Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.208
Filtrar
1.
Am J Psychiatry ; 177(9): 855-866, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32600152

RESUMO

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric disorder. The objective of this study was to define ADHD-associated candidate genes and their associated molecular modules and biological themes, based on the analysis of rare genetic variants. METHODS: The authors combined data from 11 published copy number variation studies in 6,176 individuals with ADHD and 25,026 control subjects and prioritized genes by applying an integrative strategy based on criteria including recurrence in individuals with ADHD, absence in control subjects, complete coverage in copy number gains, and presence in the minimal region common to overlapping copy number variants (CNVs), as well as on protein-protein interactions and information from cross-species genotype-phenotype annotation. RESULTS: The authors localized 2,241 eligible genes in the 1,532 reported CNVs, of which they classified 432 as high-priority ADHD candidate genes. The high-priority ADHD candidate genes were significantly coexpressed in the brain. A network of 66 genes was supported by ADHD-relevant phenotypes in the cross-species database. Four significantly interconnected protein modules were found among the high-priority ADHD genes. A total of 26 genes were observed across all applied bioinformatic methods. Lookup in the latest genome-wide association study for ADHD showed that among those 26 genes, POLR3C and RBFOX1 were also supported by common genetic variants. CONCLUSIONS: Integration of a stringent filtering procedure in CNV studies with suitable bioinformatics approaches can identify ADHD candidate genes at increased levels of credibility. The authors' analytic pipeline provides additional insight into the molecular mechanisms underlying ADHD and allows prioritization of genes for functional validation in validated model organisms.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Encéfalo/metabolismo , Perfilação da Expressão Gênica/métodos , RNA Polimerase III , Fatores de Processamento de RNA , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Variações do Número de Cópias de DNA/fisiologia , Bases de Dados Genéticas , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Humanos , Mapeamento de Interação de Proteínas/métodos , RNA Polimerase III/genética , RNA Polimerase III/metabolismo , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo
2.
Anticancer Res ; 40(7): 3707-3712, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620609

RESUMO

BACKGROUND/AIM: Oral cancer incidence is highest worldwide in Taiwan, and practical markers for personalized therapeutic strategies such as immunotherapies, is lacking. Interleukin-12 (IL12) is a cytokine that is reported to exhibit potent tumoricidal effects, however, its genotypic contribution to oral cancer is still largely unknown. We aimed to examine whether IL12A rs568408 and rs2243115 genotypes are associated with oral cancer risk in Taiwan. MATERIALS AND METHODS: Genotypic characteristics of IL12A were determined among 958 oral cancer cases and age- and gender-matched individuals via typical polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The variant genotypes of IL12A rs568408 and rs2243115 were not found to be significantly associated with elevated oral cancer risk (all p>0.05). Moreover, there was no interaction between IL12A genotypes and personal smoking, alcohol drinking and betel quid chewing behaviors (all p>0.05). CONCLUSION: IL12A rs568408 and rs2243115 genotypes may not serve as good predictors for oral cancer risk.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Subunidade p35 da Interleucina-12/genética , Neoplasias Bucais/genética , Polimorfismo de Nucleotídeo Único/genética , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição/genética , Fatores de Risco , Fumar/efeitos adversos , Fumar/genética , Taiwan
3.
PLoS Genet ; 16(7): e1008785, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32628676

RESUMO

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.


Assuntos
Doenças Cardiovasculares/genética , Análise da Randomização Mendeliana , Proteoma/genética , Esquizofrenia/genética , Antígenos de Diferenciação/genética , Doenças Cardiovasculares/patologia , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Fator 5 de Crescimento de Fibroblastos/genética , Estudos de Associação Genética/métodos , Humanos , Lipase Lipoproteica/genética , Linfotoxina-alfa/genética , Masculino , Locos de Características Quantitativas , Receptores Imunológicos/genética , Receptores de Interleucina-6/genética , Esquizofrenia/patologia
4.
Cancer Sci ; 111(9): 3367-3378, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619037

RESUMO

Although next-generation sequencing-based panel testing is well practiced in the field of cancer medicine for the identification of target molecules in solid tumors, the clinical utility and clinical issues surrounding panel testing in hematological malignancies have yet to be fully evaluated. We conducted a multicenter prospective clinical sequencing study to verify the feasibility of a panel test for hematological tumors, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and diffuse large B-cell lymphoma. Out of 96 eligible patients, 79 patients (82%) showed potentially actionable findings, based on the clinical sequencing assays. We identified that genetic alterations with a strong clinical significance were found at a higher frequency in terms of diagnosis (n = 60; 63%) and prognosis (n = 61; 64%) than in terms of therapy (n = 8; 8%). Three patients who harbored a germline mutation in either DDX41 (n = 2) or BRCA2 (n = 1) were provided with genetic counseling. At 6 mo after sequencing, clinical actions based on the diagnostic (n = 5) or prognostic (n = 3) findings were reported, but no patients were enrolled in a clinical trial or received targeted therapies based on the sequencing results. These results suggest that panel testing for hematological malignancies would be feasible given the availability of useful diagnostic and prognostic information. This study is registered with the UMIN Clinical Trial Registry (UMIN000029879, multiple myeloma; UMIN000031343, adult acute myeloid leukemia; UMIN000033144, diffuse large B-cell lymphoma; and UMIN000034243, childhood leukemia).


Assuntos
Biomarcadores Tumorais , Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
5.
PLoS One ; 15(6): e0234328, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32579617

RESUMO

FABP4 is a candidate gene for carcass and meat quality traits in livestock and poultry. However, the effects of FABP4 have not been examined in the Yanbian yellow cattle, an economically important local cattle breed in China. In this study, we characterized single nucleotide polymorphisms (SNPs) in FABP4 in this cattle breed and their associations with meat quality traits. Six SNPs (referred to as SNP1-6) were identified in FABP4 by direct sequencing and polymerase chain reaction-restriction fragment length polymorphism. The six SNPs were significantly correlated with meat quality traits. In particular, the GG and GA genotypes of SNP1 were significantly associated with water and fat contents and GG and AA genotypes of SNP1 were significantly associated with protein contents (P < 0.05). The fat content and marbling in heterozygous individuals at SNP2-6 were significantly higher than those in wild-type or mutant individuals (P < 0.05), while protein content was significantly higher in wild-type and mutant individuals than in heterozygous individuals (P < 0.05). A gene expression analysis indicated that the lipid metabolism-related genes FABP4, PPARγ, ANGPTL4, and LPL show similar expression patterns with respect to FABP4 genotypes, with the highest levels in wild-type individuals and the lowest levels in mutants. In conclusion, FABP4 SNPs can be used for marker-assisted selection in Yanbian yellow cattle breeding.


Assuntos
Bovinos/genética , Proteínas de Ligação a Ácido Graxo/genética , Metabolismo dos Lipídeos/genética , Animais , China , Feminino , Qualidade dos Alimentos , Expressão Gênica/genética , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Genótipo , Masculino , Mutação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Carne Vermelha/análise , Análise de Sequência de DNA/métodos
6.
Mol Genet Genomics ; 295(5): 1197-1209, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32500265

RESUMO

Growing evidence indicates that the development and progression of multiple complex diseases are influenced by microRNA (miRNA). Identifying more miRNAs as biomarkers for clinical diagnosis, treatment and prognosis is vital to promote the development of bioinformatics and medicine. Considering that the traditional biological experimental methods are generally time-consuming and expensive, high-efficient computational methods are encouraged to uncover potential disease-related miRNAs. In this paper, FCGCNMDA is presented to predict latent miRNA-disease associations by utilizing fully connected graph convolutional networks. Specially, our method first constructs a fully connected graph in which edge weights represent correlation coefficient between any two pairs of miRNA-disease pair, and then feeds this fully connected graph along with miRNA-disease pairs feature matrix into a two-layer graph convolutional networks (GCN) for training. At last, we utilize the trained network to predict the scores for unknown miRNA-disease pairs. As a result, FCGCNMDA achieves AUC value of [Formula: see text] and AUPRC value of [Formula: see text] in HMDD v2.0 based on five-fold cross validation. Moreover, case studies on Lymphoma, Breast Neoplasms and Prostate Neoplasms shown that 98%, 98%, 98% of the top 50 selected miRNAs were validated by recent experimental evidence. From above results, we can deduce that FCGCNMDA can be regarded as reliable method for potential miRNA-disease associations prediction.


Assuntos
Neoplasias da Mama/genética , Biologia Computacional/métodos , Estudos de Associação Genética/métodos , Linfoma/genética , MicroRNAs/genética , Neoplasias da Próstata/genética , Algoritmos , Área Sob a Curva , Aprendizado Profundo , Diagnóstico Precoce , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Prognóstico
7.
PLoS Genet ; 16(5): e1008612, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32427991

RESUMO

Estimating the polygenicity (proportion of causally associated single nucleotide polymorphisms (SNPs)) and discoverability (effect size variance) of causal SNPs for human traits is currently of considerable interest. SNP-heritability is proportional to the product of these quantities. We present a basic model, using detailed linkage disequilibrium structure from a reference panel of 11 million SNPs, to estimate these quantities from genome-wide association studies (GWAS) summary statistics. We apply the model to diverse phenotypes and validate the implementation with simulations. We find model polygenicities (as a fraction of the reference panel) ranging from ≃ 2 × 10-5 to ≃ 4 × 10-3, with discoverabilities similarly ranging over two orders of magnitude. A power analysis allows us to estimate the proportions of phenotypic variance explained additively by causal SNPs reaching genome-wide significance at current sample sizes, and map out sample sizes required to explain larger portions of additive SNP heritability. The model also allows for estimating residual inflation (or deflation from over-correcting of z-scores), and assessing compatibility of replication and discovery GWAS summary statistics.


Assuntos
Estudos de Associação Genética , Heterogeneidade Genética , Padrões de Herança/fisiologia , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Simulação por Computador , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Genética Populacional , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Heterozigoto , Humanos , Desequilíbrio de Ligação , Herança Multifatorial , Distribuição Normal , Fenótipo , Característica Quantitativa Herdável
8.
Mol Immunol ; 123: 18-25, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32388106

RESUMO

INTRODUCTION: Asthma is a worldwide problem that is caused by complex underlying immune dysregulation. The identification of potential prognostic markers of asthma may provide information for treatment. The purpose of this study was to explore the key mechanisms involved in the development of asthma on the basis of microarray analysis. METHODS: The expression profile data of GSE43696, which contains 20 endobronchial epithelial brushing samples from healthy patients and 88 from asthma patients, were obtained from Gene Expression Omnibus. For the present study, we built co-expression modules by weighted gene co-expression network analysis (WGCNA). This new analysis strategy was applied to the data set to investigate the relationships underlying the modules and the pathogenesis of asthma. Functional enrichment analysis was performed on these co-expression genes from the modules, and a gene network was then constructed. In addition, mouse models of HDM-induced and OVA-induced asthma were established, and the expression of hub genes was measured. RESULTS: First, using WGCNA, 20 co-expression modules were constructed with 19,596 genes obtained from 108 human endobronchial epithelial brushing samples. The number of genes within the modules ranged from 41 to 845. According to the colours assigned by the system, the module positively correlated with asthma status was named 'red module', and the module positively correlated with asthma severity was named 'purple module'. The results of a functional enrichment analysis showed that the red module was mainly enriched in intracellular calcium-activated chloride channel activity, intracellular chloride channel activity and endopeptidase inhibitor activity. The purple module was mainly enriched in microtubule motor activity and microtubule-binding and motor activity. Moreover, the mRNA expression levels of the 15 hub genes were confirmed to be significantly upregulated in the HDM mouse model, and 12 hub genes were upregulated in the OVA model. CONCLUSIONS: The hub genes ANO7, PYCR1 and UBE2C might play potential roles in the pathogenesis of asthma. Our findings provided a framework of co-expression gene modules of asthma and led to the identification of some new markers that might be potential targets for the development of new drugs and diagnostic markers.


Assuntos
Asma/genética , Asma/patologia , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Adulto , Animais , Biomarcadores/análise , Brônquios/metabolismo , Brônquios/patologia , Células Cultivadas , Estudos de Coortes , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Índice de Gravidade de Doença , Transdução de Sinais/genética , Adulto Jovem
9.
Cancer Sci ; 111(7): 2482-2487, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32426915

RESUMO

The pathogenesis of lung cancer associated with idiopathic pulmonary fibrosis (IPF) has remained largely uncharacterized. To provide insight into this condition, we undertook genomic profiling of IPF-associated lung cancer as well as of adjacent fibrosing lung tissue in surgical specimens. Isolated DNA and RNA from 17 IPF-associated non-small cell lung cancer and 15 paired fibrosing lung tissue specimens were analyzed by next-generation sequencing with a panel that targets 161 cancer-related genes. Somatic genetic alterations were frequently identified in TP53 (n = 6, 35.3%) and PIK3CA (n = 5, 29.4%) genes in tumor samples as well as in EGFR (n = 7, 46.7%), PIK3CA (n = 5, 33.3%), ERBB3 (n = 4, 26.7%), and KDR (n = 4, 26.7%) in IPF samples. Genes related to the RAS-RAF signaling pathway were also frequently altered in tumor (n = 7, 41.2%) and IPF (n = 3, 20.0%) samples. The number of somatic alterations identified in IPF samples was almost as large as that detected in paired tumor samples (81 vs 90, respectively). However, only 6 of the 81 somatic alterations detected in IPF samples overlapped with those in paired tumor samples. The accumulation of somatic mutations was thus apparent in IPF tissue of patients with IPF-associated lung cancer, and the RAS-RAF pathway was implicated in lung tumorigenesis. The finding that somatic alterations were not frequently shared between tumor and corresponding IPF tissue indicates that IPF-associated lung cancer does not develop through the stepwise accumulation of somatic alterations in IPF.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Fibrose Pulmonar Idiopática/genética , Neoplasias Pulmonares/genética , Adulto , Idoso , Biomarcadores , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência de DNA
10.
PLoS Biol ; 18(5): e3000719, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32421711

RESUMO

Identification of target genes that mediate required functions downstream of transcription factors is hampered by the large number of genes whose expression changes when the factor is removed from a specific tissue and the numerous binding sites for the factor in the genome. Retinoic acid (RA) regulates transcription via RA receptors bound to RA response elements (RAREs) of which there are thousands in vertebrate genomes. Here, we combined chromatin immunoprecipitation sequencing (ChIP-seq) for epigenetic marks and RNA-seq on trunk tissue from wild-type and Aldh1a2-/- embryos lacking RA synthesis that exhibit body axis and forelimb defects. We identified a relatively small number of genes with altered expression when RA is missing that also have nearby RA-regulated deposition of histone H3 K27 acetylation (H3K27ac) (gene activation mark) or histone H3 K27 trimethylation (H3K27me3) (gene repression mark) associated with conserved RAREs, suggesting these genes function downstream of RA. RA-regulated epigenetic marks were identified near RA target genes already known to be required for body axis and limb formation, thus validating our approach; plus, many other candidate RA target genes were found. Nuclear receptor 2f1 (Nr2f1) and nuclear receptor 2f2 (Nr2f2) in addition to Meis homeobox 1 (Meis1) and Meis homeobox 2 (Meis2) gene family members were identified by our approach, and double knockouts of each family demonstrated previously unknown requirements for body axis and/or limb formation. A similar epigenetic approach can be used to determine the target genes for any transcriptional regulator for which a knockout is available.


Assuntos
Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética/métodos , Código das Histonas , Tretinoína/metabolismo , Animais , Sequência de Bases , Sequenciamento de Cromatina por Imunoprecipitação , Sequência Conservada , Epigênese Genética , Camundongos , Família Multigênica , Elementos de Resposta , Análise de Sequência de RNA , Fatores de Transcrição/metabolismo
11.
Cancer Sci ; 111(7): 2579-2587, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32378780

RESUMO

We performed a genome-wide association study to investigate the association between single nucleotide polymorphisms and anthracycline-induced cardiotoxicity (ACT) in patients diagnosed with early breast cancer. From January 2000 to December 2015, 8490 patients underwent breast surgery at the National Cancer Center in Korea. Patients who received doxorubicin (cumulative dose 240 mg/m2 -300 mg/m2 ) with or without trastuzumab as a neoadjuvant/adjuvant therapy were included in our cohort. Sixty-seven patients in our cohort were diagnosed with ACT. Clinical data, including age, body weight, height, cancer stage, trastuzumab treatment, comorbidities, and concomitant medications, were collected retrospectively. Patients were classified as having either persistent or transient ACT based on their clinical course. In total, 346 946 single nucleotide polymorphisms in 42 cases and 215 controls were tested in this study. Body mass index (BMI) ≥25 kg/m2 [odds ratio (OR) = 2.45, 95% confidence interval (CI), 1.23-4.88, P = .011] and trastuzumab use (OR = 2.40, 95% CI, 1.11-5.17, P = .026) were identified as significant risk factors. We found 7 genetic variants for ACT including rs17530621 (SHISA3, P = 3.10E-06), rs11894115 (MPP4, P = 4.71E-06), rs58328254 (RPL7, P = 6.09E-06), and rs117299725 (PRUNE2, P = 8.53E-06), although none of these variants reached the Bonferroni-corrected significance level when adjusted for BMI and trastuzumab use ( = α1.44E-07 based on 0.05/346 946). rs117299725 was a common variant when only the persistent ACT group was analyzed separately. It is meaningful that our study analyzed comprehensively the influence of genetic variation on ACT, along with some clinical factors in Asian breast cancer patients who received anthracycline with or without trastuzumab. Further research will be needed on candidate genetic variants found in this study.


Assuntos
Antraciclinas/efeitos adversos , Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Cardiotoxicidade/etiologia , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Antraciclinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/epidemiologia , Estudos de Casos e Controles , Comorbidade , Feminino , Estudos de Associação Genética/métodos , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Vigilância da População , República da Coreia
12.
Nat Rev Genet ; 21(6): 367-376, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32317787

RESUMO

Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.


Assuntos
Transtorno do Espectro Autista/genética , Medicina Baseada em Evidências/métodos , Estudos de Associação Genética/métodos , Encéfalo/crescimento & desenvolvimento , Cognição/fisiologia , Humanos , Deficiência Intelectual/genética
13.
PLoS One ; 15(4): e0230587, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271766

RESUMO

As high-throughput sequencing is increasingly applied to the molecular diagnosis of rare Mendelian disorders, a large number of patients with diverse phenotypes have their genetic and phenotypic data pooled together to uncover new gene-phenotype relations. We introduce Phenogenon, a statistical tool that combines, Human Phenotype Ontology (HPO) annotated patient phenotypes, gnomAD allele population frequency, and Combined Annotation Dependent Depletion (CADD) score for variant pathogenicity, in order to jointly predict the mode of inheritance and gene-phenotype associations. We ran Phenogenon on our cohort of 3,290 patients who had undergone whole exome sequencing. Among the top associations, we recapitulated previously known, such as "SRD5A3-Abnormal full-field electroretinogram-recessive" and "GRHL2 -Nail dystrophy-recessive", and discovered one potentially novel, "RRAGA-Abnormality of the skin-dominant". We also developed an interactive web interface available at https://phenogenon.phenopolis.org to visualise and explore the results.


Assuntos
Biologia Computacional/métodos , Estudos de Associação Genética , Doenças Genéticas Inatas , Sequenciamento de Nucleotídeos em Larga Escala , Doenças Raras , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Bases de Dados Genéticas , Frequência do Gene , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Proteínas de Membrana/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Doenças da Unha/epidemiologia , Doenças da Unha/genética , Fenótipo , Doenças Raras/epidemiologia , Doenças Raras/genética , Distrofias Retinianas/epidemiologia , Distrofias Retinianas/genética , Dermatopatias/epidemiologia , Dermatopatias/genética , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma
14.
Anim Sci J ; 91(1): e13335, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32219932

RESUMO

In our previous study, we performed genome-wide association study (GWAS) to identify the genomic region associated with Fat area ratio to rib eye area (FAR) and detected a candidate in BTA7 at 10-30 Mbp. The present study aims to comprehensively detect all polymorphisms in the candidate region using whole-genome resequencing data. Based on whole-genome resequencing of eight animals, we detected 127,090 polymorphisms within the region. Of these, 31,945 were located within the genes. We further narrowed the polymorphisms to 6,044 with more than five allele differences between the high and low FAR groups that were located within 179 genes. We subsequently investigated the functions of these genes and selected 170 polymorphisms in eight genes as possible candidate polymorphisms. We focused on SLC27A6 K81M as a putative candidate polymorphism. We genotyped the SNP in a Japanese Black population (n = 904) to investigate the effect on FAR. Analysis of variance revealed that SLC27A6 K81M had a lower p-value (p = .0009) than the most significant SNP in GWAS (p = .0049). Although only SLC27A6 K81M was verified in the present study, subsequent verification of the remaining candidate genes and polymorphisms could lead to the identification of genes and polymorphisms responsible for FAR.


Assuntos
Bovinos/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Sequenciamento Completo do Genoma/veterinária , Animais , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/veterinária , Japão , Sequenciamento Completo do Genoma/métodos
15.
Med Sci (Paris) ; 36(2): 137-140, 2020 Feb.
Artigo em Francês | MEDLINE | ID: mdl-32129749

RESUMO

Spinal muscular atrophy (SMA) is the most common genetic disease leading to infant mortality. This neuro-muscular disorder is caused by the loss or mutation of the telomeric copy of the 'survival of motor neuron' (Smn) gene, termed SMN1. Loss of SMN1 leads to reduced SMN protein levels, inducing degeneration of motor neurons (MN) and progressive muscle weakness and atrophy. Gene therapy, consisting of reintroducing SMN1 in the MNs, is an attractive approach for SMA. We showed the most efficient rescue of SMA mice to date after a single intravenous injection of an AAV9 expressing SMN1, highlighting the considerable potential of this method for the treatment of human SMA. Recently, a startup led by the Dr Kaspar decided to test this experimental approach in children with SMA type 1. Dr Mendell, in charge of this clinical project, showed a very significant increase of the lifespan and motor function of the patients (until 4 years) after a single injection of AAV9-SMN1 (named ZolgenSMA®) into an arm or leg vein. This gene therapy treatment obtained a marketing authorization by the FDA in May 24 and is now the first efficient therapy for neuromuscular disease.


Assuntos
Estudos de Associação Genética , Terapia Genética , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Animais , Criança , Modelos Animais de Doenças , Estudos de Associação Genética/métodos , Estudos de Associação Genética/tendências , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Camundongos , Neurônios Motores/fisiologia , Atrofia Muscular Espinal/diagnóstico , Mutação , Atrofias Musculares Espinais da Infância/diagnóstico , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/terapia
16.
Nat Commun ; 11(1): 655, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005800

RESUMO

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.


Assuntos
Doença/genética , Estudos de Associação Genética/métodos , Animais , Genes Essenciais , Genômica , Humanos , Camundongos , Camundongos Knockout
17.
PLoS One ; 15(2): e0227254, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32059009

RESUMO

The TORC2 gene is responsible for nutrient metabolism, gluconeogenesis, myogenesis and adipogenesis through the PI3K-Akt, AMPK, glucagon and insulin resistance signaling pathways. Sequencing of PCR amplicons explored three novel SNPs at loci g.16534694G>A, g.16535011C>T, and g.16535044A>T in the promoter region of the TORC2 gene in the Qinchuan breed of cattle. Allelic and genotypic frequencies of these SNPs deviated from Hardy-Weinberg equilibrium (HWE) (P < 0.05). SNP1 genotype GG, SNP2 genotype CT and SNP3 genotype AT showed significantly (P <0.05) larger body measurement and improved carcass quality traits. Haplotype H1 (GCA) showed significantly (p<0.01) higher transcriptional activity (51.44%) followed by H4 (ATT) (34.13%) in bovine preadipocytes. The diplotypes HI-H3 (GG-CC-AT), H1-H2 (GG-CT-AT) and H3-H4 (GA-CT-TT) showed significant (P<0.01) associations with body measurement and improved carcass quality traits. Analysis of the relative mRNA expression level of the TORC2 gene in different tissues within two different age groups revealed a significant increase (P<0.01) in liver, small intestine, muscle and fat tissues with growth from calf stage to adult stage. We can conclude that variants mapped within TORC2 can be used in marker-assisted selection for carcass quality and body measurement traits in breed improvement programs of Qinchuan cattle.


Assuntos
Pesos e Medidas Corporais , Osso e Ossos , Estudos de Associação Genética/métodos , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Regiões Promotoras Genéticas/genética , Animais , Bovinos , Feminino , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
18.
Am J Hematol ; 95(5): 472-482, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32043619

RESUMO

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.


Assuntos
Anemia Hemolítica Congênita não Esferocítica/genética , Estudos de Associação Genética/métodos , Piruvato Quinase/deficiência , Erros Inatos do Metabolismo dos Piruvatos/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Piruvato Quinase/genética , Adulto Jovem
19.
Acta Diabetol ; 57(6): 733-741, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32025861

RESUMO

AIMS: The milk fat globule-epidermal growth factor 8 (MFGE8), also called lactadherin, is an integrin ligand and a known mediator of inflammation and atherosclerosis in T2DM in studies using animal models. However, its role in the pathophysiology of human T2DM, obesity, and cardiovascular disease has been poorly explored. Aim of this study  was to investigate the role of a missense variant (rs371227978 C/T: Arg148His) in the MFGE8 gene identified through exome sequencing for its association with T2DM and cardiometabolic traits. METHODS: Exome-wide sequencing was performed using DNA samples from 68 Sikh individuals from multi-generation pedigrees affected with diabetes on Illumina's GAIIx using "SureSelect Human All Exon" panels. We further replicated this variant by de novo genotyping in a total of 4242 individuals of the Asian Indian Diabetic Heart Study/Sikh Diabetes Study using custom TaqMan genotyping assay. We also measured circulating concentrations of Mfge8 using frozen serum aliquots by enzyme-linked immunosorbent assay. RESULTS: Overall, only 1.78% of 4242 individuals were carriers of this variant with MAF being 0.009. Except for the significant correlation of this variant with T2DM and triglycerides, no other quantitative risk phenotype was significant. The minor per allele-associated increased risk for T2DM showed odds ratio of 1.95 (95% CI 1.18-3.23; p = 0.008) in unadjusted model and was 1.73 (95% CI 1.02-2.93; p = 0.043) after adjusting for the age, gender, and BMI. However, there was a strong correlation between serum Mfge8 concentrations with T2DM, (r2 = 0.38; p = 0.001), fasting glucose (r2= 0.36; p = 0.002), and triglycerides (r2 = 0.33; p = 0.005). Our data revealed a significant dose-related increase in MFGE8 genotypes for affecting serum Mfge8 (p = 2.1 × 10-3) and triglyceride concentrations (p = 3.2 × 10-3). For a per risk allele-associated increase of 4.74 ng/ml ± SD of 1.62 ng/ml of the Mfge8 concentration was found to increase T2DM risk to 1.7 fold (95% CI from 1 to 3 fold). CONCLUSIONS: Here, we report for the first time a novel population-specific rare variant in the MFGE8 gene linked with the increased Mfge8 concentrations and the risk for developing T2DM and cardiovascular risk factors in a population of Punjabi Sikhs from India. In view of a strong evidence from animal studies supporting the role of Mfge8 in obesity, insulin resistance, and the development of atherosclerosis in T2DM, our findings are important and timely. If validated in a large independent dataset, early screening of Mfge8 in blood levels may especially benefit those patients with genetically elevated Mfge8 levels to preventing or reducing the risk of T2DM and cardiovascular disease.


Assuntos
Antígenos de Superfície/genética , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/genética , Grupos Étnicos/genética , Proteínas do Leite/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Doenças Cardiovasculares/etnologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etnologia , Angiopatias Diabéticas/etnologia , Grupos Étnicos/estatística & dados numéricos , Feminino , Frequência do Gene , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/etnologia , Genética Populacional , Genótipo , Humanos , Índia/epidemiologia , Índia/etnologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Sequenciamento Completo do Exoma , Adulto Jovem
20.
Am J Otolaryngol ; 41(3): 102434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32093976

RESUMO

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a refractory and poor prognosis tumor Present study aimed to investigate the underlying biological functions and pathways involved in the development of ATC and to identify potential hub genes and candidate biomarkers of ATC. MATERIALS AND METHODS: Bioinformatics analyses were performed to identify the differentially expressed genes (DEGs) between ATC tissue samples and adjacent normal tissue samples. Protein-protein interaction (PPI) networks of the DEGs were constructed using Search Tool for the Retrieval of Interacting Genes online tool and Cytoscape software and divided into sub-networks using the Molecular Complex Detection (MCODE) plug-in. DEGs in each module was analyzed by enrichment analysis of the KEGG Orthology Based Annotation System (KOBAS) web software version 3.0. Eventually, the hub genes from bioinformatics analysis were verified by qRT-PCR assay in different ATC cell lines. RESULTS: Thirty hub genes were selected and three modules were built by the Cytoscape software from the PPI network. Seven genes (CDK1, CCNB2, BUB1B, CDC20, RRM2, CHEK1 and CDC45) were screened from thirty hub genes. Enrichment analysis showed that these hub genes were primarily accumulated in 'cell cycle', 'p53 signaling pathway', 'viral carcinogenesis', 'pyrimidine metabolism' and 'ubiquitin mediated proteolysis'. The results of qRT-PCR indicated that seven hub genes were unregulated in three ATC cell lines compared with normal thyroid gland cell. CONCLUSIONS: These findings suggest that CDK1, CCNB2, BUB1B, CDC20, RRM2, CHEK1 and CDC45 may serve as novel diagnosis biomarkers and potential therapeutic target for ATC.


Assuntos
Proteína Quinase CDC2/genética , Proteínas de Ciclo Celular/genética , Biologia Computacional/métodos , Ciclina B2/genética , Estudos de Associação Genética/métodos , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Proteínas Cdc20 , Ciclo Celular/genética , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/genética , Marcadores Genéticos , Humanos , Terapia de Alvo Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonucleosídeo Difosfato Redutase/genética , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA