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1.
Sci Adv ; 7(3)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33523907

RESUMO

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

2.
Nat Protoc ; 15(9): 2759-2772, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32709988

RESUMO

A polygenic score (PGS) or polygenic risk score (PRS) is an estimate of an individual's genetic liability to a trait or disease, calculated according to their genotype profile and relevant genome-wide association study (GWAS) data. While present PRSs typically explain only a small fraction of trait variance, their correlation with the single largest contributor to phenotypic variation-genetic liability-has led to the routine application of PRSs across biomedical research. Among a range of applications, PRSs are exploited to assess shared etiology between phenotypes, to evaluate the clinical utility of genetic data for complex disease and as part of experimental studies in which, for example, experiments are performed that compare outcomes (e.g., gene expression and cellular response to treatment) between individuals with low and high PRS values. As GWAS sample sizes increase and PRSs become more powerful, PRSs are set to play a key role in research and stratified medicine. However, despite the importance and growing application of PRSs, there are limited guidelines for performing PRS analyses, which can lead to inconsistency between studies and misinterpretation of results. Here, we provide detailed guidelines for performing and interpreting PRS analyses. We outline standard quality control steps, discuss different methods for the calculation of PRSs, provide an introductory online tutorial, highlight common misconceptions relating to PRS results, offer recommendations for best practice and discuss future challenges.


Assuntos
Predisposição Genética para Doença/genética , Guias de Prática Clínica como Assunto , Medição de Risco/métodos , Humanos , Controle de Qualidade
3.
Am J Med Genet B Neuropsychiatr Genet ; 183(6): 309-330, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681593

RESUMO

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

4.
PLoS Med ; 17(6): e1003137, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32479557

RESUMO

BACKGROUND: Identifying causal risk factors for self-harm is essential to inform preventive interventions. Epidemiological studies have identified risk factors associated with self-harm, but these associations can be subject to confounding. By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm. METHODS AND FINDINGS: Using summary statistics from 24 genome-wide association studies (GWASs) comprising 16,067 to 322,154 individuals, polygenic scores (PSs) were generated to index 24 possible individual risk factors for self-harm (i.e., mental health vulnerabilities, substance use, cognitive traits, personality traits, and physical traits) among a subset of UK Biobank participants (N = 125,925, 56.2% female) who completed an online mental health questionnaire in the period from 13 July 2016 to 27 July 2017. In total, 5,520 (4.4%) of these participants reported having self-harmed in their lifetime. In binomial regression models, PSs indexing 6 risk factors (major depressive disorder [MDD], attention deficit/hyperactivity disorder [ADHD], bipolar disorder, schizophrenia, alcohol dependence disorder, and lifetime cannabis use) predicted self-harm, with effect sizes ranging from odds ratio (OR) = 1.05 (95% CI 1.02 to 1.07, q = 0.008) for lifetime cannabis use to OR = 1.20 (95% CI 1.16 to 1.23, q = 1.33 × 10-35) for MDD. No systematic differences emerged between suicidal and non-suicidal self-harm. To further probe causal relationships, two-sample Mendelian randomisation (MR) analyses were conducted, with MDD, ADHD, and schizophrenia emerging as the most plausible causal risk factors for self-harm. The genetic liabilities for MDD and schizophrenia were associated with self-harm independently of diagnosis and medication. Main limitations include the lack of representativeness of the UK Biobank sample, that self-harm was self-reported, and the limited power of some of the included GWASs, potentially leading to possible type II error. CONCLUSIONS: In addition to confirming the role of MDD, we demonstrate that ADHD and schizophrenia likely play a role in the aetiology of self-harm using multivariate genetic designs for causal inference. Among the many individual risk factors we simultaneously considered, our findings suggest that systematic detection and treatment of core psychiatric symptoms, including psychotic and impulsivity symptoms, may be beneficial among people at risk for self-harm.


Assuntos
Comportamento Autodestrutivo/genética , Idoso , Idoso de 80 Anos ou mais , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Bipolar/complicações , Transtorno Bipolar/genética , Bases de Dados como Assunto , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fatores de Risco , Esquizofrenia , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/etiologia , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/genética , Inquéritos e Questionários , Reino Unido/epidemiologia
6.
Mol Psychiatry ; 25(7): 1430-1446, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31969693

RESUMO

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

7.
Biol Psychiatry ; 87(5): 419-430, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31570195

RESUMO

BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

8.
Addiction ; 115(3): 482-492, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31833150

RESUMO

BACKGROUND AND AIMS: The use of cannabis has previously been linked to both depression and self-harm; however, the role of genetics in this relationship is unclear. This study aimed to estimate the phenotypic and genetic associations between cannabis use and depression and self-harm. DESIGN: Cross-sectional data collected through UK Biobank were used to test the phenotypic association between cannabis use, depression and self-harm. UK Biobank genetic data were then combined with consortia genome-wide association study summary statistics to further test the genetic relationships between these traits using LD score regression, polygenic risk scoring and Mendelian randomization methods. SETTING: United Kingdom, with additional international consortia data. PARTICIPANTS: A total of 126 291 British adults aged between 40 and 70 years, recruited into UK Biobank. MEASUREMENTS: Phenotypic outcomes were life-time history of cannabis use (including initial and continued cannabis use), depression (including single-episode and recurrent depression) and self-harm. Genome-wide genetic data were used and assessment centre, batch and the first six principal components were included as key covariates when handling genetic data. FINDINGS: In UK Biobank, cannabis use is associated with an increased likelihood of depression [odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.59-1.70] and self-harm (OR = 2.85, 95% CI = 2.69-3.01). The strength of this phenotypic association is stronger when more severe trait definitions of cannabis use and depression are considered. Using consortia genome-wide summary statistics, significant genetic correlations are seen between cannabis use and depression [rg = 0.289, standard error (SE) = 0.036]. Polygenic risk scores for cannabis use and depression explain a small but significant proportion of variance in cannabis use, depression and self-harm within a UK Biobank target sample. However, two-sample Mendelian randomization analyses were not significant. CONCLUSIONS: Cannabis use appeared to be both phenotypically and genetically associated with depression and self-harm. Limitations in statistical power mean that conclusions could not be made on the direction of causality between these traits.

9.
Gigascience ; 8(7)2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31307061

RESUMO

BACKGROUND: Polygenic risk score (PRS) analyses have become an integral part of biomedical research, exploited to gain insights into shared aetiology among traits, to control for genomic profile in experimental studies, and to strengthen causal inference, among a range of applications. Substantial efforts are now devoted to biobank projects to collect large genetic and phenotypic data, providing unprecedented opportunity for genetic discovery and applications. To process the large-scale data provided by such biobank resources, highly efficient and scalable methods and software are required. RESULTS: Here we introduce PRSice-2, an efficient and scalable software program for automating and simplifying PRS analyses on large-scale data. PRSice-2 handles both genotyped and imputed data, provides empirical association P-values free from inflation due to overfitting, supports different inheritance models, and can evaluate multiple continuous and binary target traits simultaneously. We demonstrate that PRSice-2 is dramatically faster and more memory-efficient than PRSice-1 and alternative PRS software, LDpred and lassosum, while having comparable predictive power. CONCLUSION: PRSice-2's combination of efficiency and power will be increasingly important as data sizes grow and as the applications of PRS become more sophisticated, e.g., when incorporated into high-dimensional or gene set-based analyses. PRSice-2 is written in C++, with an R script for plotting, and is freely available for download from http://PRSice.info.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial , Software , Animais , Big Data , Humanos , Locos de Características Quantitativas
10.
JAMA Psychiatry ; 76(7): 730-738, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30942833

RESUMO

Importance: Exposure to bullying is a prevalent experience with adverse consequences throughout the life span. Individual vulnerabilities and traits, such as preexisting mental health problems, may be associated with increased likelihood of experiencing bullying. Identifying such individual vulnerabilities and traits is essential for a better understanding of the etiology of exposure to bullying and for tailoring effective prevention. Objective: To identify individual vulnerabilities and traits associated with exposure to bullying in childhood and adolescence. Design, Setting, and Participants: For this study, data were drawn from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort study. The initial ALSPAC sample consisted of 14 062 children born to women residing in Avon, United Kingdom, with an expected date of delivery between April 1, 1991, and December 31, 1992. Collection of the ALSPAC data began in September 6, 1990, and the last follow-up assessment of exposure to bullying was conducted when participants were 13 years of age. Data analysis was conducted from November 1, 2017, to January 1, 2019. Exposures: The polygenic score approach was used to derive genetic proxies that indexed vulnerabilities and traits. A total of 35 polygenic scores were computed for a range of mental health vulnerabilities (eg, depression) and traits related to cognition (eg, intelligence), personality (eg, neuroticism), and physical measures (eg, body mass index), as well as negative controls (eg, osteoporosis). Main Outcomes and Measures: Single and multi-polygenic score regression models were fitted to test the association between indexed traits and exposure to bullying. Children completed the Bullying and Friendship Interview Schedule at the ages of 8, 10, and 13 years. A mean score of exposure to bullying across ages was used as the main outcome. Results: A total of 5028 genotyped individuals (2481 boys and 2547 girls) with data on exposure to bullying were included. Among the 35 initially included polygenic scores, 11 were independently associated with exposure to bullying; no significant association was detected for the 24 remaining scores. In multivariable analyses, 5 polygenic scores were associated with exposure to bullying; the largest associations were present for genetic risk relating to mental health vulnerabilities, including diagnosis of depression (standardized b = 0.065; 95% CI, 0.035-0.095) and attention-deficit/hyperactivity disorder (standardized b = 0.063; 95% CI, 0.035-0.091), followed by risk taking (standardized b = 0.041; 95% CI, 0.013-0.069), body mass index (standardized b = 0.036; 95% CI, 0.008-0.064), and intelligence (standardized b = -0.031; 95% CI, -0.059 to 0.003). Conclusion and Relevance: Using the multi-polygenic score approach, the findings implicate preexisting mental health vulnerabilities as risk factors for exposure to bullying. A mechanistic understanding of how these vulnerabilities link to exposure of bullying is important to inform prevention strategies.


Assuntos
Bullying/psicologia , Vítimas de Crime/psicologia , Inteligência , Personalidade , Adolescente , Criança , Depressão/psicologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Fatores de Risco
11.
Artigo em Inglês | MEDLINE | ID: mdl-30047479

RESUMO

BACKGROUND: A recent large-scale mega genome-wide association study identified, for the first time, genetic variants at 12 loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). In this study we use a powerful polygenic approach, with polygenic scores derived from the genome-wide association study, to investigate the etiological overlap between ADHD and frequently co-occurring traits and disorders. METHODS: Polygenic risk scores for ADHD derived from the mega genome-wide association study (20,183 cases and 35,191 control subjects) were computed in a large-scale adult population sample (N = 135,726) recruited by the UK Biobank. Regression analyses were conducted to investigate whether polygenic risk for ADHD is associated with related traits and disorders in this population sample. The effects of sex were investigated via inclusion of an interaction term in the models. RESULTS: Polygenic risk for ADHD significantly and positively predicted body mass index (R2 = .45%; p = 5 × 10-129), neuroticism (R2 = .09%; p = 2 × 10-24), depression (R2 = .11%; p = 2 × 10-13), anxiety (R2 = .06%; p = 3 × 10-4), risk taking (R2 = .12%; p = 9 × 10-25), alcohol intake (R2 = .09%; p = 8 × 10-29), smoking (R2 = .33%; p = 4 × 10-21), alcohol dependency (R2 = .21%; p = 5 × 10-6), and negatively predicted verbal-numerical reasoning (R2 = .38%; p = 5 × 10-36). Polygenic risk scores did not significantly predict schizophrenia or bipolar disorder, although this may be because of the small number of diagnostic cases. We found no interaction effects between polygenic risk for ADHD and sex on any phenotypes. CONCLUSIONS: Our findings suggest that common genetic variation underlying risk for clinically diagnosed ADHD also contributes to higher body mass index, neuroticism, anxiety and depressive disorders, alcohol and nicotine use, risk taking, and lower general cognitive ability in the general population. These findings suggest that the co-occurrence of several traits with ADHD is partly explained by the same common genetic variants.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Comorbidade , Bases de Dados Factuais , Feminino , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Transtornos Mentais/epidemiologia , Herança Multifatorial , Fenótipo , Risco , Reino Unido/epidemiologia
12.
Genet Epidemiol ; 41(6): 469-480, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28480976

RESUMO

Polygenic scores (PGS) summarize the genetic contribution of a person's genotype to a disease or phenotype. They can be used to group participants into different risk categories for diseases, and are also used as covariates in epidemiological analyses. A number of possible ways of calculating PGS have been proposed, and recently there is much interest in methods that incorporate information available in published summary statistics. As there is no inherent information on linkage disequilibrium (LD) in summary statistics, a pertinent question is how we can use LD information available elsewhere to supplement such analyses. To answer this question, we propose a method for constructing PGS using summary statistics and a reference panel in a penalized regression framework, which we call lassosum. We also propose a general method for choosing the value of the tuning parameter in the absence of validation data. In our simulations, we showed that pseudovalidation often resulted in prediction accuracy that is comparable to using a dataset with validation phenotype and was clearly superior to the conservative option of setting the tuning parameter of lassosum to its lowest value. We also showed that lassosum achieved better prediction accuracy than simple clumping and P-value thresholding in almost all scenarios. It was also substantially faster and more accurate than the recently proposed LDpred.


Assuntos
Herança Multifatorial/genética , Estatística como Assunto , Estudos de Casos e Controles , Simulação por Computador , Bases de Dados Genéticas , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Análise de Regressão
13.
Circulation ; 134(18): 1373-1389, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27678261

RESUMO

BACKGROUND: Danon disease is an X-linked disorder that leads to fatal cardiomyopathy caused by a deficiency in lysosome-associated membrane protein-2 (LAMP2). In female patients, a later onset and less severe clinical phenotype have been attributed to the random inactivation of the X chromosome carrying the mutant diseased allele. We generated a patient-specific induced pluripotent stem cell (iPSCs)-based model of Danon disease to evaluate the therapeutic potential of Xi-chromosome reactivation using a DNA methylation inhibitor. METHODS: Using whole-exome sequencing, we identified a nonsense mutation (c.520C>T, exon 4) of the LAMP2 gene in a family with Danon disease. We generated iPSC lines from somatic cells derived from the affected mother and her 2 sons, and we then differentiated them into cardiomyocytes (iPSC-CMs) for modeling the histological and functional signatures, including autophagy failure of Danon disease. RESULTS: Our iPSC-CM platform provides evidence that random inactivation of the wild-type and mutant LAMP2 alleles on the X chromosome is responsible for the unusual phenotype in female patients with Danon disease. In vitro, iPSC-CMs from these patients reproduced the histological features and autophagy failure of Danon disease. Administration of the DNA demethylating agent 5-aza-2'-deoxycytidine reactivated the silent LAMP2 allele in iPSCs and iPSC-CMs in female patients with Danon disease and ameliorated their autophagy failure, supporting the application of a patient-specific iPSC platform for disease modeling and drug screening. CONCLUSIONS: Our iPSC-CM platform provides novel mechanistic and therapeutic insights into the contribution of random X chromosome inactivation to disease phenotype in X-linked Danon disease.


Assuntos
Autofagia , Azacitidina/farmacologia , Cromossomos Humanos X/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo , Adulto , Alelos , Autofagia/efeitos dos fármacos , Autofagia/genética , Linhagem Celular , Feminino , Doença de Depósito de Glicogênio Tipo IIb/genética , Doença de Depósito de Glicogênio Tipo IIb/metabolismo , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/biossíntese , Proteína 2 de Membrana Associada ao Lisossomo/genética , Masculino
14.
J Hepatol ; 64(6): 1256-64, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26867494

RESUMO

BACKGROUND & AIMS: Hepatitis B virus (HBV) integration is common in HBV-associated hepatocellular carcinoma (HCC) and may play an important pathogenic role through the production of chimeric HBV-human transcripts. We aimed to screen the transcriptome for HBV integrations in HCCs. METHODS: Transcriptome sequencing was performed on paired HBV-associated HCCs and corresponding non-tumorous liver tissues to identify viral-human chimeric sites. Validation was further performed in an expanded cohort of human HCCs. RESULTS: Here we report the discovery of a novel pre-mRNA splicing mechanism in generating HBV-human chimeric protein. This mechanism was exemplified by the formation of a recurrent HBV-cyclin A2 (CCNA2) chimeric transcript (A2S), as detected in 12.5% (6 of 48) of HCC patients, but in none of the 22 non-HCC HBV-associated cirrhotic liver samples examined. Upon the integration of HBV into the intron of the CCNA2 gene, the mammalian splicing machinery utilized the foreign splice sites at 282nt. and 458nt. of the HBV genome to generate a pseudo-exon, forming an in-frame chimeric fusion with CCNA2. The A2S chimeric protein gained a non-degradable property and promoted cell cycle progression, demonstrating its potential oncogenic functions. CONCLUSIONS: A pre-mRNA splicing mechanism is involved in the formation of HBV-human chimeric proteins. This represents a novel and possibly common mechanism underlying the formation of HBV-human chimeric transcripts from intronically integrated HBV genome with functional impact. LAY SUMMARY: HBV is involved in the mammalian pre-mRNA splicing machinery in the generation of potential tumorigenic HBV-human chimeras. This study also provided insight on the impact of intronic HBV integration with the gain of splice sites in the development of HBV-associated HCC.


Assuntos
Carcinoma Hepatocelular/virologia , Vírus da Hepatite B/genética , Neoplasias Hepáticas/virologia , Proteínas de Fusão Oncogênica/biossíntese , Precursores de RNA/genética , Processamento de RNA , Integração Viral , Adulto , Idoso , Carcinoma Hepatocelular/genética , Quimera , Ciclina A2/genética , Feminino , Humanos , Íntrons , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Transcriptoma
15.
Psychiatr Genet ; 26(1): 1-47, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26565519

RESUMO

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported.

16.
Hum Mol Genet ; 22(7): 1395-403, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23300193

RESUMO

In this paper, we report a novel heterozygous mutation of A285V codon conversion on exon 4 of the desmin (DES), using whole exome sequencing (WES) in an isolated proband with documented dilated cardiomyopathy (DCM). This mutation is predicted to cause three-dimensional structure changes of DES. Immunohistological and electron microscopy studies demonstrated diffuse abnormal DES aggregations in DCM-induced-pluripotent stem cell (iPSC)-derived cardiomyocytes, and control-iPSC-derived cardiomyocytes transduced with A285V-DES. DCM-iPSC-derived cardiomyocytes also exhibited functional abnormalities in vitro. This is the first demonstration that patient-specific iPSC-derived cardiomyocytes can be used to provide histological and functional confirmation of a suspected genetic basis for DCM identified by WES.


Assuntos
Cardiomiopatia Dilatada/genética , Desmina/genética , Células-Tronco Pluripotentes Induzidas/fisiologia , Miócitos Cardíacos/metabolismo , Adulto , Sequência de Aminoácidos , Sequência de Bases , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/fisiopatologia , Diferenciação Celular , Desmina/química , Desmina/metabolismo , Exoma , Éxons , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Análise de Sequência de DNA , Volume Sistólico/genética , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia
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