and PCa risk. METHODS: Systematic literature searches were conducted with PubMed, EMBASE, Science Direct/Elsevier, CNKI, and the Cochrane Library up to January 2019 for studies focusing on the association of 17q24 rs1859962 gene polymorphism with PCa risk. Meta-analysis was performed with Review Manager and stata software. Combined OR were identified with 95% confidence intervals (95% CI) in a random or fixed effects model. RESULTS: Eight studies were identified, including 7863 cases of PCa patients and 17122 normal controls. Our results revealed significant associations between the 17q24 rs1859962 gene polymorphism and PCa in all genetic models (P < 0.05). The combined odds ratios and 95% confidence intervals were as follows: Additive model (odds ratios [ORs] 1.44, 95%, confidence interval [CI] [1.32, 1.57]); Codominant model (ORs 1.22, 95% CI [1.08, 1.39]); Dominant model (ORs 1.25, 95%, CI [1.17, 1.34]); recessive model (ORs 1.27, 95% CI [1.18, 1.36]); allele model (ORs 1.32, 95% CI [1.12, 1.55]). CONCLUSION: The present study supports the proposed association between the 17q24 gene rs1859962 and PCa progression. Specifically, this polymorphism is suggested to be a risk factor of PCa. However, studies with larger sample sizes are needed to better illuminate the correlation between 17q24 rs1859962 gene polymorphism and PCa.


Asunto(s)
Neoplasias de la Próstata/genética , Alelos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Proyectos de Investigación , Factores de Riesgo
5.
Nat Ecol Evol ; 4(3): 334-345, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32094539

RESUMEN

Steppe-pastoralist-related ancestry reached Central Europe by at least 2500 BC, whereas Iranian farmer-related ancestry was present in Aegean Europe by at least 1900 BC. However, the spread of these ancestries into the western Mediterranean, where they have contributed to many populations that live today, remains poorly understood. Here, we generated genome-wide ancient-DNA data from the Balearic Islands, Sicily and Sardinia, increasing the number of individuals with reported data from 5 to 66. The oldest individual from the Balearic Islands (~2400 BC) carried ancestry from steppe pastoralists that probably derived from west-to-east migration from Iberia, although two later Balearic individuals had less ancestry from steppe pastoralists. In Sicily, steppe pastoralist ancestry arrived by ~2200 BC, in part from Iberia; Iranian-related ancestry arrived by the mid-second millennium BC, contemporary to its previously documented spread to the Aegean; and there was large-scale population replacement after the Bronze Age. In Sardinia, nearly all ancestry derived from the island's early farmers until the first millennium BC, with the exception of an outlier from the third millennium BC, who had primarily North African ancestry and who-along with an approximately contemporary Iberian-documents widespread Africa-to-Europe gene flow in the Chalcolithic. Major immigration into Sardinia began in the first millennium BC and, at present, no more than 56-62% of Sardinian ancestry is from its first farmers. This value is lower than previous estimates, highlighting that Sardinia, similar to every other region in Europe, has been a stage for major movement and mixtures of people.


Asunto(s)
Agricultura , ADN Antiguo , Estudio de Asociación del Genoma Completo , África , Antropología , Emigración e Inmigración , Europa (Continente) , Humanos , Irán , Islas , Sicilia , España
6.
Hum Genet ; 139(4): 421-446, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32020362

RESUMEN

Y chromosome (ChrY), the male-specific sex chromosome, has been considered as a genetic wasteland. Aging-related mosaic loss of ChrY (LOY) has been known for more than half a century, but it was constantly considered as a neutral karyotype related to normal aging. These views have been challenged with genome-wide association studies identifying mosaic LOY in human somatic cells is the most commonly acquired mutation in male's genome and is associated with a wide spectrum of human diseases including cancer, Alzheimer's disease, and cardiovascular disease. These previously undescribed clinical significances deeply modify our perception on ChrY and open up a range of new questions. Here, we review the latest advances in our knowledge of the biological origins and clinical consequences of mosaic LOY. We highlight the association of mosaic LOY to pathogenic conditions and evaluate the cause-and-consequence relationships between mosaic LOY and pathogenesis. The known risk factors of mosaic LOY including age, genetic variants, ChrY structural aberrations and environmental stressors are discussed. In light of evidence from pioneering and more recent studies, we propose the micronucleation hypothesis and centromere-dysfunction and telomere-attrition models to explain how mosaic LOY occurs and why ChrY is prone to lose. We believe it is importantly and timely to extend mosaic LOY research from epidemiological associations to mechanistic studies. In this regard, we outline important gaps and assess several future directions from a biological and clinical perspective. An improved understanding of mosaic LOY will open new pathways to modify and increase healthy aging in males.


Asunto(s)
Enfermedad de Alzheimer , Enfermedades Cardiovasculares , Cromosomas Humanos Y , Mosaicismo , Neoplasias , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Cromosomas Humanos Y/genética , Cromosomas Humanos Y/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Neoplasias/genética , Neoplasias/metabolismo
7.
Gene ; 736: 144422, 2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32007584

RESUMEN

Late embryogenesis abundant (LEA) proteins are involved in plant stress responses and osmotic regulation, and they are accumulated in the late embryonic stage. There have been no previous genome-wide analyses of the LEA gene family members in wheat and its close relatives. In this study, 281, 53, 151, 89, 99, and 99 LEA genes were identified in wheat (Triticum aestivum), Triticum urartu, Triticum dicoccoides, Aegilops tauschii, barley, and Brachypodium distachyon, respectively. The wheat LEA gene family (TaLEA genes) was divided into eight subfamilies according to the conserved domains. All TaLEA genes contain very few introns (<3) and they are unevenly distributed on the 21 chromosomes. We identified 39 pairs of tandem duplication genes and 9 pairs of segmental duplication genes in the wheat LEA gene family. This proved that the tandem duplication and segmental duplication played an important role in the expansion of the TaLEA gene family. According to published transcriptome data and qRT-PCR analysis, the TaLEA genes exhibit different tissue expression patterns and they are regulated by various abiotic stresses, especially salt and cold stress. This study provides a comprehensive understanding of the wheat LEA gene family.


Asunto(s)
Regulación de la Expresión Génica de las Plantas/genética , Proteínas de Plantas/genética , Estrés Fisiológico/genética , Triticum/genética , Mapeo Cromosómico/métodos , Cromosomas de las Plantas/genética , Perfilación de la Expresión Génica/métodos , Genoma de Planta/genética , Estudio de Asociación del Genoma Completo/métodos , Filogenia , Transcriptoma/genética
8.
Gene ; 736: 144412, 2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32007586

RESUMEN

The emergence of somaclonal variability in in vitro cultures is undesirable during micropropagation, but this phenomenon may be a source of genetic variability sought by breeders. The main factors that affect the appearance of variability are known, but the exact mechanism has not yet been determined. In this paper, we used next-generation sequencing and comparative genomics to study changes in the genomes of cucumber lines resulting from in vitro regeneration and somaclonal mutation in comparison to a reference, the highly inbred B10 line. The total number of obtained polymorphisms differed between the three somaclonal lines S1, S2 and S3, with 8369, 7591 and 44510, respectively. Polymorphisms occurred most frequently in non-coding regions and were mainly SNPs. High-impact changes accounted for 1%-3% of all polymorphisms and most often caused an open reading frame shift. Functional analysis of genes affected by high impact variants showed that they were related to transport, biosynthetic processes, nucleotide-containing compounds and cellular protein modification processes. The obtained results indicated significant factors affecting somaclonal variability and the appearance of changes in the genome, and demonstrated a lack of dependence between phenotype and the number of genomic polymorphisms.


Asunto(s)
Cucumis sativus/genética , ADN/genética , Genoma de Planta/genética , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Estudio de Asociación del Genoma Completo , Genómica/métodos , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Sistemas de Lectura Abierta/genética , Fenotipo , Análisis de Secuencia de ADN/métodos
9.
JAMA ; 323(7): 627-635, 2020 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-32068817

RESUMEN

Importance: Polygenic risk scores comprising millions of single-nucleotide polymorphisms (SNPs) could be useful for population-wide coronary heart disease (CHD) screening. Objective: To determine whether a polygenic risk score improves prediction of CHD compared with a guideline-recommended clinical risk equation. Design, Setting, and Participants: A retrospective cohort study of the predictive accuracy of a previously validated polygenic risk score was assessed among 4847 adults of white European ancestry, aged 45 through 79 years, participating in the Atherosclerosis Risk in Communities (ARIC) study and 2390 participating in the Multi-Ethnic Study of Atherosclerosis (MESA) from 1996 through December 31, 2015, the final day of follow-up. The performance of the polygenic risk score was compared with that of the 2013 American College of Cardiology and American Heart Association pooled cohort equations. Exposures: Genetic risk was computed for each participant by summing the product of the weights and allele dosage across 6 630 149 SNPs. Weights were based on an international genome-wide association study. Main Outcomes and Measures: Prediction of 10-year first CHD events (including myocardial infarctions, fatal coronary events, silent infarctions, revascularization procedures, or resuscitated cardiac arrest) assessed using measures of model discrimination, calibration, and net reclassification improvement (NRI). Results: The study population included 4847 adults from the ARIC study (mean [SD] age, 62.9 [5.6] years; 56.4% women) and 2390 adults from the MESA cohort (mean [SD] age, 61.8 [9.6] years; 52.2% women). Incident CHD events occurred in 696 participants (14.4%) and 227 participants (9.5%), respectively, over median follow-up of 15.5 years (interquartile range [IQR], 6.3 years) and 14.2 (IQR, 2.5 years) years. The polygenic risk score was significantly associated with 10-year CHD incidence in ARIC with hazard ratios per SD increment of 1.24 (95% CI, 1.15 to 1.34) and in MESA, 1.38 (95% CI, 1.21 to 1.58). Addition of the polygenic risk score to the pooled cohort equations did not significantly increase the C statistic in either cohort (ARIC, change in C statistic, -0.001; 95% CI, -0.009 to 0.006; MESA, 0.021; 95% CI, -0.0004 to 0.043). At the 10-year risk threshold of 7.5%, the addition of the polygenic risk score to the pooled cohort equations did not provide significant improvement in reclassification in either ARIC (NRI, 0.018, 95% CI, -0.012 to 0.036) or MESA (NRI, 0.001, 95% CI, -0.038 to 0.076). The polygenic risk score did not significantly improve calibration in either cohort. Conclusions and Relevance: In this analysis of 2 cohorts of US adults, the polygenic risk score was associated with incident coronary heart disease events but did not significantly improve discrimination, calibration, or risk reclassification compared with conventional predictors. These findings suggest that a polygenic risk score may not enhance risk prediction in a general, white middle-aged population.


Asunto(s)
Enfermedad Coronaria/genética , Predisposición Genética a la Enfermedad , Herencia Multifactorial , Medición de Riesgo/métodos , Anciano , Estudios de Cohortes , Enfermedad Coronaria/epidemiología , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Oportunidad Relativa , Fenotipo , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Riesgo
10.
JAMA ; 323(7): 636-645, 2020 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-32068818

RESUMEN

Importance: The incremental value of polygenic risk scores in addition to well-established risk prediction models for coronary artery disease (CAD) is uncertain. Objective: To examine whether a polygenic risk score for CAD improves risk prediction beyond pooled cohort equations. Design, Setting, and Participants: Observational study of UK Biobank participants enrolled from 2006 to 2010. A case-control sample of 15 947 prevalent CAD cases and equal number of age and sex frequency-matched controls was used to optimize the predictive performance of a polygenic risk score for CAD based on summary statistics from published genome-wide association studies. A separate cohort of 352 660 individuals (with follow-up to 2017) was used to evaluate the predictive accuracy of the polygenic risk score, pooled cohort equations, and both combined for incident CAD. Exposures: Polygenic risk score for CAD, pooled cohort equations, and both combined. Main Outcomes and Measures: CAD (myocardial infarction and its related sequelae). Discrimination, calibration, and reclassification using a risk threshold of 7.5% were assessed. Results: In the cohort of 352 660 participants (mean age, 55.9 years; 205 297 women [58.2%]) used to evaluate the predictive accuracy of the examined models, there were 6272 incident CAD events over a median of 8 years of follow-up. CAD discrimination for polygenic risk score, pooled cohort equations, and both combined resulted in C statistics of 0.61 (95% CI, 0.60 to 0.62), 0.76 (95% CI, 0.75 to 0.77), and 0.78 (95% CI, 0.77 to 0.79), respectively. The change in C statistic between the latter 2 models was 0.02 (95% CI, 0.01 to 0.03). Calibration of the models showed overestimation of risk by pooled cohort equations, which was corrected after recalibration. Using a risk threshold of 7.5%, addition of the polygenic risk score to pooled cohort equations resulted in a net reclassification improvement of 4.4% (95% CI, 3.5% to 5.3%) for cases and -0.4% (95% CI, -0.5% to -0.4%) for noncases (overall net reclassification improvement, 4.0% [95% CI, 3.1% to 4.9%]). Conclusions and Relevance: The addition of a polygenic risk score for CAD to pooled cohort equations was associated with a statistically significant, yet modest, improvement in the predictive accuracy for incident CAD and improved risk stratification for only a small proportion of individuals. The use of genetic information over the pooled cohort equations model warrants further investigation before clinical implementation.


Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad , Herencia Multifactorial , Medición de Riesgo/métodos , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Riesgo
11.
Nat Commun ; 11(1): 164, 2020 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-31919360

RESUMEN

Host dependency factors that are required for influenza A virus infection may serve as therapeutic targets as the virus is less likely to bypass them under drug-mediated selection pressure. Previous attempts to identify host factors have produced largely divergent results, with few overlapping hits across different studies. Here, we perform a genome-wide CRISPR/Cas9 screen and devise a new approach, meta-analysis by information content (MAIC) to systematically combine our results with prior evidence for influenza host factors. MAIC out-performs other meta-analysis methods when using our CRISPR screen as validation data. We validate the host factors, WDR7, CCDC115 and TMEM199, demonstrating that these genes are essential for viral entry and regulation of V-type ATPase assembly. We also find that CMTR1, a human mRNA cap methyltransferase, is required for efficient viral cap snatching and regulation of a cell autonomous immune response, and provides synergistic protection with the influenza endonuclease inhibitor Xofluza.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Interacciones Huésped-Patógeno/genética , Virus de la Influenza A/patogenicidad , Gripe Humana/genética , Gripe Humana/patología , Células A549 , Proteínas Adaptadoras Transductoras de Señales/genética , Antivirales/farmacología , Sistemas CRISPR-Cas , Línea Celular , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Estudio de Asociación del Genoma Completo , Humanos , Proteínas de la Membrana/genética , Metiltransferasas/metabolismo , Proteínas del Tejido Nervioso/genética , Oxazinas/farmacología , Piridinas/farmacología , Tiepinas/farmacología , Triazinas/farmacología , ATPasas de Translocación de Protón Vacuolares/metabolismo , Internalización del Virus
12.
Nat Commun ; 11(1): 163, 2020 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-31919418

RESUMEN

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.


Asunto(s)
Fibrilación Atrial/genética , Cardiomiopatías/genética , Enfermedad de la Arteria Coronaria/genética , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Función Ventricular Izquierda/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genética , Cardiomiopatías/patología , Proteínas Portadoras/genética , Estudios de Casos y Controles , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Proteínas de Microfilamentos/genética , Proteínas Musculares/genética , Factores de Riesgo
13.
Nat Commun ; 11(1): 542, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31992710

RESUMEN

Understanding the impact of rare variants is essential to understanding human health. We analyze rare (MAF < 0.1%) variants against 4264 phenotypes in 49,960 exome-sequenced individuals from the UK Biobank and 1934 phenotypes (1821 overlapping with UK Biobank) in 21,866 members of the Healthy Nevada Project (HNP) cohort who underwent Exome + sequencing at Helix. After using our rare-variant-tailored methodology to reduce test statistic inflation, we identify 64 statistically significant gene-based associations in our meta-analysis of the two cohorts and 37 for phenotypes available in only one cohort. Singletons make significant contributions to our results, and the vast majority of the associations could not have been identified with a genotyping chip. Our results are available for interactive browsing in a webapp (https://ukb.research.helix.com). This comprehensive analysis illustrates the biological value of large, deeply phenotyped cohorts of unselected populations coupled with NGS data.


Asunto(s)
Exoma/genética , Variación Genética , Genoma Humano , Estudio de Asociación del Genoma Completo , Fenotipo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Bases de Datos Genéticas , Europa (Continente) , Femenino , Genética de Población/estadística & datos numéricos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Programas Informáticos , Secuenciación del Exoma Completo , Adulto Joven
14.
BMC Bioinformatics ; 21(1): 14, 2020 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-31924160

RESUMEN

BACKGROUND: Linkage disequilibrium (LD)-the non-random association of alleles at different loci-defines population-specific haplotypes which vary by genomic ancestry. Assessment of allelic frequencies and LD patterns from a variety of ancestral populations enables researchers to better understand population histories as well as improve genetic understanding of diseases in which risk varies by ethnicity. RESULTS: We created an interactive web module which allows for quick geographic visualization of linkage disequilibrium (LD) patterns between two user-specified germline variants across geographic populations included in the 1000 Genomes Project. Interactive maps and a downloadable, sortable summary table allow researchers to easily compute and compare allele frequencies and LD statistics of dbSNP catalogued variants. The geographic mapping of each SNP's allele frequencies by population as well as visualization of LD statistics allows the user to easily trace geographic allelic correlation patterns and examine population-specific differences. CONCLUSIONS: LDpop is a free and publicly available cross-platform web tool which can be accessed online at https://ldlink.nci.nih.gov/?tab=ldpop.


Asunto(s)
Estudio de Asociación del Genoma Completo , Desequilibrio de Ligamiento , Interfaz Usuario-Computador , Alelos , Frecuencia de los Genes , Genómica/métodos , Haplotipos , Humanos , Polimorfismo de Nucleótido Simple
15.
Curr Opin Ophthalmol ; 31(2): 101-106, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31895154

RESUMEN

PURPOSE OF REVIEW: The genetic basis of primary angle closure (PAC) glaucoma is slowly being elucidated. In recent years, genome-wide association studies have identified eight new susceptibility loci for PAC. Our purpose in this review is to summarize our current knowledge of genetics in angle closure, to take a closer look at the eight novel loci and what we have learned about their function, and consider what they might teach us about angle closure disease. RECENT FINDINGS: Multiple novel loci associated with PAC glaucoma have been identified in large genome-wide association studies. Moreover, primary open angle glaucoma and PAC glaucoma are found to have partly overlapping genetic features. SUMMARY: The genetic basis of PAC glaucoma is being deciphered. Even though there is still much more to be uncovered, this process has already provided new insights in the pathogenesis of this blinding disease. A better understanding of the pathogenic mechanisms through genomics may be valuable for the development of novel therapies.


Asunto(s)
Estudio de Asociación del Genoma Completo , Genómica , Glaucoma de Ángulo Cerrado/genética , Glaucoma de Ángulo Cerrado/fisiopatología , Humanos
16.
Adv Clin Chem ; 94: 85-153, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31952575

RESUMEN

Metabolomics is an intriguing field of study providing a new readout of the biochemical activities taking place at the moment of sampling within a subject's biofluid or tissue. Metabolite concentrations are influenced by several factors including disease, environment, drugs, diet and, importantly, genetics. Metabolomics signatures, which describe a subject's phenotype, are useful for disease diagnosis and prognosis, as well as for predicting and monitoring the effectiveness of treatments. Metabolomics is conventionally divided into targeted (i.e., the quantitative analysis of a predetermined group of metabolites) and untargeted studies (i.e., analysis of the complete set of small-molecule metabolites contained in a biofluid without a pre-imposed metabolites-selection). Both approaches have demonstrated high value in the investigation and understanding of several monogenic and multigenic conditions. Due to low costs per sample and relatively short analysis times, metabolomics can be a useful and robust complement to genetic sequencing.


Asunto(s)
Pruebas Genéticas , Metabolómica , Genoma Humano , Estudio de Asociación del Genoma Completo , Humanos , Recién Nacido , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/genética , Fenotipo
17.
Anaesthesia ; 75 Suppl 1: e111-e120, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31903573

RESUMEN

Chronic postoperative pain is common and can have a negative impact on quality of life. Recent studies show that genetic risk factors are likely to play a role, although only gene-targeted analysis has been used to date. This is the first genome-wide association study to identify single-nucleotide polymorphisms associated with the development of chronic postoperative pain based on two independent cohorts. In a discovery cohort, 330 women scheduled for hysterectomy were genotyped. A case-control association analysis compared patients without chronic postoperative pain and the 34 who had severe chronic postoperative pain 3 months after surgery. No single-nucleotide polymorphisms reached genome-wide significance, but several showed suggestive associations with chronic postoperative pain (p < 1 × 10-5 ). Single-nucleotide polymorphisms with significance p < 1 × 10-5 were followed up in a replication cohort consisting of 203 men and women scheduled for orthopaedic or abdominal surgery. Ten of these patients developed severe chronic postoperative pain. A single-nucleotide polymorphism in NAV3 was significantly replicated with chronic postoperative pain in the replication cohort (p = 0.009). Meta-analysis revealed that two loci (IQGAP1 and CRTC3) were significantly associated with chronic postoperative pain at 3 months (IQGAP1 p = 3.93 × 10-6 ß = 2.3863, CRTC3 p = 2.26 × 10-6 , ß = 2.4209). The present genome-wide association study provides initial evidence for genetic risk factors of chronic postoperative pain and supports follow-up studies.


Asunto(s)
Dolor Crónico/genética , Estudio de Asociación del Genoma Completo/métodos , Dolor Postoperatorio/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Estudios Prospectivos
18.
Genome Biol ; 21(1): 8, 2020 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-31910858

RESUMEN

BACKGROUND: Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. RESULTS: We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region. CONCLUSIONS: Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.


Asunto(s)
Neoplasias de la Mama/genética , Cromatina/metabolismo , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Genoma Humano , Estudio de Asociación del Genoma Completo , Humanos
19.
Genome Biol ; 21(1): 7, 2020 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-31910864

RESUMEN

BACKGROUND: Genetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, the contribution of non-coding RNAs to complex traits is not clear. RESULTS: Using targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants. CONCLUSIONS: We have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits.


Asunto(s)
Neoplasias de la Mama/genética , ARN no Traducido/genética , Estudio de Asociación del Genoma Completo , Humanos , Análisis de Secuencia de ARN
20.
Nat Commun ; 11(1): 186, 2020 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-31924762

RESUMEN

Sodium (Na+) toxicity is one of the major damages imposed on crops by saline-alkaline stress. Here we show that natural maize inbred lines display substantial variations in shoot Na+ contents and saline-alkaline (NaHCO3) tolerance, and reveal that ZmNSA1 (Na+ Content under Saline-Alkaline Condition) confers shoot Na+ variations under NaHCO3 condition by a genome-wide association study. Lacking of ZmNSA1 promotes shoot Na+ homeostasis by increasing root Na+ efflux. A naturally occurred 4-bp deletion decreases the translation efficiency of ZmNSA1 mRNA, thus promotes Na+ homeostasis. We further show that, under saline-alkaline condition, Ca2+ binds to the EF-hand domain of ZmNSA1 then triggers its degradation via 26S proteasome, which in turn increases the transcripts levels of PM-H+-ATPases (MHA2 and MHA4), and consequently enhances SOS1 Na+/H+ antiporter-mediated root Na+ efflux. Our studies reveal the mechanism of Ca2+-triggered saline-alkaline tolerance and provide an important gene target for breeding saline-alkaline tolerant maize varieties.


Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Tolerancia a la Sal/fisiología , Sodio/metabolismo , Zea mays/fisiología , Proteínas de Unión al Calcio/genética , Regulación de la Expresión Génica de las Plantas , Estudio de Asociación del Genoma Completo , Homeostasis , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raíces de Plantas/metabolismo , Tolerancia a la Sal/genética , Cloruro de Sodio/metabolismo , Intercambiadores de Sodio-Hidrógeno/metabolismo , Estrés Fisiológico/genética , Estrés Fisiológico/fisiología , Zea mays/genética
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