Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 24
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Genet ; 51(7): 1160-1169, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31253979

RESUMO

Most of the millions of SNPs in the human genome are non-coding, and many overlap with putative regulatory elements. Genome-wide association studies (GWAS) have linked many of these SNPs to human traits or to gene expression levels, but rarely with sufficient resolution to identify the causal SNPs. Functional screens based on reporter assays have previously been of insufficient throughput to test the vast space of SNPs for possible effects on regulatory element activity. Here we leveraged the throughput and resolution of the survey of regulatory elements (SuRE) reporter technology to survey the effect of 5.9 million SNPs, including 57% of the known common SNPs, on enhancer and promoter activity. We identified more than 30,000 SNPs that alter the activity of putative regulatory elements, partially in a cell-type-specific manner. Integration of this dataset with GWAS results may help to pinpoint SNPs that underlie human traits.

2.
Genetics ; 212(3): 905-918, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31123039

RESUMO

Expression QTL (eQTL) detection has emerged as an important tool for unraveling the relationship between genetic risk factors and disease or clinical phenotypes. Most studies are predicated on the assumption that only a single causal variant explains the association signal in each interval. This greatly simplifies the statistical modeling, but is liable to biases in scenarios where multiple local causal-variants are responsible. Here, our primary goal was to address the prevalence of secondary cis-eQTL signals regulating peripheral blood gene expression locally, utilizing two large human cohort studies, each >2500 samples with accompanying whole genome genotypes. The CAGE (Consortium for the Architecture of Gene Expression) dataset is a compendium of Illumina microarray studies, and the Framingham Heart Study is a two-generation Affymetrix dataset. We also describe Bayesian colocalization analysis of the extent of sharing of cis-eQTL detected in both studies as well as with the BIOS RNAseq dataset. Stepwise conditional modeling demonstrates that multiple eQTL signals are present for ∼40% of over 3500 eGenes in both microarray datasets, and that the number of loci with additional signals reduces by approximately two-thirds with each conditioning step. Although <20% of the peak signals across platforms fine map to the same credible interval, the colocalization analysis finds that as many as 50-60% of the primary eQTL are actually shared. Subsequently, colocalization of eQTL signals with GWAS hits detected 1349 genes whose expression in peripheral blood is associated with 591 human phenotype traits or diseases, including enrichment for genes with regulatory functions. At least 10%, and possibly as many as 40%, of eQTL-trait colocalized signals are due to nonprimary cis-eQTL peaks, but just one-quarter of these colocalization signals replicated across the gene expression datasets. Our results are provided as a web-based resource for visualization of multi-site regulation of gene expression and its association with human complex traits and disease states.

3.
Hum Genet ; 138(4): 375-388, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30852652

RESUMO

Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of 'transcriptomic' MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Therefore, we performed a genome-wide association study (GWAS) of MC in the 1000 Genomes/ GEUVADIS data (n = 457) and identified a solitary genome-wide significant association with single nucleotide polymorphisms (SNPs) in the intronic region of the cadherin 18 (CDH18) gene on chromosome 5 (lead SNP: rs11744487, p = 1.2 × 10- 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis.


Assuntos
Caderinas/genética , Loci Gênicos , Redes e Vias Metabólicas/genética , Metabolismo/genética , Transcriptoma , Estudos de Coortes , Feminino , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
4.
Nat Genet ; 51(4): 600-605, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30778224

RESUMO

Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity1. However, the causal relationships remain largely unresolved. We leveraged information from 952 normoglycemic individuals for whom genome-wide genotyping, gut metagenomic sequence and fecal short-chain fatty acid (SCFA) levels were available2, then combined this information with genome-wide-association summary statistics for 17 metabolic and anthropometric traits. Using bidirectional Mendelian randomization (MR) analyses to assess causality3, we found that the host-genetic-driven increase in gut production of the SCFA butyrate was associated with improved insulin response after an oral glucose-tolerance test (P = 9.8 × 10-5), whereas abnormalities in the production or absorption of another SCFA, propionate, were causally related to an increased risk of T2D (P = 0.004). These data provide evidence of a causal effect of the gut microbiome on metabolic traits and support the use of MR as a means to elucidate causal relationships from microbiome-wide association findings.


Assuntos
Ácidos Graxos Voláteis/genética , Microbioma Gastrointestinal/genética , Doenças Metabólicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/genética , Feminino , Genótipo , Teste de Tolerância a Glucose/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Adulto Jovem
5.
Am J Hum Genet ; 103(5): 691-706, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388399

RESUMO

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

6.
Nat Genet ; 50(12): 1752, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30341443

RESUMO

In the version of this paper originally published, there was a typographical error. In the Discussion, the sentence "In line with this, Ep-CAM-deficient mice exhibited increased intestinal permeability and decreased ion transport60, which may contribute to CVD susceptibility risk59" originally read iron instead of ion transport. This error has been corrected in the HTML, PDF and print versions of the article.

7.
Nat Genet ; 50(11): 1524-1532, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30250126

RESUMO

Despite a growing body of evidence, the role of the gut microbiome in cardiovascular diseases is still unclear. Here, we present a systems-genome-wide and metagenome-wide association study on plasma concentrations of 92 cardiovascular-disease-related proteins in the population cohort LifeLines-DEEP. We identified genetic components for 73 proteins and microbial associations for 41 proteins, of which 31 were associated to both. The genetic and microbial factors identified mostly exert additive effects and collectively explain up to 76.6% of inter-individual variation (17.5% on average). Genetics contribute most to concentrations of immune-related proteins, while the gut microbiome contributes most to proteins involved in metabolism and intestinal health. We found several host-microbe interactions that impact proteins involved in epithelial function, lipid metabolism, and central nervous system function. This study provides important evidence for a joint genetic and microbial effect in cardiovascular disease and provides directions for future applications in personalized medicine.

8.
Nat Immunol ; 19(7): 776-786, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29784908

RESUMO

The immune response to pathogens varies substantially among people. Whereas both genetic and nongenetic factors contribute to interperson variation, their relative contributions and potential predictive power have remained largely unknown. By systematically correlating host factors in 534 healthy volunteers, including baseline immunological parameters and molecular profiles (genome, metabolome and gut microbiome), with cytokine production after stimulation with 20 pathogens, we identified distinct patterns of co-regulation. Among the 91 different cytokine-stimulus pairs, 11 categories of host factors together explained up to 67% of interindividual variation in cytokine production induced by stimulation. A computational model based on genetic data predicted the genetic component of stimulus-induced cytokine production (correlation 0.28-0.89), and nongenetic factors influenced cytokine production as well.

9.
Brief Bioinform ; 19(4): 575-592, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28077403

RESUMO

Gene co-expression networks can be used to associate genes of unknown function with biological processes, to prioritize candidate disease genes or to discern transcriptional regulatory programmes. With recent advances in transcriptomics and next-generation sequencing, co-expression networks constructed from RNA sequencing data also enable the inference of functions and disease associations for non-coding genes and splice variants. Although gene co-expression networks typically do not provide information about causality, emerging methods for differential co-expression analysis are enabling the identification of regulatory genes underlying various phenotypes. Here, we introduce and guide researchers through a (differential) co-expression analysis. We provide an overview of methods and tools used to create and analyse co-expression networks constructed from gene expression data, and we explain how these can be used to identify genes with a regulatory role in disease. Furthermore, we discuss the integration of other data types with co-expression networks and offer future perspectives of co-expression analysis.

10.
Sci Rep ; 7(1): 10077, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28855728

RESUMO

Previous transcriptome studies of the human endometrium have revealed hundreds of simultaneously up- and down-regulated genes that are involved in endometrial receptivity. However, the overlap between the studies is relatively small, and we are still searching for potential diagnostic biomarkers. Here we perform a meta-analysis of endometrial-receptivity associated genes on 164 endometrial samples (76 from 'pre-receptive' and 88 from mid-secretory, 'receptive' phase endometria) using a robust rank aggregation (RRA) method, followed by enrichment analysis, and regulatory microRNA prediction. We identify a meta-signature of endometrial receptivity involving 57 mRNA genes as putative receptivity markers, where 39 of these we confirm experimentally using RNA-sequencing method in two separate datasets. The meta-signature genes highlight the importance of immune responses, the complement cascade pathway and the involvement of exosomes in mid-secretory endometrial functions. Bioinformatic prediction identifies 348 microRNAs that could regulate 30 endometrial-receptivity associated genes, and we confirm experimentally the decreased expression of 19 microRNAs with 11 corresponding up-regulated meta-signature genes in our validation experiments. The 57 identified meta-signature genes and involved pathways, together with their regulatory microRNAs could serve as promising and sought-after biomarkers of endometrial receptivity, fertility and infertility.

11.
Reprod Biomed Online ; 35(3): 253-263, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28647356

RESUMO

Several studies have demonstrated that human embryonic stem cells (hESC) can be differentiated into trophoblast-like cells if exposed to bone morphogenic protein 4 (BMP4) and/or inhibitors of fibroblast growth factor 2 (FGF2) and the transforming growth factor beta (TGF-ß)/activin/nodal signalling pathways. The goal of this study was to investigate how the inhibitors of these pathways improve the efficiency of hESC differentiation when compared with basic BMP4 treatment. RNA sequencing was used to analyse the effects of all possible inhibitor combinations on the differentiation of hESC into trophoblast-like cells over 12 days. Genes differentially expressed compared with untreated cells were identified at seven time points. Additionally, expression of total human chorionic gonadotrophin (HCG) and its hyperglycosylated form (HCG-H) were determined by immunoassay from cell culture media. We showed that FGF2 inhibition with BMP4 activation up-regulates syncytiotrophoblast-specific genes (CGA, CGB and LGALS16), induces several molecular pathways involved in embryo implantation and triggers HCG-H production. In contrast, inhibition of the TGF-ß/activin/nodal pathway decreases the ability of hESC to form trophoblast-like cells. Information about the conditions needed for hESC differentiation toward trophoblast-like cells helps us to find an optimal model for studying the early development of human trophoblasts in normal and in complicated pregnancy.


Assuntos
Proteína Morfogenética Óssea 4/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos , Ativinas/genética , Ativinas/metabolismo , Técnicas de Cultura de Células/métodos , Diferenciação Celular/genética , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Células-Tronco Embrionárias Humanas/fisiologia , Humanos , Proteína Nodal/genética , Proteína Nodal/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Trofoblastos/fisiologia
12.
Nature ; 545(7654): 305-310, 2017 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-28489816

RESUMO

Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment.


Assuntos
Microbioma Gastrointestinal/imunologia , Hemangioma Cavernoso do Sistema Nervoso Central/imunologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Imunidade Inata , Receptor 4 Toll-Like/imunologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Suscetibilidade a Doenças , Células Endoteliais/metabolismo , Feminino , Vida Livre de Germes , Bactérias Gram-Negativas/imunologia , Hemangioma Cavernoso do Sistema Nervoso Central/microbiologia , Humanos , Injeções Intravenosas , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Transdução de Sinais , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/genética
14.
Nat Genet ; 48(9): 1043-8, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27455348

RESUMO

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.


Assuntos
Esclerose Amiotrófica Lateral/genética , Predisposição Genética para Doença , Proteínas Munc18/genética , Mutação/genética , Proteínas da Mielina/genética , Proteínas/genética , Esclerose Amiotrófica Lateral/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Estudo de Associação Genômica Ampla , Humanos , Países Baixos/epidemiologia
15.
Eur Neuropsychopharmacol ; 26(9): 1475-1483, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27461515

RESUMO

The reasons for variability in treatment response in major depressive disorder (MDD) are not fully understood, but there is accumulating evidence suggesting that therapeutic outcomes of antidepressants can be influenced by genetic factors. In the present study we applied the microarray Illumina platform for whole genome expression profiling in depressive patients treated with escitalopram medication in order to identify genes underlying response to antidepressant treatment. The initial study sample consisted of 135 outpatients with major depressive disorder (mean age 31.1±11.6 years, 68% females) treated with escitalopram 10-20mg/day for 12 weeks, from which 87 patients (55 females) were included in gene expression analyzing. The gene expression profiles were measured on peripheral blood cells at baseline, at week 4 and at the end of treatment (week 12) using BeadChips Illumina. The fold change was used to demonstrate rate of changes in average gene expressions between studied groups. Statistical analyses were performed using the false discovery rate (FDR). The most interesting gene, which showed the predictive effect on treatment outcome by delineating low dose responders and treatment-resistant patients at the beginning of medication, was NLGN2, belonging to a family of neuronal cell surface proteins and involving in synapse formation. In addition, the several gene clusters, related to immune response, signal transduction and neurotrophin pathway, have distinguished responders from non-responders at the week 4 of treatment. After 4 weeks of escitalopram treatment (10mg/day), the YWHAZ gene has showed the highest transcriptional change in responders as compared with non-responders. Finally, at the end of the treatment we noticed that at least three genes (NR2C2, ZNF641, FKBP1A) have been strongly associated with resistance to escitalopram. Thus the results of this study support that exploration of peripheral gene expression is a useful tool in the further identification of novel genetic biomarkers for antidepressant treatment response.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Adulto , Feminino , Perfilação da Expressão Gênica , Genoma , Humanos , Masculino , Análise em Microsséries , Escalas de Graduação Psiquiátrica , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Proteínas de Ligação a Tacrolimo/genética , Transativadores/genética , Resultado do Tratamento
16.
PLoS One ; 10(10): e0141351, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26496489

RESUMO

Allele-specific gene expression associated with genetic variation in regulatory regions can play an important role in the development of complex traits. We hypothesized that polymorphisms in microRNA (miRNA) response elements (MRE-SNPs) that either disrupt a miRNA binding site or create a new miRNA binding site can affect the allele-specific expression of target genes. By integrating public expression quantitative trait locus (eQTL) data, miRNA binding site predictions, small RNA sequencing, and Argonaute crosslinking immunoprecipitation (AGO-CLIP) datasets, we identified genetic variants that can affect gene expression by modulating miRNA binding efficiency. We also identified MRE-SNPs located in regions associated with complex traits, indicating possible causative mechanisms associated with these loci. The results of this study expand the current understanding of gene expression regulation and help to interpret the mechanisms underlying eQTL effects.


Assuntos
Expressão Gênica , MicroRNAs/metabolismo , Interferência de RNA , Regiões 3' não Traduzidas , Sequência de Bases , Sítios de Ligação , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Proteínas com Ferro-Enxofre/genética , Desequilíbrio de Ligação , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Locos de Características Quantitativas
17.
Methods Mol Biol ; 1182: 361-73, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25055923

RESUMO

Differential microRNA (miRNA) expression profiling by high-throughput methods has generated a vast amount of information about the complex role of these small regulatory molecules in a broad spectrum of human diseases. However, the results of such studies are often inconsistent, mostly due to the lack of cross-platform standardization, ongoing discovery of novel miRNAs, and small sample size. Therefore, a critical and systematic analysis of all available information is essential for successful identification of the most relevant miRNAs. Meta-analysis approach allows integrating the results from several independent studies in order to achieve greater statistical power and estimate the variability between the studies. Here we describe as an example the use of a robust rank aggregation (RRA) method for identification of miRNA meta-signature in lung cancer. This method analyzes prioritized gene lists and finds commonly overlapping genes, which are ranked consistently better than expected by chance. An RRA approach not only helps to prioritize the putative targets for further experimental studies but also highlights the challenges related with the development of miRNA-based tests and emphasizes the need for rigorous evaluation of the results before proceeding to clinical trials.


Assuntos
Perfilação da Expressão Gênica/métodos , MicroRNAs/genética , Animais , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/genética
18.
Curr Genet ; 60(1): 11-6, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23842853

RESUMO

Human mitochondrial DNA (mtDNA) research has entered a massively parallel sequencing (MPS) era, providing deep insight into mtDNA genomics and molecular diagnostics. Analysis can simultaneously include coding and control regions, many samples can be studied in parallel, and even minor heteroplasmic changes can be detected. We investigated heteroplasmy using 16 different tissues from three unrelated males aged 40-54 years at the time of death. mtDNA was enriched using two independent overlapping long-range PCR amplicons and analysed by employing illumina paired-end sequencing. Point mutation heteroplasmy at position 16,093 (m.16093T > C) in the non-coding regulatory region showed great variability among one of the studied individuals; heteroplasmy extended from 5.1 % in red bone marrow to 62.0 % in the bladder. Red (5.1 %) and yellow bone marrow (8.9 %) clustered into one group and two arteries and two aortas from different locations into another (31.2-50.9 %), giving an ontogenetic explanation for the formation of somatic mitochondrial heteroplasmy. Our results demonstrate that multi-tissue screening using MPS provides surprising data even when there is a limited number (3) of study subjects and they give reason to speculate that mtDNA heteroplasmic frequency, distribution, and even its possible role in complex diseases or phenotypes seem to be underestimated.


Assuntos
DNA Mitocondrial , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Genoma Mitocondrial , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Especificidade de Órgãos/genética , Mutação Puntual
19.
J Psychopharmacol ; 27(10): 915-20, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23926243

RESUMO

Although antidepressants are widely used in the pharmacotherapy of major depressive disorder (MDD), their efficacy is still insufficient as approximately one-third of the patients do not fully recover even after several treatment trials. Inter-individual genetic differences are thought to contribute to the variability in antidepressant response; however, current findings from pharmacogenetic studies are uncertain or not clearly replicated. Here we report the first application of full exome sequencing for the analysis of pharmacogenomics on antidepressant treatment. After 12 weeks of treatment with the selective serotonin re-uptake inhibitor escitalopram, we selected five clear responders and five clear non-responders for exome sequencing. By comparing the allele counts of previously known single nucleotide polymorphisms and novel polymorphisms we selected 38 markers for further genotyping in two independent patient samples treated with escitalopram (n=116 and n=394). The A allele, carried by approximately 30% of the patients with MDD, of rs41271330 in the bone morphogenetic protein (BMP5) gene showed strong association with worse treatment response in both sample sets (p=0.001), indicating that this is an promising pharmacogenetic marker for prediction of antidepressant therapeutic outcome.


Assuntos
Proteína Morfogenética Óssea 5/genética , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Exoma/genética , Adulto , Alelos , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Inibidores de Captação de Serotonina/uso terapêutico , Resultado do Tratamento
20.
PLoS Genet ; 9(1): e1003201, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23341781

RESUMO

Recently it has become clear that only a small percentage (7%) of disease-associated single nucleotide polymorphisms (SNPs) are located in protein-coding regions, while the remaining 93% are located in gene regulatory regions or in intergenic regions. Thus, the understanding of how genetic variations control the expression of non-coding RNAs (in a tissue-dependent manner) has far-reaching implications. We tested the association of SNPs with expression levels (eQTLs) of large intergenic non-coding RNAs (lincRNAs), using genome-wide gene expression and genotype data from five different tissues. We identified 112 cis-regulated lincRNAs, of which 45% could be replicated in an independent dataset. We observed that 75% of the SNPs affecting lincRNA expression (lincRNA cis-eQTLs) were specific to lincRNA alone and did not affect the expression of neighboring protein-coding genes. We show that this specific genotype-lincRNA expression correlation is tissue-dependent and that many of these lincRNA cis-eQTL SNPs are also associated with complex traits and diseases.


Assuntos
Regulação da Expressão Gênica , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , RNA Longo não Codificante , Estudo de Associação Genômica Ampla , Genótipo , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Distribuição Tecidual
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA