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1.
Biol Psychiatry ; 86(6): 433-442, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202489

RESUMO

The identification and understanding of resilience mechanisms holds potential for the development of mechanistically informed prevention and interventions in psychiatry. However, investigating resilience mechanisms is conceptually and methodologically challenging because resilience does not merely constitute the absence of disease-specific risk but rather reflects active processes that aid in the maintenance of physiological and psychological homeostasis across a broad range of environmental circumstances. In this conceptual review, we argue that the principle used in gene-by-environment interaction studies may help to unravel resilience mechanisms on different investigation levels. We present how this could be achieved by top-down designs that start with gene-by-environment interaction effects on disease phenotypes as well as by bottom-up approaches that start at the molecular level. We also discuss how recent technological advances may improve both top-down and bottom-up strategies.

2.
Bipolar Disord ; 2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29956436

RESUMO

OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

3.
Front Psychiatry ; 9: 207, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29904359

RESUMO

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

4.
JAMA Psychiatry ; 75(1): 65-74, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29121268

RESUMO

Importance: Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). Objectives: To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. Design, Setting, and Participants: A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. Main Outcomes and Measures: Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. Results: Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. Conclusions and Relevance: This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

5.
J Affect Disord ; 228: 20-25, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29197740

RESUMO

BACKGROUND: Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. METHODS: We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan. RESULTS: Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system. LIMITATIONS: Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients. CONCLUSIONS: Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.


Assuntos
Transtorno Bipolar/genética , Encéfalo/crescimento & desenvolvimento , Proteína Adaptadora GRB2/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais , Algoritmos , Transtorno Bipolar/metabolismo , Transtorno Bipolar/fisiopatologia , Encéfalo/metabolismo , Feminino , Proteína Adaptadora GRB2/genética , Expressão Gênica , Genes erbB-2/fisiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA/metabolismo
6.
J Mol Neurosci ; 62(3-4): 304-308, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28616776

RESUMO

Lithium has been used for more than six decades for the management of bipolar disorder (BD). In a previous transcriptomic study, we showed that patients affected by either BD or cluster headache, both disorders characterized by circadian disturbances and response to lithium in a subgroup of patients, have higher expression of the RNA binding motif (RNP1, RRM) protein 3 (RBM3) gene compared to controls. To investigate whether RBM3 could represent a biomarker of lithium response, we screened raw microarray expression data from lymphoblastoid cell lines (LCLs) derived from 20 BD patients, responders or non-responders to lithium. RBM3 was the most significantly differentially expressed gene in the list, being overexpressed in responders compared to non-responders (fold change = 2.0; p = 1.5 × 10-16). We therefore sought to validate the microarray finding by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and explore whether RBM3 expression was modulated by lithium treatment in vitro in LCLs as well as in human-derived neural progenitor cells (NPCs). Our findings confirmed the higher expression of RBM3 in responders compared to non-responders (fold change = 3.78; p = 0.0002). Lithium did not change RBM3 expression in LCLs in any of the groups, but it increased its expression in NPCs. While preliminary, our data suggest that higher levels of RBM3 might be required for better lithium response and that the expression of this gene could be modulated by lithium in a tissue-specific manner.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Bipolar/metabolismo , Compostos de Lítio/uso terapêutico , Proteínas de Ligação a RNA/metabolismo , Adolescente , Adulto , Sítios de Ligação , Biomarcadores/metabolismo , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/tratamento farmacológico , Estudos de Casos e Controles , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ligação Proteica , RNA/metabolismo , Proteínas de Ligação a RNA/química
7.
Nat Commun ; 8: 15497, 2017 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-28530238

RESUMO

Antidepressants (ADs) are the most common treatment for major depressive disorder (MDD). However, only ∼30% of patients experience adequate response after a single AD trial, and this variability remains poorly understood. Here, we investigated microRNAs (miRNAs) as biomarkers of AD response using small RNA-sequencing in paired samples from MDD patients enrolled in a large, randomized placebo-controlled trial of duloxetine collected before and 8 weeks after treatment. Our results revealed differential expression of miR-146a-5p, miR-146b-5p, miR-425-3p and miR-24-3p according to treatment response. These results were replicated in two independent clinical trials of MDD, a well-characterized animal model of depression, and post-mortem human brains. Furthermore, using a combination of bioinformatics, mRNA studies and functional in vitro experiments, we showed significant dysregulation of genes involved in MAPK/Wnt signalling pathways. Together, our results indicate that these miRNAs are consistent markers of treatment response and regulators of the MAPK/Wnt systems.

9.
Am J Med Genet A ; 173(2): 395-406, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27759917

RESUMO

We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders. © 2016 Wiley Periodicals, Inc.


Assuntos
Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Estudos de Associação Genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Canais de Potássio/genética , Receptores de Superfície Celular/genética , Regiões 5' não Traduzidas , Adolescente , Adulto , Apraxias/diagnóstico , Apraxias/genética , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Inversão Cromossômica , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Família Multigênica , Linhagem , Translocação Genética , Adulto Jovem
10.
Artigo em Inglês | MEDLINE | ID: mdl-29503977

RESUMO

Exposure to chronic stress, either repeated severe acute or moderate sustained stress, is one of the strongest risk factors for the development of psychopathologies such as post-traumatic stress disorder and depression. Chronic stress is linked with several lasting biological consequences, particularly to the stress endocrine system but also affecting intermediate phenotypes such as brain structure and function, immune function, and behavior. Although genetic predisposition confers a proportion of the risk, the most relevant molecular mechanisms determining those susceptible and resilient to the effects of stress and trauma may be epigenetic. Epigenetics refers to the mechanisms that regulate genomic information by dynamically changing the patterns of transcription and translation of genes. Mounting evidence from preclinical rodent and clinical population studies strongly support that epigenetic modifications can occur in response to traumatic and chronic stress. Here, we discuss this literature examining stress-induced epigenetic changes in preclinical models and clinical cohorts of stress and trauma occurring early in life or in adulthood. We highlight that a complex relationship between the timing of environmental stressors and genetic predispositions likely mediate the response to chronic stress over time, and that a better understanding of epigenetic changes is needed by further investigations in longitudinal and postmortem brain clinical cohorts.

11.
BMC Psychiatry ; 16(1): 286, 2016 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-27515700

RESUMO

BACKGROUND: The Synapsins (SYN1, SYN2, and SYN3) are important players in the adult brain, given their involvement in synaptic transmission and plasticity, as well as in the developing brain through roles in axon outgrowth and synaptogenesis. We and others previously reported gene expression dysregulation, both as increases and decreases, of Synapsins in mood disorders, but little is known about the regulatory mechanisms leading to these differences. Thus, we proposed to study DNA methylation at theses genes' promoter regions, under the assumption that altered epigenetic marks at key regulatory sites would be the cause of gene expression changes and thus part of the mood disorder etiology. METHODS: We performed CpG methylation mapping focusing on the three genes' predicted CpG islands using the Sequenom EpiTYPER platform. DNA extracted from post-mortem brain tissue (BA10) from individuals who had lived with bipolar disorder (BD), major depressive disorder (MDD), as well as psychiatrically healthy individuals was used. Differences in methylation across all CpGs within a CpG island and between the three diagnostic groups were assessed by 2-way mixed model analyses of variance. RESULTS: We found no significant results for SYN1 or SYN3, but there was a significant group difference in SYN2 methylation, as well as an overall pattern of hypomethylation across the CpG island. Furthermore, we found a significant inverse correlation of DNA methylation with SYN2a mRNA expression. CONCLUSIONS: These findings contribute to previous work showing dysregulation of Synapsins, particularly SYN2, in mood disorders and improve our understanding of the regulatory mechanisms that precipitate these changes likely leading to the BD or MDD phenotype.


Assuntos
Proteínas de Arabidopsis/genética , Transtorno Bipolar/genética , Proteínas de Ciclo Celular/genética , Metilação de DNA/genética , Transtorno Depressivo Maior/genética , Adulto , Ilhas de CpG , Feminino , Humanos , Masculino , Regiões Promotoras Genéticas/genética
12.
Hum Mol Genet ; 25(15): 3383-3394, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27329760

RESUMO

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 - 9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 - 9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

13.
Eur Neuropsychopharmacol ; 26(7): 1241-7, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27084304

RESUMO

Bipolar disorder (BD) has been suggested to be associated with accelerated aging and premature cell senescence. While findings on shorter telomeres in BD are controversial, a recent study showed that long-term lithium treatment correlates with longer telomeres in BD. In our study, we sought to investigate the correlation between leukocyte telomere length (LTL) and long-term lithium treatment in a sample of 200 BD patients characterized for lithium response. We also compared data from two different methods commonly used to measure telomere length, quantitative PCR (qPCR) and quantitative fluorescence in situ hybridization (Q-FISH). We also measured, for the first time, the effect of lithium in vitro on the expression of the telomerase gene in human-derived neural progenitor cells (NPCs). Our findings showed that LTL correlated negatively with age (p=0.0002) and was independent of sex, diagnosis, age at onset, suicidal behavior, number of mood episodes, response to lithium and use of other psychotropic medications. After correcting for age, LTL was positively correlated with lithium treatment duration in patients treated for more than two years (n=150, R=0.17, p=0.037). There was a significant correlation between data measured with qPCR and Q-FISH (p=0.012, R=0.826). Lithium treatment increased telomerase expression in NPCs, though this effect was not statistically significant. Our data support previous findings showing that long-term lithium treatment associates with longer telomeres in BD, though this effect appeared to be independent from clinical response to the treatment. Moreover, we suggested for the first time that lithium increases the expression of telomerase gene in human neural progenitor cells.


Assuntos
Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Compostos de Lítio/uso terapêutico , Telômero/efeitos dos fármacos , Telômero/metabolismo , Adulto , Fatores Etários , Transtorno Bipolar/genética , Linhagem Celular , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Reação em Cadeia da Polimerase , Fatores Sexuais , Telomerase/metabolismo , Encurtamento do Telômero/efeitos dos fármacos , Fatores de Tempo
14.
Lancet ; 387(10023): 1085-1093, 2016 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-26806518

RESUMO

BACKGROUND: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. METHODS: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. FINDINGS: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). INTERPRETATION: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. FUNDING: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.


Assuntos
Transtorno Bipolar/genética , Compostos de Lítio/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Transtorno Bipolar/tratamento farmacológico , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Resultado do Tratamento
15.
Am J Psychiatry ; 172(11): 1131-40, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26238605

RESUMO

OBJECTIVE: Gene expression dysregulation in the brain has been associated with bipolar disorder through candidate gene and microarray expression studies, but questions remain about isoform-specific dysregulation and the role of noncoding RNAs whose importance in the brain has been suggested recently but not yet characterized for bipolar disorder. METHOD: The authors used RNA sequencing, a powerful technique that captures the complexity of gene expression, in postmortem tissue from the anterior cingulate cortex from 13 bipolar disorder case subjects and 13 matched comparison subjects. Differential expression was computed, and a global pattern of downregulation was detected, with 10 transcripts significant at a false discovery rate ≤5%. Importantly, all 10 genes were also replicated in an independent RNA sequencing data set (N=61) from the anterior cingulate cortex. RESULTS: Among the most significant results were genes coding for class A G protein-coupled receptors: SSTR2 (somatostatin receptor 2), CHRM2 (cholinergic receptor, muscarinic 2), and RXFP1 (relaxin/insulin-like family peptide receptor 1). A gene ontology analysis of the entire set of differentially expressed genes pointed to an overrepresentation of genes involved in G protein-coupled receptor regulation. The top genes were followed up by querying the effect of treatment with mood stabilizers commonly prescribed in bipolar disorder, which showed that these drugs modulate expression of the candidate genes. CONCLUSIONS: By using RNA sequencing in the postmortem bipolar disorder brain, an interesting profile of G protein-coupled receptor dysregulation was identified, several new bipolar disorder genes were indicated, and the noncoding transcriptome in bipolar disorder was characterized. These findings have important implications with regard to fine-tuning our understanding of the bipolar disorder brain, as well as for identifying potential new drug target pathways.


Assuntos
Transtorno Bipolar/genética , Regulação da Expressão Gênica/genética , Giro do Cíngulo/metabolismo , RNA Mensageiro/metabolismo , Receptor Muscarínico M2/genética , Receptores Acoplados a Proteínas-G/genética , Receptores de Peptídeos/genética , Receptores de Somatostatina/genética , Adulto , Antimaníacos/farmacologia , Transtorno Bipolar/metabolismo , Carbamazepina/farmacologia , Estudos de Casos e Controles , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Compostos de Lítio/farmacologia , Masculino , Pessoa de Meia-Idade , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , RNA Mensageiro/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Receptor Muscarínico M2/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores de Peptídeos/efeitos dos fármacos , Receptores de Somatostatina/efeitos dos fármacos , Análise de Sequência de RNA , Ácido Valproico/farmacologia
16.
BMC Med Genomics ; 8: 35, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26130076

RESUMO

BACKGROUND: Small ncRNAs (sncRNAs) offer great hope as biomarkers of disease and response to treatment. This has been highlighted in the context of several medical conditions such as cancer, liver disease, cardiovascular disease, and central nervous system disorders, among many others. Here we assessed several steps involved in the development of an ncRNA biomarker discovery pipeline, ranging from sample preparation to bioinformatic processing of small RNA sequencing data. METHODS: A total of 45 biological samples were included in the present study. All libraries were prepared using the Illumina TruSeq Small RNA protocol and sequenced using the HiSeq2500 or MiSeq Illumina sequencers. Small RNA sequencing data was validated using qRT-PCR. At each stage, we evaluated the pros and cons of different techniques that may be suitable for different experimental designs. Evaluation methods included quality of data output in relation to hands-on laboratory time, cost, and efficiency of processing. RESULTS: Our results show that good quality sequencing libraries can be prepared from small amounts of total RNA and that varying degradation levels in the samples do not have a significant effect on the overall quantification of sncRNAs via NGS. In addition, we describe the strengths and limitations of three commercially available library preparation methods: (1) Novex TBE PAGE gel; (2) Pippin Prep automated gel system; and (3) AMPure XP beads. We describe our bioinformatics pipeline, provide recommendations for sequencing coverage, and describe in detail the expression and distribution of all sncRNAs in four human tissues: whole-blood, brain, heart and liver. CONCLUSIONS: Ultimately this study provides tools and outcome metrics that will aid researchers and clinicians in choosing an appropriate and effective high-throughput sequencing quantification method for various study designs, and overall generating valuable information that can contribute to our understanding of small ncRNAs as potential biomarkers and mediators of biological functions and disease.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , MicroRNAs/genética , Análise de Sequência de RNA/métodos , Biologia Computacional , Marcadores Genéticos/genética , Humanos , Especificidade de Órgãos , Controle de Qualidade , Transcriptoma
17.
J Neuropathol Exp Neurol ; 74(5): 459-69, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25868148

RESUMO

Postmortem brain research is invaluable to the study of neurologic and neuropsychiatric disorders, including Alzheimer disease, schizophrenia, and major depression. A major confounder in molecular studies using human brain tissue is postmortem interval (i.e. the amount of time between a subject's death and processing of tissue). We examined the integrity of biomolecules that were of interest to molecular studies of neurologic disorders, including RNA, microRNA, histone modifications, and proteins, at various postmortem intervals in an animal model to assess their robustness and suitability for experimentation. Sprague-Dawley rats were selected as model and subjected to 2 conditions: a variable postmortem interval at room temperature and a fixed time of 24 hours at 4°C, which simulates the period commonly spent in the morgue before brain collection. Eight time points were investigated. MicroRNA was impressively resistant to postmortem intervals; methylated histone modifications showed a threshold between 72 and 96 hours, mirroring results from histone proteins at 72 hours. RNA degradation was transcript-specific, with housekeeping genes being more robust than genes with lower expression. Our results suggest that molecules commonly investigated in genetic and epigenetic studies were highly stable through the postmortem intervals investigated. These results support the continued use of postmortem tissue for neuropsychiatric research.


Assuntos
Encéfalo/metabolismo , Mudanças Depois da Morte , Análise de Variância , Animais , Imunoprecipitação da Cromatina , Regulação da Expressão Gênica , Histonas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
19.
Nat Med ; 20(7): 764-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24908571

RESUMO

Major depressive disorder (MDD) is a prevalent mood disorder that is associated with differential prefrontal brain expression patterns. Treatment of MDD includes a variety of biopsychosocial approaches. In medical practice, antidepressant drugs are the most common treatment for depressive episodes, and they are among the most prescribed medications in North America. Although antidepressants are clearly effective, particularly for moderate to severe depressive episodes, there is variability in how individuals respond to antidepressant treatment. Failure to respond has individual, economic and social consequences for patients and their families. Several lines of evidence demonstrate that genes are regulated through the activity of microRNAs (miRNAs), which act as fine-tuners and on-off switches of gene expression. Here we report on complementary studies using postmortem human brain samples, cellular assays and samples from clinical trials of patients with depression and show that miR-1202, a miRNA specific to primates and enriched in the human brain, is differentially expressed in individuals with depression. Additionally, miR-1202 regulates expression of the gene encoding metabotropic glutamate receptor-4 (GRM4) and predicts antidepressant response at baseline. These results suggest that miR-1202 is associated with the pathophysiology of depression and is a potential target for new antidepressant treatments.


Assuntos
Antidepressivos/uso terapêutico , Encéfalo/metabolismo , Transtorno Depressivo Maior/genética , MicroRNAs/fisiologia , Linhagem Celular , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , MicroRNAs/metabolismo
20.
Brain Behav Immun ; 42: 50-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24858659

RESUMO

Despite increasing evidence supporting the neuroinflammatory theory of depression, little is known about cerebral macrophages in individuals suffering from major depression. In the present study, we investigated the morphology and distribution of cells immunostained for the macrophage-specific marker ionized calcium binding adaptor molecule 1 (IBA1) in the dorsal anterior cingulate cortex (dACC) white matter of middle-aged depressed suicides and matched non-psychiatric controls. This region is known for its implication in mood disorders, and its white matter compartment was previously found to display hypertrophic astrocytes in depressed suicides. Distributions of IBA1-immunoreactive (IBA-IR) microglial phenotypes were assessed using stereology and cell morphometry, and blood vessels were characterized as being intimately associated with either a high or a low density of IBA1-IR amoeboid-like cells. Total densities of IBA1-IR microglia did not differ between depressed suicides and controls. However, a finer analysis examining relative proportions of microglial phenotypes revealed that the ratio of primed over ramified ("resting") microglia was significantly increased in depressed suicides. Strikingly, the proportion of blood vessels surrounded by a high density of macrophages was more than twice higher in depressed suicides than in controls, and this difference was strongly significant. Consistent with these observations, gene expression of IBA1 and MCP-1, a chemokine involved in the recruitment of circulating monocytes, was significantly upregulated in depressed suicides. Furthermore, mRNA for CD45, a marker enriched in perivascular macrophages, was also significantly increased in samples from depressed suicides. An increase compared to controls was also observed in the proportion of blood vessels surrounded by a high density of CD45-IR cells, but this difference did not reach significance. These histological and molecular data suggest the recruitment of monocytes in dACC white matter of depressed suicides, although it cannot be excluded that other types of macrophages (including microglia) account for the observed accumulation of macrophages closely associated with blood vessels. Altogether, these findings suggest that the previously reported depression- and suicide-associated increases in circulating pro-inflammatory cytokines may be associated with low-grade cerebral neuroinflammation involving the recruitment of circulating monocytes.


Assuntos
Transtorno Depressivo/imunologia , Giro do Cíngulo/imunologia , Macrófagos/imunologia , Microglia/imunologia , Suicídio/psicologia , Substância Branca/imunologia , Adulto , Transtorno Depressivo/patologia , Transtorno Depressivo/psicologia , Feminino , Giro do Cíngulo/patologia , Humanos , Ativação de Macrófagos/imunologia , Macrófagos/patologia , Masculino , Microglia/patologia , Pessoa de Meia-Idade , Substância Branca/patologia
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