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1.
Adv Exp Med Biol ; 1180: 19-57, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31784956

RESUMO

Major depressive disorder (MDD) and bipolar disorder (BPD) are both chronic, severe mood disorder with high misdiagnosis rate, leading to substantial health and economic burdens to patients around the world. There is a high misdiagnosis rate of bipolar depression (BD) just based on symptomology in depressed patients whose previous manic or mixed episodes have not been well recognized. Therefore, it is important for psychiatrists to identify these two major psychiatric disorders. Recently, with the accumulation of clinical sample sizes and the advances of methodology and technology, certain progress in the genetics of major depression and bipolar disorder has been made. This article reviews the candidate genes for MDD and BD, genetic variation loci, chromosome structural variation, new technologies, and new methods.


Assuntos
Transtorno Bipolar/genética , Transtorno Depressivo Maior/genética , Humanos
2.
Psychiatr Danub ; 31(Suppl 3): 591-594, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488796

RESUMO

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare monogenic disorder caused by mutations in the NOTCH3 gene. The clinical features are primarily neurological, which include recurrent transient ischaemic attacks, strokes, and migraines. However, psychiatric manifestations which mainly include mood disturbances have also been reported in CADASIL. Manic symptoms and bipolar disorders are rarely documented in CADASIL and existing reports generally lack detailed descriptions of the psychiatric evaluation. We discuss a case of Bipolar Affective Disorder (BD) in a British woman with a family history of CADASIL. This case provides insight into the diagnosis and management of BD as well as the possible underlying aetiologies that should be considered. The similarities between BD and CADASIL in terms of imaging, genetic, and therapeutic aspects raise the possibility of common dysfunctional pathways. BD in CADASIL may warrant greater consideration by both psychiatrists as well as non-psychiatric specialists and further studies are required to understand the pathological significance.


Assuntos
Transtorno Bipolar/complicações , CADASIL/complicações , Transtorno Bipolar/genética , Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/psicologia , CADASIL/genética , CADASIL/fisiopatologia , CADASIL/psicologia , Feminino , Humanos , Transtornos de Enxaqueca/complicações , Transtornos do Humor/complicações , Mutação , Receptor Notch3/genética , Reino Unido
3.
Nat Commun ; 10(1): 2417, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160569

RESUMO

Accumulating evidence from genome wide association studies (GWAS) suggests an abundance of shared genetic influences among complex human traits and disorders, such as mental disorders. Here we introduce a statistical tool, MiXeR, which quantifies polygenic overlap irrespective of genetic correlation, using GWAS summary statistics. MiXeR results are presented as a Venn diagram of unique and shared polygenic components across traits. At 90% of SNP-heritability explained for each phenotype, MiXeR estimates that 8.3 K variants causally influence schizophrenia and 6.4 K influence bipolar disorder. Among these variants, 6.2 K are shared between the disorders, which have a high genetic correlation. Further, MiXeR uncovers polygenic overlap between schizophrenia and educational attainment. Despite a genetic correlation close to zero, the phenotypes share 8.3 K causal variants, while 2.5 K additional variants influence only educational attainment. By considering the polygenicity, discoverability and heritability of complex phenotypes, MiXeR analysis may improve our understanding of cross-trait genetic architectures.


Assuntos
Transtorno Bipolar/genética , Modelos Genéticos , Modelos Estatísticos , Herança Multifatorial , Esquizofrenia/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação
4.
Nat Genet ; 51(5): 793-803, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043756

RESUMO

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Loci Gênicos , Transtorno Bipolar/classificação , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/genética , Esquizofrenia/genética , Biologia de Sistemas
5.
Nat Commun ; 10(1): 2046, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053723

RESUMO

Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. Here we perform a multi-omics study of neurons isolated from the prefrontal cortex in schizophrenia and bipolar disorder (n = 55 cases and 27 controls). DNA methylation, transcriptomic, and genetic-epigenetic interactions in major psychosis converged on pathways of neurodevelopment, synaptic activity, and immune functions. We observe prominent hypomethylation of an enhancer within the insulin-like growth factor 2 (IGF2) gene in major psychosis neurons. Chromatin conformation analysis revealed that this enhancer targets the nearby tyrosine hydroxylase (TH) gene responsible for dopamine synthesis. In patients, we find hypomethylation of the IGF2 enhancer is associated with increased TH protein levels. In mice, Igf2 enhancer deletion disrupts the levels of TH protein and striatal dopamine, and induces transcriptional and proteomic abnormalities affecting neuronal structure and signaling. Our data suggests that epigenetic activation of the enhancer at IGF2 may enhance dopamine synthesis associated with major psychosis.


Assuntos
Transtorno Bipolar/genética , Dopamina/biossíntese , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Fator de Crescimento Insulin-Like II/genética , Esquizofrenia/genética , Tirosina 3-Mono-Oxigenase/genética , Adulto , Idoso , Animais , Transtorno Bipolar/patologia , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neurônios/patologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/patologia , Proteômica , Esquizofrenia/patologia , Transcriptoma/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Adulto Jovem
6.
PLoS One ; 14(3): e0213236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30917131

RESUMO

We study computational approaches for detecting SNP-SNP interactions that are characterized by a set of "two-locus, two-allele, two-phenotype and complete-penetrance" disease models. We argue that existing methods, which use data to determine a best-fitting disease model for each pair of SNPs prior to screening, may be too greedy. We present a less greedy strategy which, for each given pair of SNPs, limits the number of candidate disease models to a set of prototypes determined a priori.


Assuntos
Epistasia Genética , Modelos Genéticos , Alelos , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Análise por Conglomerados , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
7.
J Affect Disord ; 251: 86-90, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30909162

RESUMO

OBJECTIVE: The X-linked ZMYM3 gene (also known as ZNF261) contains the longest STR, (GA)32, identified in a human protein-coding gene 5'UTR (ENST00000373998.5: ZMYM3-207). This STR reaches maximum length in human, and is located in a complex string of four consecutive GA-STRs with a human-specific formula across the complex. A previous study in Iranian male schizophrenia (SCZ) patients revealed co-occurrence of the extreme short and long alleles of the STR with SCZ. Here we studied the allelic distribution of this STR in bipolar disorder (BD) type I. The interval encompassing the human ZMYM3 STR complex was PCR-amplified and sequenced in 546 male subjects, consisting of 157 BD patients and 389 controls. RESULTS: We found three alleles at the extreme short (17-repeat) and long (38- and 43-repeat) ends of the allele distribution curve in the BD cases (4.4% of the BD alleles) that were not detected in the controls (Mid p < 0.0001). These alleles overlapped with the extreme disease-only alleles detected previously in the SCZ patients. Domain reconstruction of the GA-STR complex revealed significant structural alteration as a result of various sequence repeats and nucleotide compositions at the inter and intraspecies levels. CONCLUSION: The ZMYM3 "exceptionally long" 5' UTR STR findings may alter our perspective of disease pathogenesis in psychiatric disorders, and set an example in which the low frequency alleles at the extreme short and long ends of the human STRs are, at least in part, a result of natural selection against these alleles and their unambiguous link to major human disorders.


Assuntos
Regiões 5' não Traduzidas/genética , Transtorno Bipolar/genética , Repetições de Microssatélites/genética , Proteínas Nucleares/genética , Adulto , Alelos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase
8.
Transl Psychiatry ; 9(1): 60, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718465

RESUMO

We searched for genetic causes of major psychiatric disorders (bipolar disorder, schizoaffective disorder, and schizophrenia) in a large, densely affected pedigree from Northern Sweden that originated with three pairs of founders born around 1650. We applied a systematic genomic approach to the pedigree via karyotyping (N = 9), genome-wide SNP arrays (N = 418), whole-exome sequencing (N = 26), and whole-genome sequencing (N = 10). Comprehensive analysis did not identify plausible variants of strong effect. Rather, pedigree cases had significantly higher genetic risk scores compared to pedigree and community controls.


Assuntos
Transtorno Bipolar/genética , Genômica/métodos , Transtornos Psicóticos/genética , Esquizofrenia/genética , Adulto , Idoso , Transtorno Bipolar/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Cariotipagem/métodos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Linhagem , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/epidemiologia , Esquizofrenia/epidemiologia , Suécia/epidemiologia , Sequenciamento Completo do Exoma/métodos , Sequenciamento Completo do Genoma/métodos
9.
Transl Psychiatry ; 9(1): 74, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718481

RESUMO

Common genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between the two disorders. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome-wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genetic association with schizophrenia is positively correlated with expression in the prefrontal cortex during early midfetal development and early infancy, and negatively correlated with expression during late childhood, which stabilises in adolescence. In contrast, risk-associated genes for bipolar disorder did not exhibit a bias towards expression at any prenatal stage, although the pattern of postnatal expression was similar to that of schizophrenia. These results highlight the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the hypothesis that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.


Assuntos
Desenvolvimento do Adolescente/fisiologia , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Desenvolvimento Infantil/fisiologia , Desenvolvimento Fetal/fisiologia , Perfilação da Expressão Gênica , Expressão Gênica/genética , Predisposição Genética para Doença , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudo de Associação Genômica Ampla , Humanos , Lactente , Adulto Jovem
10.
J Affect Disord ; 249: 159-168, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30772743

RESUMO

BACKGROUND: Bipolar disorder (BD) is one of the most heritable psychiatric disorders. A growing number of whole-exome sequencing (WES) studies for BD has been performed, however, no research has examined the association between single nucleotide variants (SNVs) from WES and structural magnetic resonance imaging (MRI) data. METHODS: We sequenced whole-exomes in 53 patients with BD and 82 healthy control participants at an initial discovery stage and investigated the impacts of SNVs in risk genes from WES analysis on the cortical gray-matter thickness and integrity of white matter tracts and in the following stage. Cortical thickness and white matter integrity were investigated using the FreeSurfer and TRACULA (Tracts Constrained by UnderLying Anatomy). RESULTS: We identified 122 BD-related genes including KMT2C, AHNAK, CDH23, DCHS1, FRAS1, MACF1 and RYR3 and observed 27 recurrent copy number alteration regions including gain on 8p23.1 and loss on 15q11.1 - q11.2. Among them, single nucleotide polymorphism (SNP) rs4639425 in KMT2C gene, which regulates histone H3 lysine 4 (H3K4) methylation involved in chromatin remodeling, was associated with widespread alterations of white matter integrity including the cingulum, uncinate fasciculus, cortico-spinal tract, and superior longitudinal fasciculus. LIMITATION: The small sample size of patients with BD in the genome data may cause our study to be underpowered when searching for putative rare mutations. CONCLUSION: This study first combined a WES approach and neuroimaging findings in psychiatric disorders. We postulate the rs4639425 may be associated with BD-related microstructural changes of white matter tracts.


Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Sequenciamento Completo do Exoma , Adulto , Biomarcadores , Caderinas/genética , Imagem de Tensor de Difusão/métodos , Feminino , Genoma Humano , Substância Cinzenta/patologia , Humanos , Masculino , Fibras Nervosas , Neuroimagem , Polimorfismo de Nucleotídeo Único/genética , Substância Branca/patologia
11.
J Affect Disord ; 249: 169-174, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30772744

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) have established roles in the pathogenesis of diverse human disorders including neuropsychiatric disorders. METHODS: In the current study, we evaluated expression levels of six apoptosis-related lncRNAs (CCAT2, TUG1, PANDA, NEAT1, FAS-AS1 and OIP5-AS1) in the peripheral blood of bipolar disorder (BD) patients and healthy subjects to assess their contribution in the pathogenesis of BD. RESULTS: CCAT2, TUG1 and PANDA were up-regulated in total BD patients compared with total healthy subjects (P values = 0.006, <0.001 and 0.004 respectively) while OIP5-AS1 was down-regulated (P = 0.001). When expression levels of these genes were compared between patients and sex-matched healthy subjects, CCAT2 and TUG1 expression levels were only different in male subgroups; while PANDA expression was different in both male and female subgroups compared with the corresponding control subgroups. Transcript levels of lncRNAs were not correlated with any of demographic or clinical parameters of BD patients or controls after adjustment for gender. Pairwise correlations between expression levels of lncRNAs followed a disease-dependent manner. Based on receiver operating characteristic curves, among the assessed lncRNAs TUG1 had the highest diagnostic power in BD. Combination of transcript levels of CCAT2, TUG1, PANDA and OIP5-AS1 improved both sensitivity and specificity resulting in diagnostic power of 0.96. CONCLUSION: Our data demonstrated a possible role of certain lncRNAs in the pathogenesis of BD and potentiated them as diagnostic markers in this disorder.


Assuntos
Transtorno Bipolar/sangue , RNA Longo não Codificante/sangue , Apoptose , Biomarcadores/sangue , Transtorno Bipolar/genética , Estudos de Casos e Controles , Regulação para Baixo/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , Curva ROC , Regulação para Cima/fisiologia
12.
Psychiatry Res ; 274: 49-57, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30780062

RESUMO

Melatonin secretion and polysomnography (PSG) were compared among a group of healthy adolescents who were at high familial risk for bipolar disorder (HR) and a second group at low familial risk (LR). Adolescent participants (n = 12) were a mean age 14 ± 2.3 years and included 8 females and 4 males. Saliva samples were collected under standardized condition light (red light) and following a 200 lux light exposure over two consecutive nights in a sleep laboratory. Red Light Melatonin onset (RLMO) was defined as saliva melatonin level exceeding the mean of the first 3 readings plus 2 standard deviations. Polysomnography was also completed during each night. HR youth, relative to LR, experienced a significantly earlier melatonin onset following 200 lux light exposure. Polysomnography revealed that LR youth, relative to HR, spent significantly more time in combined stages 3 and 4 (deep sleep) following red light exposure. Additionally, regardless of the group status (HR or LR), there was no significant difference in Red Light Melatonin Onset recorded at home or in the laboratory, implying its feasibility and reliability.


Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/metabolismo , Predisposição Genética para Doença , Melatonina/metabolismo , Estimulação Luminosa/métodos , Saliva/metabolismo , Adolescente , Adulto , Biomarcadores/química , Biomarcadores/metabolismo , Transtorno Bipolar/genética , Criança , Ritmo Circadiano/fisiologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Polissonografia/tendências , Reprodutibilidade dos Testes , Saliva/química , Sono/fisiologia , Transtornos do Sono do Ritmo Circadiano/diagnóstico , Transtornos do Sono do Ritmo Circadiano/genética , Transtornos do Sono do Ritmo Circadiano/metabolismo
13.
J Affect Disord ; 248: 175-179, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30738251

RESUMO

BACKGROUND: Bipolar disorder is a neuropsychiatric disorder that is characterized by fluctuations between manic and depressive phases. Lithium is the original and best mood stabilizing treatment for bipolar disorder. While its mechanism is not well understood, it is believed to have a strong genetic component, as several studies suggest that lithium responsiveness, in bipolar disorder, is heritable. In this study we aimed to identify genetic variants that are associated with lithium responsiveness in bipolar disorder. METHODS: Here we present two cohorts; a retrospective cohort in which patients were surveyed about their response to lithium, and a prospective cohort, in which patients were placed on a lithium monotherapy and monitored for their response to lithium. In both cohorts, patients were stratified into two categories in terms of lithium response; good responders and poor responders. 45 genes were selected based on previous associations with lithium pathways or bipolar disorder and 684 SNPs within these genes were selected to test for association with lithium response. RESULTS: While no single SNP was significant after correcting for multiple comparisons, there were several that were nominally significant (p < 0.05). Of these nominally significant SNPs, the most highly significant SNP in both the prospective and retrospective cohorts were found to be in CACNG2, or Stargazin. The second best association with lithium response was several SNPs in NRG1, a gene that has previously been associated with schizophrenia. CONCLUSIONS: Evidence for the association of lithium response with SNPs in CACNG2 is consistent with previous findings that have identified CACNG2 as associated with both bipolar disorder and lithium responsiveness.


Assuntos
Antimaníacos/farmacocinética , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Canais de Cálcio/efeitos dos fármacos , Compostos de Lítio/farmacocinética , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Estudos Retrospectivos , Adulto Jovem
14.
Nervenarzt ; 90(2): 99-106, 2019 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-30758637

RESUMO

A long-established hypothesis is that genetic factors contribute to the development of psychiatric diseases, including common illnesses such as schizophrenia and the affective disorders; however, reliable molecular identification of these factors represents a far more recent innovation. This has been rendered possible by technological advances in the individual characterization of the human genome and the combining of large genetic datasets at the international level. For the first time, the results of genome-wide analyses provide researchers with systematic insights into disease-relevant biological mechanisms. Here, the integrated analysis of different omics level data generates important insights into the functional interpretation of the genetic findings. The results of genetic studies also demonstrated the degree of etiological overlap between differing psychiatric disorders, with the greatest commonality having been observed to date between schizophrenia and bipolar affective disorder. Although the translation of genetic findings into routine clinical practice is being pursued at various levels, elaborate follow-up studies are typically necessary. The diagnostic investigation of rare genomic deletions/duplications (so-called copy number variants) in patients with schizophrenia is likely to represent one of the first examples of routine clinical application. The necessary prerequisites for this are currently being defined.


Assuntos
Predisposição Genética para Doença , Transtornos Mentais , Transtorno Bipolar/genética , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Genômica , Humanos , Transtornos Mentais/genética , Esquizofrenia/genética
15.
Transl Psychiatry ; 9(1): 32, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670680

RESUMO

Similar environmental risk factors have been implicated in different neuropsychiatric disorders (including major psychiatric and neurodegenerative diseases), indicating the existence of common epigenetic mechanisms underlying the pathogenesis shared by different illnesses. To investigate such commonality, we applied an unsupervised computational approach identifying several consensus co-expression and co-methylation signatures from a data cohort of postmortem prefrontal cortex (PFC) samples from individuals with six different neuropsychiatric disorders-schizophrenia, bipolar disorder, major depression, alcoholism, Alzheimer's and Parkinson's-as well as healthy controls. Among our results, we identified a pair of strongly interrelated co-expression and co-methylation (E-M) signatures showing consistent and significant disease association in multiple types of disorders. This E-M signature was enriched for interneuron markers, and we further demonstrated that it is unlikely for this enrichment to be due to varying subpopulation abundance of normal interneurons across samples. Moreover, gene set enrichment analysis revealed overrepresentation of stress-related biological processes in this E-M signature. Our integrative analysis of expression and methylation profiles, therefore, suggests a stress-related epigenetic mechanism in the brain, which could be associated with the pathogenesis of multiple neuropsychiatric diseases.


Assuntos
Alcoolismo/genética , Doença de Alzheimer/genética , Transtorno Bipolar/genética , Metilação de DNA , Transtorno Depressivo Maior/genética , Doença de Parkinson/genética , Esquizofrenia/genética , Epigênese Genética , Redes Reguladoras de Genes , Humanos
16.
Artigo em Inglês | MEDLINE | ID: mdl-30664971

RESUMO

INTRODUCTION: The activation of the ATP-gated P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) produces microglial activation, a process which has been demonstrated in depression, bipolar disorder, and schizophrenia. Emerging data over the last years highlighted the importance of P2X7 cation channel as a potential drug target for these central nervous system disorders. The Gln460Arg (rs2230912) polymorphism of the P2RX7 gene has been widely studied in mood disorders, however the results are still controversial. Therefore, we aimed to investigate the C-terminal region of this gene in major depressive and bipolar disorders (MDD and BD) by studying possibly functional, non-synonymous polymorphisms within a 7 kb long region around the Gln460Arg, including Ala348Thr (rs1718119), Thr357Ser (rs2230911), and Glu496Ala (rs3751143) variants. Since Gln460Arg is located at the 3' end of the P2RX7 gene, we included additional, potentially functional single nucleotide polymorphisms (SNPs) from the 3' untranslated region (UTR), which can be in linkage with Gln460Arg. Based on in silico search, we chose two SNPs in putative microRNA target sites which are located in consecutive positions: rs1653625 and rs1718106. METHODS: P2RX7 SNPs from the C-terminal region were selected based on previous functional assays, 3' UTR variants were chosen using PolymiRTS and Patrocles databases. The genotyping of the non-synonymous SNPs was carried out by pre-designed TaqMan® kits, while the 3' UTR variants were analyzed by PCR-RFLP method. Case-control analyses were carried out between 315 inpatients with acute major depressive episode (195 MDD, 120 BD) and 406 healthy control subjects. The two subscales of the Hospital Anxiety and Depression Scale (HADS) self-report questionnaire were used for quantitative analyses, including an additional, "at-risk" population of 218 patients with diabetes mellitus. The in vitro reporter gene assays were carried out on HEK and SK-N-FI cells transiently transfected with pMIR vector constructs containing the P2RX7 3' UTR downstream of the luciferase gene. RESULTS: Haplotype analysis indicated a relatively high linkage between the analyzed P2RX7 SNPs. Our case-control study did not yield any association between P2RX7 gene variants and depression. However, dimensional analyses showed significant associations of the HADS depression severity scores with Gln460Arg (rs2230912) and Ala348Thr (rs1718119) in the depressed and diabetic patient groups. In the in vitro experiments, the P2RX7 3' UTR constructs with the lowest predicted binding efficiency to their miRNAs showed the highest expression of the gene. The combination of the depression-associated P2RX7 C-terminal and 3' UTR SNPs contributed to the highest depression severity score in the haplotype analysis. CONCLUSION: Based on our findings, we propose that a P2RX7 haplotype combination of the Gln460Arg and neighboring SNPs contribute to the observed genetic association with depressive symptoms.


Assuntos
Transtorno Bipolar/genética , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptores Purinérgicos P2X7/genética , Adulto , Transtorno Bipolar/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Simulação por Computador , Transtorno Depressivo Maior/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Feminino , Frequência do Gene , Estudos de Associação Genética , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Receptores Purinérgicos P2X7/metabolismo
17.
J Affect Disord ; 246: 633-639, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611060

RESUMO

BACKGROUND: Studying the phenotypic manifestations of increased genetic liability for Bipolar Disorder (BD) can increase understanding of this disorder. AIMS: We assessed whether genetic risk for BD was associated with childhood psychopathology and features of hypomania in young adulthood within a large population-based birth cohort. METHODS: We used data from the second Psychiatric Genetics Consortium Genome Wide Association Study (GWAS) for Bipolar Disorder to construct a polygenic risk score (PRS) for each individual in the Avon Longitudinal Study of Parents and Children (ALSPAC). Linear and logistic regression models were used to assess associations between the BD-PRS and emotional/behavioural difficulties, attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD) traits in childhood, as well as hypomania in early adulthood (sample sizes from 2654 to 6111). RESULTS: The BD-PRS was not associated with total hypomania score, but was weakly associated with a binary measure of hypomania (OR = 1.13, 95%CI 0.98,1.32; p = 0.097), and particularly at higher hypomania symptom thresholds (strongest evidence OR = 1.33, 95%CI 1.07, 1.65; p = 0.01). The BD-PRS was also associated with ADHD (OR = 1.31, 95%CI 1.10, 1.57; p = 0.018), but not with other childhood psychopathology. LIMITATIONS: The PRS only captures common genetic variation and currently explains a relatively small proportion of the variance for BD. CONCLUSIONS: The BD-PRS was associated with ADHD in childhood, and weakly with adult hypomania, but not with other psychopathology examined. Our findings suggest that genetic risk for BD does not appear to manifest in childhood to the same extent as schizophrenia genetic risk has been reported to do.


Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno da Personalidade Borderline/genética , Criança , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Herança Multifatorial , Fenótipo , Psicopatologia , Medição de Risco , Esquizofrenia/genética , Adulto Jovem
18.
PLoS One ; 14(1): e0207353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30605476

RESUMO

BACKGROUND: Human endogenous retroviruses (HERV) comprise 8% of the human genome and can be classified into at least 31 families. Increased levels of transcripts from the W and H families of HERV have been observed in association with human diseases, such as multiple sclerosis and schizophrenia. Although HERV transcripts have been detected in many tissues and cell-types based on microarray and PCR studies, the extent of HERV expression in different cell-types and diseases state has been less comprehensively studied. RESULTS: We examined overall transcription of HERV, and particularly of HERV-W and HERV-H elements in human postmortem brain samples obtained from individuals with psychiatric diagnoses (n = 111) and healthy controls (n = 51) by analyzing publicly available RNA sequencing datasets. Sequence reads were aligned to prototypical sequences representing HERV, downloaded from Repbase. We reported a consistent expression (0.1~0.2% of mappable reads) of different HERV families across three regions of human brains. Spearman correlations revealed highly correlated expression levels between three brain regionsacross 475 consensus sequences. By mapping sequences that aligned to the consensus sequences of HERV-W and HERV-H families to individual loci on chromosome 7, more than 60 loci from each family were identified, part of which are being transcribed. The ERVWE1, locus located at chr7q21.2, exhibited high levels of transcription across the three datasets. Notably, we demonstrated a trend of increased expression of overall HERV, as well as HERV-W family in samples from both schizophrenia and bipolar disorder patients. CONCLUSIONS: The current analyses indicate that RNA sequencing is a useful approach for investigating global expression of repetitive elements, such as HERV, in the human genome. HERV-W/H with the tendency of transcription up-regulation in patients suggests potential implication of HERV-W/H in psychiatric diseases.


Assuntos
Encéfalo/metabolismo , Encéfalo/virologia , Retrovirus Endógenos/genética , Análise de Sequência de RNA , Transcrição Genética , Transtorno Bipolar/genética , Transtorno Bipolar/virologia , Cromossomos Humanos Par 7/genética , Depressão/genética , Depressão/virologia , Regulação Viral da Expressão Gênica , Loci Gênicos , Genoma Humano , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sequências Repetitivas de Ácido Nucleico/genética , Esquizofrenia/genética , Esquizofrenia/virologia , Estatísticas não Paramétricas
19.
Neurosci Lett ; 696: 206-211, 2019 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-30599263

RESUMO

Bipolar disorder (BD) is a mental disorder that is often misdiagnosed with ineffective treatment. It has strong genetic component but unknown pathophysiology. Long non-coding RNAs (lncRNAs) have been recently recognized as one of the important genetic factors and are considered as one of the regulatory mechanisms of nervous system. Given that lncRNAs may be diagnostic biomarkers for BD, we aimed to quantify the levels of DISC1 and DISC2 lncRNA transcripts. The levels of DISC1 and DISC2 lncRNA were tested in peripheral blood mononuclear cells (PBMCs) of 50 BD and 50 controls by real-time PCR. In addition, we performed ROC curve analysis as well as correlation analysis between the gene expression and some clinical features of BD cases. Computational analysis of miRNAs binding sites and CpG Islands on DISC1 and DISC2 lncRNA was performed as well. Significant down-regulation of DISC1 and up-regulation of DISC2 were observed in BD cases compared with controls. The areas under the ROC curve (AUC) for DISC1 and DISC2 lncRNA were 0.76 and 0.68 respectively. There was no significant correlation between the levels of mRNA expression in PBMCs of BD patients and clinical features. These data demonstrated that DISC1 and DISC2 lncRNA expression was potentially associated with an increased risk of bipolar disorder and might involve several molecular mechanisms. Our results revealed that the transcript levels of DISC1 and DISC2 lncRNA could be considered as a good putative biomarker for individuals with bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Adulto , Idoso , Área Sob a Curva , Biomarcadores/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Adulto Jovem
20.
J Affect Disord ; 245: 597-601, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445384

RESUMO

BACKGROUND: Patients with bipolar disorder demonstrate sex differences in clinical presentation, particularly in the sub-phenotypes related to periodicity of mood episodes, such as rapid cycling. Additionally, recent studies have linked P2RX7 gene variants with the risk of rapid cycling in clinical cohorts of patients with bipolar disorder, as well as other mood disorders. However, little is known about potential sex differences in the relationship between variants in P2RX7 and bipolar disorder. METHODS: We investigated sex-specific genetic associations between variants of P2RX7 (rs1621388 and rs2230912) in 756 patients with bipolar disorder and 787 control patients matched on age, sex, and ancestry. We examined sex-specific genetic associations with bipolar disorder by comparing cases and controls, as well as rapid cycling of mood episodes in cases. Findings were replicated in an independent dataset. RESULTS: P2RX7 variants implying an increased pore activity were more common in bipolar disorder, in females but not in males. Neither P2RX7 variants associated with rapid cycling among bipolar patients. LIMITATIONS: Low sample size limited power for tests of SNP by sex interaction, and data about the onset of rapid cycling and the timing of medication use were not available. CONCLUSION: The effects of P2RX7 variants on bipolar disorder may be sex-specific, with increased P2X7 activity potentially elevating risk for bipolar disorder in females. Future research to examine the effect of P2RX7 on bipolar disorder should consider sex-specific effects.


Assuntos
Transtorno Bipolar/genética , Mutação com Ganho de Função , Receptores Purinérgicos P2X7/genética , Fatores Sexuais , Adulto , Afeto/fisiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/genética
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