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1.
Nat Genet ; 51(8): 1207-1214, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31308545

RESUMO

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

2.
Mol Ther Nucleic Acids ; 17: 374-387, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31302497

RESUMO

Small non-coding RNAs (sncRNAs), including microRNAs (miRNAs) are important post-transcriptional gene expression regulators relevant in physiological and pathological processes. Here, we combined a high-throughput functional screening (HTFS) platform with a library of antisense oligonucleotides (ASOs) to systematically identify sncRNAs that affect neuronal cell survival in basal conditions and in response to oxidative stress (OS), a major hallmark in neurodegenerative diseases. We considered hits commonly detected by two statistical methods in three biological replicates. Forty-seven ASOs targeting miRNAs (miRNA-ASOs) consistently decreased cell viability under basal conditions. A total of 60 miRNA-ASOs worsened cell viability impairment mediated by OS, with 36.6% commonly affecting cell viability under basal conditions. In addition, 40 miRNA-ASOs significantly protected neuronal cells from OS. In agreement with cell viability impairment, damaging miRNA-ASOs specifically induced increased free radical biogenesis. miRNAs targeted by the detrimental ASOs are enriched in the fraction of miRNAs downregulated by OS, suggesting that the miRNA expression pattern after OS contributes to neuronal damage. The present HTFS highlighted potentially druggable sncRNAs. However, future studies are needed to define the pathways by which the identified ASOs regulate cell survival and OS response and to explore the potential of translating the current findings into clinical applications.

3.
Toxicol Sci ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31359052

RESUMO

Cardiovascular drug toxicity is responsible for 17% of drug withdrawals in clinical phases, half of post-marketed drug withdrawals and remains an important adverse effect of several marketed drugs. Early assessment of drug-induced cardiovascular toxicity is mandatory and typically done in cellular systems and mammals. Current in vitro screening methods allow high throughput but are biologically reductionist. The use of mammal models, which allow a better translatability for predicting clinical outputs, is low-throughput, highly expensive and ethically controversial. Given the analogies between the human and the zebrafish cardiovascular systems, we propose the use of zebrafish larvae during early drug discovery phases as a balanced model between biological translatability and screening throughput for addressing potential liabilities. To this end, we have developed a high-throughput screening platform that enables fully automatized in vivo image acquisition and analysis to extract a plethora of relevant cardiovascular parameters: heart rate, arrhythmia, AV blockage, ejection fraction and blood flow, among others. We have used this platform to address the predictive power of zebrafish larvae for detecting potential cardiovascular liabilities in humans. We tested a chemical library of 92 compounds with known clinical cardiotoxicity profiles. The cross-comparison with clinical data and data acquired from human induced pluripotent stem cell cardiomyocytes (hiPSC-CM) calcium imaging showed that zebrafish larvae allow a more reliable prediction of cardiotoxicity than cellular systems. Interestingly, our analysis with zebrafish yields similar predictive performance as previous validation meta-studies performed with dogs, the standard regulatory preclinical model for predicting cardiotoxic liabilities prior to clinical phases.

4.
Hum Mutat ; 40(1): 115-126, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30353964

RESUMO

In recent years, next-generation sequencing (NGS) has become a cornerstone of clinical genetics and diagnostics. Many clinical applications require high precision, especially if rare events such as somatic mutations in cancer or genetic variants causing rare diseases need to be identified. Although random sequencing errors can be modeled statistically and deep sequencing minimizes their impact, systematic errors remain a problem even at high depth of coverage. Understanding their source is crucial to increase precision of clinical NGS applications. In this work, we studied the relation between recurrent biases in allele balance (AB), systematic errors, and false positive variant calls across a large cohort of human samples analyzed by whole exome sequencing (WES). We have modeled the AB distribution for biallelic genotypes in 987 WES samples in order to identify positions recurrently deviating significantly from the expectation, a phenomenon we termed allele balance bias (ABB). Furthermore, we have developed a genotype callability score based on ABB for all positions of the human exome, which detects false positive variant calls that passed state-of-the-art filters. Finally, we demonstrate the use of ABB for detection of false associations proposed by rare variant association studies. Availability: https://github.com/Francesc-Muyas/ABB.

5.
Psychiatr Genet ; 27(4): 152-158, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28368970

RESUMO

Anorexia nervosa (AN) is a serious and heritable psychiatric disorder. To date, studies of copy number variants (CNVs) have been limited and inconclusive because of small sample sizes. We conducted a case-only genome-wide CNV survey in 1983 female AN cases included in the Genetic Consortium for Anorexia Nervosa. Following stringent quality control procedures, we investigated whether pathogenic CNVs in regions previously implicated in psychiatric and neurodevelopmental disorders were present in AN cases. We observed two instances of the well-established pathogenic CNVs in AN cases. In addition, one case had a deletion in the 13q12 region, overlapping with a deletion reported previously in two AN cases. As a secondary aim, we also examined our sample for CNVs over 1 Mbp in size. Out of the 40 instances of such large CNVs that were not implicated previously for AN or neuropsychiatric phenotypes, two of them contained genes with previous neuropsychiatric associations, and only five of them had no associated reports in public CNV databases. Although ours is the largest study of its kind in AN, larger datasets are needed to comprehensively assess the role of CNVs in the etiology of AN.


Assuntos
Anorexia Nervosa/genética , Anorexia Nervosa/psicologia , Variações do Número de Cópias de DNA/genética , Adulto , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
6.
Epigenomics ; 8(1): 43-54, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26679211

RESUMO

BACKGROUND: In utero exposure to xenostrogens may modify the epigenome. We explored the association of prenatal exposure to mixtures of xenoestrogens and genome-wide placental DNA methylation. MATERIALS & METHODS: Sex-specific associations between methylation changes in placental DNA by doubling the concentration of TEXB-alpha exposure were evaluated by robust multiple linear regression. Two CpG sites were selected for validation and replication in additional male born placentas. RESULTS: No significant associations were found, although the top significant CpGs in boys were located in the LRPAP1, HAGH, PPARGC1B, KCNQ1 and KCNQ1DN genes, previously associated to birth weight, Type 2 diabetes, obesity or steroid hormone signaling. Neither technical validation nor biological replication of the results was found in boys for LRPAP and PPARGC1B. CONCLUSION: Some suggestive genes were differentially methylated in boys in relation to prenatal xenoestrogen exposure, but our initial findings could not be validated or replicated.


Assuntos
Metilação de DNA , Estrogênios/toxicidade , Estudo de Associação Genômica Ampla/métodos , Placenta/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/genética , Peso ao Nascer , Proteínas de Transporte/genética , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Canal de Potássio KCNQ1/genética , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Gravidez , Proteínas de Ligação a RNA , Fatores Sexuais , Tioléster Hidrolases/genética
7.
Bioinformatics ; 32(5): 673-81, 2016 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-26530722

RESUMO

MOTIVATION: Most computational tools for small non-coding RNAs (sRNA) sequencing data analysis focus in microRNAs (miRNAs), overlooking other types of sRNAs that show multi-mapping hits. Here, we have developed a pipeline to non-redundantly quantify all types of sRNAs, and extract patterns of expression in biologically defined groups. We have used our tool to characterize and profile sRNAs in post-mortem brain samples of control individuals and Parkinson's disease (PD) cases at early-premotor and late-symptomatic stages. RESULTS: Clusters of co-expressed sRNAs mapping onto tRNAs significantly separated premotor and motor cases from controls. A similar result was obtained using a matrix of miRNAs slightly varying in sequence (isomiRs). The present framework revealed sRNA alterations at premotor stages of PD, which might reflect initial pathogenic perturbations. This tool may be useful to discover sRNA expression patterns linked to different biological conditions. AVAILABILITY AND IMPLEMENTATION: The full code is available at http://github.com/lpantano/seqbuster CONTACT: lpantano@hsph.harvard.edu or eulalia.marti@crg.eu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Doença de Parkinson , Tonsila do Cerebelo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MicroRNAs , Análise de Sequência de RNA
8.
Brief Funct Genomics ; 14(5): 305-14, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25877305

RESUMO

In the past decade, the view on genomic structural variation (SV) has been changed completely. SVs, previously considered rare events, are now recognized as the largest source of interindividual genetic variation affecting more bases than single nucleotide polymorphisms, variable number of tandem repeats and other small genetic variants. They have also been shown to play a role in phenotypic variation and in disease. In this review, the authors will provide an introduction to SV; a short historical perspective on the research of this source of genomic variation; a description of the types of structural variants, and on how they may have arisen; and an overview on methods of detecting structural variants, focusing on the analysis of high-throughput sequencing data.


Assuntos
Genoma Humano , Variação Estrutural do Genoma/genética , Genômica/história , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , História do Século XX , História do Século XXI , Humanos
9.
Pain ; 155(6): 1102-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24582949

RESUMO

Fibromyalgia (FM) is a highly disabling syndrome defined by a low pain threshold and a permanent state of pain. The mechanisms explaining this complex disorder remain unclear, and its genetic factors have not yet been identified. With the aim of elucidating FM genetic susceptibility factors, we selected 313 FM cases having low comorbidities, and we genotyped them on the Illumina 1 million duo array. Genotypic data from 220 control women (Illumina 610k array) was obtained for genome-wide association scan (GWAS) analysis. Copy number variants in FM susceptibility were analyzed by array comparative genomic hybridization (aCGH) experiments on pooled samples using the Agilent 2×400K platform. No single nucleotide polymorphism (SNP) reached GWAS association threshold, but 21 of the most associated SNPs were chosen for replication in 952 cases and 644 controls. Four of the SNPs selected for replication showed a nominal association in the joint analysis, and rs11127292 (MYT1L) was found to be associated to FM with low comorbidities (P=4.28×10(-5), odds ratio [95% confidence interval]=0.58 [0.44-0.75]). aCGH detected 5 differentially hybridized regions. They were followed up, and an intronic deletion in NRXN3 was demonstrated to be associated to female cases of FM with low levels of comorbidities (P=.021, odds ratio [95% confidence interval]=1.46 [1.05-2.04]). Both GWAS and aCGH results point to a role for the central nervous system in FM genetic susceptibility. If the proposed FM candidate genes were further validated in replication studies, this would highlight a neurocognitive involvement in agreement with latest reports.


Assuntos
Sistema Nervoso Central/fisiologia , Variações do Número de Cópias de DNA/genética , Fibromialgia/diagnóstico , Fibromialgia/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Sistema Nervoso Central/patologia , Análise por Conglomerados , Estudos de Coortes , Feminino , Humanos
10.
Stat Med ; 33(1): 117-28, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23825013

RESUMO

The analysis of concordance among repeated measures has received a huge amount of attention in the statistical literature leading to a range of different approaches. However, because all the approaches are able to assess the closeness among the readings taken on the same subject, the conclusions about the degree of concordance should be similar regardless the approach applied. Here, two indices to assess the concordance among continuous repeated measures, the intraclass correlation coefficient and the total deviation index, are applied and compared in two case examples. The first example concerns the repeatability of individual nutrient allocation strategy assessed by stable isotope analysis. The second example dealt with the assessment of the concordance of functional magnetic resonance imaging data that shows spatial correlation. The results differ depending upon the approach applied leading to contradictory conclusions about the degree of concordance. The reason behind these results is discussed reaching the conclusion that the total deviation index is just assessing agreement among repeated measurements, whereas the intraclass correlation coefficient assesses the concept of distinguishability among subjects that involves agreement among repeated measurements and spread of subjects at once. Therefore, the best way to select the right approach is to understand the right question behind the research hypothesis.


Assuntos
Biometria/métodos , Reprodutibilidade dos Testes , Albuminas/análise , Animais , Charadriiformes/metabolismo , Ovos/análise , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Isótopos de Nitrogênio/análise , Limiar Sensorial/fisiologia
11.
Eur Neuropsychopharmacol ; 24(3): 420-4, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24230997

RESUMO

Methadone maintenance treatment is the most widely-used therapy in opioid dependence, but some patients relapse or drop out from treatment. We genotyped a genetic variant in the succinic semialdehyde dehydrogenase enzyme gene, ALDH5A1, and found that subjects carrying the T variant allele have a higher risk to be nonresponders to methadone treatment (OR=3.16; 95% CI [1.48-6.73], P=0.0024). This could be due to a reduction in the ALDH5A1 enzyme activity, that would increase endogenous gamma-hydroxbutyric acid (GHB) and gamma-aminobutyric acid (GABA) levels and therefore, inducing symptoms such as sedation and impaired pschomotor performance. These neuropsychological effects related with the reduction in enzyme activity could be responsible for a higher propensity to relapse in these genetically predisposed patients.


Assuntos
Metadona/uso terapêutico , Entorpecentes/uso terapêutico , Tratamento de Substituição de Opiáceos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/genética , Succinato-Semialdeído Desidrogenase/genética , Adolescente , Adulto , Idoso , Alelos , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Inquéritos e Questionários , Falha de Tratamento , Adulto Jovem
12.
Eur J Hum Genet ; 22(4): 528-34, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23942198

RESUMO

Genetic diagnostics of phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficient hyperphenylalaninemia (BH4DH) rely on methods that scan for known mutations or on laborious molecular tools that use Sanger sequencing. We have implemented a novel and much more efficient strategy based on high-throughput multiplex-targeted resequencing of four genes (PAH, GCH1, PTS, and QDPR) that, when affected by loss-of-function mutations, cause PKU and BH4DH. We have validated this approach in a cohort of 95 samples with the previously known PAH, GCH1, PTS, and QDPR mutations and one control sample. Pooled barcoded DNA libraries were enriched using a custom NimbleGen SeqCap EZ Choice array and sequenced using a HiSeq2000 sequencer. The combination of several robust bioinformatics tools allowed us to detect all known pathogenic mutations (point mutations, short insertions/deletions, and large genomic rearrangements) in the 95 samples, without detecting spurious calls in these genes in the control sample. We then used the same capture assay in a discovery cohort of 11 uncharacterized HPA patients using a MiSeq sequencer. In addition, we report the precise characterization of the breakpoints of four genomic rearrangements in PAH, including a novel deletion of 899 bp in intron 3. Our study is a proof-of-principle that high-throughput-targeted resequencing is ready to substitute classical molecular methods to perform differential genetic diagnosis of hyperphenylalaninemias, allowing the establishment of specifically tailored treatments a few days after birth.


Assuntos
Biopterina/análogos & derivados , Sequenciamento de Nucleotídeos em Larga Escala , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/genética , Biopterina/deficiência , Biopterina/genética , Estudos de Coortes , Biologia Computacional , Éxons , Biblioteca Gênica , Rearranjo Gênico , Genoma Humano , Genômica , Genótipo , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Análise de Sequência de DNA , Deleção de Sequência
13.
PLoS One ; 8(9): e74873, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24098674

RESUMO

INTRODUCTION: Fibromyalgia (FM) is mainly characterized by widespread pain and multiple accompanying symptoms, which hinder FM assessment and management. In order to reduce FM heterogeneity we classified clinical data into simplified dimensions that were used to define FM subgroups. MATERIAL AND METHODS: 48 variables were evaluated in 1,446 Spanish FM cases fulfilling 1990 ACR FM criteria. A partitioning analysis was performed to find groups of variables similar to each other. Similarities between variables were identified and the variables were grouped into dimensions. This was performed in a subset of 559 patients, and cross-validated in the remaining 887 patients. For each sample and dimension, a composite index was obtained based on the weights of the variables included in the dimension. Finally, a clustering procedure was applied to the indexes, resulting in FM subgroups. RESULTS: VARIABLES CLUSTERED INTO THREE INDEPENDENT DIMENSIONS: "symptomatology", "comorbidities" and "clinical scales". Only the two first dimensions were considered for the construction of FM subgroups. Resulting scores classified FM samples into three subgroups: low symptomatology and comorbidities (Cluster 1), high symptomatology and comorbidities (Cluster 2), and high symptomatology but low comorbidities (Cluster 3), showing differences in measures of disease severity. CONCLUSIONS: We have identified three subgroups of FM samples in a large cohort of FM by clustering clinical data. Our analysis stresses the importance of family and personal history of FM comorbidities. Also, the resulting patient clusters could indicate different forms of the disease, relevant to future research, and might have an impact on clinical assessment.


Assuntos
Fibromialgia/classificação , Fibromialgia/epidemiologia , Análise de Variância , Análise por Conglomerados , Comorbidade , Humanos , Espanha/epidemiologia
14.
PLoS One ; 8(5): e63377, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23704902

RESUMO

UNLABELLED: Next-generation sequencing technologies expedited research to develop efficient computational tools for the identification of structural variants (SVs) and their use to study human diseases. As deeper data is obtained, the existence of higher complexity SVs in some genomes becomes more evident, but the detection and definition of most of these complex rearrangements is still in its infancy. The full characterization of SVs is a key aspect for discovering their biological implications. Here we present a pipeline (PeSV-Fisher) for the detection of deletions, gains, intra- and inter-chromosomal translocations, and inversions, at very reasonable computational costs. We further provide comprehensive information on co-localization of SVs in the genome, a crucial aspect for studying their biological consequences. The algorithm uses a combination of methods based on paired-reads and read-depth strategies. PeSV-Fisher has been designed with the aim to facilitate identification of somatic variation, and, as such, it is capable of analysing two or more samples simultaneously, producing a list of non-shared variants between samples. We tested PeSV-Fisher on available sequencing data, and compared its behaviour to that of frequently deployed tools (BreakDancer and VariationHunter). We have also tested this algorithm on our own sequencing data, obtained from a tumour and a normal blood sample of a patient with chronic lymphocytic leukaemia, on which we have also validated the results by targeted re-sequencing of different kinds of predictions. This allowed us to determine confidence parameters that influence the reliability of breakpoint predictions. AVAILABILITY: PeSV-Fisher is available at http://gd.crg.eu/tools.


Assuntos
Algoritmos , Bases de Dados Genéticas , Variação Estrutural do Genoma/genética , Análise de Sequência de DNA/métodos , Biologia Computacional , Genoma Humano/genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética
15.
RNA Biol ; 10(7): 1093-106, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23673382

RESUMO

MicroRNAs (miRNAs) and other small non-coding RNAs (sncRNAs) are post-transcriptional regulators of gene expression, playing key roles in neuronal development, plasticity, and disease. Transcriptome deregulation caused by miRNA dysfunction has been associated to neurodegenerative diseases. Parkinson disease (PD) is the second most common neurodegenerative disease showing deregulation of the coding and small non-coding transcriptome. On profiling sncRNA in PD brain areas differently affected, we found that upregulation of a small vault RNA (svtRNA2-1a) is widespread in PD brains, occurring early in the course of the disease (at pre-motor stages). SvtRNA2-1a biogenesis was dependent on Dicer activity on its precursor (vtRNA2-1) but independent of Drosha endonuclease, unlike the canonical miRNAs. Although endogenous svtRNA2-1a was enriched in Ago-2 immunoprecipitates in differentiated SH-SY5Y neuronal cells, overexpression of svtRNA2-1a induced subtle transcriptomic changes, suggesting that gene expression regulation may involve other mechanisms than mRNA decay only. Function enrichment analysis of the genes deregulated by svtRNA2-1a overexpression or svtRNA2-1a predicted targets identified pathways related to nervous system development and cell type specification. The expression pattern of svtRNA2-1a during development and aging of the human brain and the detrimental consequences of a svtRNA2-1a mimic overexpression in neuronal cells further indicate that low svtRNA2-1a levels may be important for the maintenance of neurons. Our results suggest that early svtRNA2-1a upregulation in PD may contribute to perturbations of gene expression networks, underlying metabolic impairment and cell dysfunction. A better understanding of the pathways regulated by svtRNA2-a, and also the mechanisms regulating its expression should facilitate the identification of new targets for therapeutic approaches in PD.


Assuntos
Regulação da Expressão Gênica , Neurônios/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Pequeno RNA não Traduzido/genética , Proteínas Argonauta/metabolismo , Sequência de Bases , Encéfalo/metabolismo , Diferenciação Celular/genética , Linhagem Celular , Expressão Gênica , Humanos , Dados de Sequência Molecular , Neurônios/citologia , Conformação de Ácido Nucleico , Fases de Leitura Aberta , Doença de Parkinson/tratamento farmacológico , Pequeno RNA não Traduzido/química , Reprodutibilidade dos Testes , Ribonuclease III/metabolismo , Alinhamento de Sequência , Transcriptoma , Regulação para Cima
16.
J Psychiatry Neurosci ; 37(4): 273-81, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22433450

RESUMO

BACKGROUND: Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neuro transmission in the pathogenesis of obsessive-compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes. METHODS: Between 2003 and 2008, we performed a case-control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3' untranslated region (3' UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions. RESULTS: We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37-4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22-3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions. LIMITATIONS: Study limitations included the risk of population stratification associated with the case-control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3' UTR and exon 13 of GRIN2B. CONCLUSION: Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may constitute a useful tool to disentangle the complex genetic basis of the disorder.


Assuntos
Predisposição Genética para Doença , Transtorno Obsessivo-Compulsivo/genética , Polimorfismo de Nucleotídeo Único , Receptores de N-Metil-D-Aspartato/genética , Adolescente , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade
17.
Am J Respir Crit Care Med ; 185(9): 937-43, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22323304

RESUMO

RATIONALE: Epigenetic changes may play a role in the occurrence of asthma-related phenotypes. OBJECTIVES: To identify epigenetic marks in terms of DNA methylation of asthma-related phenotypes in childhood, and to assess the effect of prenatal exposures and genetic variation on these epigenetic marks. METHODS: Data came from two cohorts embedded in the Infancia y Medio Ambiente (INMA) PROJECT: Menorca (n = 122) and Sabadell (n = 236). Wheezing phenotypes were defined at age 4-6 years. Cytosine-guanine (CpG) dinucleotide site DNA methylation differences associated with wheezing phenotypes were screened in children of the Menorca study using the Illumina GoldenGate Panel I. Findings were validated and replicated using pyrosequencing. Information on maternal smoking and folate supplement use was obtained through questionnaires. Dichlorodiphenyldichloroethylene was measured in cord blood or maternal serum. Genotypes were extracted from genome-wide data. MEASUREMENT AND MAIN RESULTS: Screening identified lower DNA methylation at a CpG site in the arachidonate 12-lipoxygenase (ALOX12) gene in children having persistent wheezing compared with those never wheezed (P = 0.003). DNA hypomethylation at ALOX12 loci was associated with higher risk of persistent wheezing in the Menorca study (odds ratio per 1% methylation decrease, 1.13; 95% confidence interval, 0.99-1.29; P = 0.077) and in the Sabadell study (odds ratio, 1.16; 95% confidence interval, 1.03-1.37; P = 0.017). Higher levels of prenatal dichlorodiphenyldichloroethylene were associated with DNA hypomethylation of ALOX12 in the Menorca study (P = 0.033), but not in the Sabadell study (P = 0.377). ALOX12 DNA methylation was strongly determined by underlying genetic polymorphisms. CONCLUSIONS: DNA methylation of ALOX12 may be an epigenetic biomarker for the risk of asthma-related phenotypes.


Assuntos
Araquidonato 12-Lipoxigenase/genética , Metilação de DNA/fisiologia , Sons Respiratórios/etiologia , Araquidonato 12-Lipoxigenase/fisiologia , Criança , Pré-Escolar , Epigênese Genética/genética , Epigênese Genética/fisiologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Sons Respiratórios/genética , Fatores de Risco
18.
Nature ; 475(7354): 101-5, 2011 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-21642962

RESUMO

Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.


Assuntos
Genoma Humano/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Sequência de Aminoácidos , Animais , Proteínas de Transporte/genética , Análise Mutacional de DNA , Humanos , Carioferinas/genética , Dados de Sequência Molecular , Fator 88 de Diferenciação Mieloide/química , Fator 88 de Diferenciação Mieloide/genética , Receptor Notch1/genética , Receptores Citoplasmáticos e Nucleares/genética , Reprodutibilidade dos Testes
19.
Hum Mol Genet ; 20(15): 3067-78, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21558425

RESUMO

MicroRNAs (miRNAs) are post-transcriptional gene expression regulators, playing key roles in neuronal development, plasticity and disease. Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the presence of protein inclusions or Lewy bodies and a progressive loss of dopaminergic neurons in the midbrain. Here, we have evaluated miRNA expression deregulation in PD brain samples. MiRNA expression profiling revealed decreased expression of miR-34b and miR-34c in brain areas with variable neuropathological affectation at clinical (motor) stages (Braak stages 4 and 5) of the disease, including the amygdala, frontal cortex, substantia nigra and cerebellum. Furthermore, misregulation of miR-34b/c was detected in pre-motor stages (stages 1-3) of the disease, and thus in cases that did not receive any PD-related treatment during life. Depletion of miR-34b or miR-34c in differentiated SH-SY5Y dopaminergic neuronal cells resulted in a moderate reduction in cell viability that was accompanied by altered mitochondrial function and dynamics, oxidative stress and reduction in total cellular adenosin triphosphate content. MiR-34b/c downregulation was coupled to a decrease in the expression of DJ1 and Parkin, two proteins associated to familial forms of PD that also have a role in idiopathic cases. Accordingly, DJ1 and Parkin expression was reduced in PD brain samples displaying strong miR-34b/c downregulation. We propose that early deregulation of miR-34b/c in PD triggers downstream transcriptome alterations underlying mitochondrial dysfunction and oxidative stress, which ultimately compromise cell viability. A better understanding of the cellular pathways controlling and/or controlled by miR-34b/c should allow identification of targets for development of therapeutic approaches.


Assuntos
MicroRNAs/genética , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Western Blotting , Linhagem Celular Tumoral , Humanos , Microscopia Eletrônica de Transmissão , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/ultraestrutura , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real
20.
Arthritis Rheum ; 63(7): 1860-5, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21400479

RESUMO

OBJECTIVE: The LCE3C_LCE3B-del variant is associated with psoriasis and rheumatoid arthritis. Its role in psoriatic arthritis (PsA) is unclear, however, as shown by 3 recent studies with contradictory results. In order to investigate whether LCE3C_LCE3B-del constitutes a risk factor for PsA susceptibility, we first tested this variant in patients with PsA from Spanish and Italian populations and then performed a meta-analysis including the previous case-control studies. METHODS: We genotyped LCE3C_LCE3B-del and its tag single-nucleotide polymorphism (SNP), rs4112788, in an original discovery cohort of 424 Italian patients with PsA and 450 unaffected control subjects. A Spanish replication cohort consisting of 225 patients with PsA and 469 control subjects was also genotyped. A meta-analysis considering 7,758 control subjects and 2,325 patients with PsA was also performed. RESULTS: We observed a significant association between PsA and the LCE3C_LCE3B-del tag SNP in the Italian and Spanish cohorts, with an overall corrected P value of 0.00019 and a corresponding odds ratio of 1.35 (95% confidence interval 1.14-1.59). Stratified analyses by subphenotype indicated a stronger association for patients with oligoarticular disease. Meta-analysis including data from all previous published studies confirmed an association of PsA with the LCE3C_LCE3B-del tag SNP. CONCLUSION: LCE3C_LCE3B-del is a susceptibility factor for PsA, confirming the existence of a shared risk factor involving the epidermal skin barrier in autoimmune disorders.


Assuntos
Artrite Psoriásica/genética , Proteínas Ricas em Prolina do Estrato Córneo/genética , Predisposição Genética para Doença , Adulto , Alelos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Espanha
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