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1.
Medicine (Baltimore) ; 98(51): e18518, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31861040

RESUMO

BACKGROUND: The correlation between single nucleotide polymorphism (SNP) rs12807809 in Neurogranin (NRGN) gene and Schizophrenia (SCZ) was investigated by several studies, whereas the results were conflicting. Thus, we performed the present meta-analysis to combine and analyze the available studies in order to provide a more accurate result on the association of rs12807809 polymorphism in NRGN gene and SCZ vulnerability. METHODS: A comprehensive retrieval in PubMed, EMBASE, Web of Science, Cochrane Library and Wanfang was performed for relevant studies on the relationship of rs12807809 polymorphism and SCZ. Summary odds ratios (OR) with 95% confidence interval (95% CI) were calculated in allelic, homozygous, heterozygous, dominant and recessive model to appraise the association. RESULTS: The meta-analysis included 8 studies containing 12552 SCZ cases and 34783 controls. The results showed a statistically significant correlation between SCZ and rs12807809 polymorphism in overall population in allelic model (OR = 1.10, 95%CI 1.04-1.17). However, subgroup analysis indicated the association only existed in Caucasians but not Asian. CONCLUSION: The results of present meta-analysis suggested significant association between SNP rs12807809 in NRGN gene and SCZ susceptibility in Caucasians but not Asians.


Assuntos
Neurogranina/genética , Esquizofrenia/genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único
2.
Adv Exp Med Biol ; 1192: 53-93, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31705490

RESUMO

Psychiatric disorders such as addiction (substance use and addictive disorders), depression, eating disorders, schizophrenia, and post-traumatic stress disorder (PTSD) are severe, complex, multifactorial mental disorders that carry a high social impact, enormous public health costs, and various comorbidities as well as premature morbidity. Their neurobiological foundation is still not clear. Therefore, it is difficult to uncover new set of genes and possible genetic markers of these disorders since the understanding of the molecular imbalance leading to these disorders is not complete. The integrative approach is needed which will combine genomics and epigenomics; evaluate epigenetic influence on genes and their influence on neuropeptides, neurotransmitters, and hormones; examine gene × gene and gene × environment interplay; and identify abnormalities contributing to development of these disorders. Therefore, novel genetic approaches based on systems biology focused on improvement of the identification of the biological underpinnings might offer genetic markers of addiction, depression, eating disorders, schizophrenia, and PTSD. These markers might be used for early prediction, detection of the risk to develop these disorders, novel subtypes of the diseases and tailored, personalized approach to therapy.


Assuntos
Comportamento Aditivo/genética , Depressão/genética , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Esquizofrenia/genética , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Marcadores Genéticos , Humanos , Psiquiatria
3.
Nat Neurosci ; 22(10): 1617-1623, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31551603

RESUMO

Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Encéfalo/crescimento & desenvolvimento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/genética , Pessoa de Meia-Idade , Testes Neuropsicológicos , Esquizofrenia/genética , Esquizofrenia/patologia , Caracteres Sexuais , Adulto Jovem
4.
Nat Commun ; 10(1): 3355, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399567

RESUMO

Schizophrenia is associated with disrupted cognitive control and sleep-wake cycles. Here we identify diurnal rhythms in gene expression in the human dorsolateral prefrontal cortex (dlPFC), in schizophrenia and control subjects. We find significant diurnal (24 h) rhythms in control subjects, however, most of these transcripts are not rhythmic in subjects with schizophrenia. Instead, subjects with schizophrenia have a different set of rhythmic transcripts. The top pathways identified in transcripts rhythmic only in subjects with schizophrenia are associated with mitochondrial function. Importantly, these rhythms drive differential expression patterns of these and several other genes that have long been implicated in schizophrenia (including BDNF and GABAergic-related transcripts). Indeed, differential expression of these transcripts is only seen in subjects that died during the night, with no change in subjects that died during the day. These data provide insights into a potential mechanism that underlies changes in gene expression in the dlPFC with schizophrenia.


Assuntos
Ritmo Circadiano/genética , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Adulto , Antipsicóticos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia , Análise de Sequência de RNA
5.
Adv Exp Med Biol ; 1121: 7-20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31392648

RESUMO

Common Non communicable diseases (NCDs), such as cardiovascular disease, cancer, schizophrenia, and diabetes, have become the major cause of death in the world. They result from an interaction between genetics, lifestyle and environmental factors. The prevalence of NCDs are increasing, and researchers hopes to find efficient strategies to predict, prevent and treat them. Given the role of epigenome in the etiology of NCDs, insight into epigenetic mechanisms may offer opportunities to predict, detect, and prevent disease long before its clinical onset.Epigenetic alterations are exerted through several mechanisms including: chromatin modification, DNA methylation and controlling gene expression by non-coding RNAs (ncRNAs). In this chapter, we will discuss about NCDs, with focus on cancer, diabetes and schizophrenia. Different epigenetic mechanisms, categorized into two main groups DNA methylation and chromatin modifications and non-coding RNAs, will be separately discussed for these NCDs.


Assuntos
Epigênese Genética , Doenças não Transmissíveis , Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Humanos , Neoplasias/genética , Esquizofrenia/genética
6.
DNA Cell Biol ; 38(10): 1030-1039, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368785

RESUMO

Both endogenous and exogenous factors can cause DNA damage that compromises genomic integrity and cell viability. A proper DNA damage response (DDR) plays a role in maintaining genome stability and preventing tumorigenesis. DNA double-strand breaks (DSBs) are the most toxic DNA lesion, whose response is dominated by the ataxia-telangiectasia mutated (ATM) protein kinase. After being activated by the sensor Mre11-Rad50-Nbs1 (MRN) complex or acetyltransferase Tip60, ATM rapidly phosphorylates downstream targets to launch DDR signaling when DNA is damaged. However, the exact mechanism of DDR is complex and ambiguous. Ufmylation, one type of ubiquitin-like modification, proceeds mainly through a three-step enzymatic reaction to help ubiquitin-fold modifier 1 (Ufm1), attach to substrates with ubiquitin-like modifier-activating enzyme 5 (Uba5), Ufm1-conjugating enzyme 1 (Ufc1) and Ufm1-specific ligase 1 (Ufl1). Although ubiquitination is essential to the DSBs response, the potential function of ufmylation in DDR is largely unknown. Herein, we review the relationship between ufmylation and DDR to elucidate the function and mechanism of ufmylation in DDR, which would reveal the pathogenesis of some diseases and provide new guidance to create a therapeutic method.


Assuntos
Doenças Cardiovasculares/metabolismo , Quebras de DNA de Cadeia Dupla , Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/metabolismo , Esquizofrenia/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Reparo do DNA , Genoma Humano , Instabilidade Genômica , Humanos , Neoplasias/genética , Neoplasias/patologia , Ligação Proteica , Proteínas/genética , Esquizofrenia/genética , Esquizofrenia/patologia , Transdução de Sinais , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
7.
Nat Neurosci ; 22(9): 1402-1412, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31455887

RESUMO

RNA editing critically regulates neurodevelopment and normal neuronal function. The global landscape of RNA editing was surveyed across 364 schizophrenia cases and 383 control postmortem brain samples from the CommonMind Consortium, comprising two regions: dorsolateral prefrontal cortex and anterior cingulate cortex. In schizophrenia, RNA editing sites in genes encoding AMPA-type glutamate receptors and postsynaptic density proteins were less edited, whereas those encoding translation initiation machinery were edited more. These sites replicate between brain regions, map to 3'-untranslated regions and intronic regions, share common sequence motifs and overlap with binding sites for RNA-binding proteins crucial for neurodevelopment. These findings cross-validate in hundreds of non-overlapping dorsolateral prefrontal cortex samples. Furthermore, ~30% of RNA editing sites associate with cis-regulatory variants (editing quantitative trait loci or edQTLs). Fine-mapping edQTLs with schizophrenia risk loci revealed co-localization of eleven edQTLs with six loci. The findings demonstrate widespread altered RNA editing in schizophrenia and its genetic regulation, and suggest a causal and mechanistic role of RNA editing in schizophrenia neuropathology.


Assuntos
Córtex Cerebral/metabolismo , Edição de RNA/genética , Esquizofrenia/genética , Córtex Cerebral/fisiopatologia , Estudos de Coortes , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas/genética
8.
Yi Chuan ; 41(8): 677-685, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31447419

RESUMO

MicroRNAs (miRNAs) compose a class of non-coding transcripts with a mean length of 22 nucleotides, and play critical roles in regulating gene expression in the process of development, proliferation and differentiation of neurons. Recent genome-wide association studies (GWAS) find most of schizophrenia-associated single nucleotide polymorphisms (SNPs) locating in the non-coding regions, providing functional implications of miRNAs in the development of schizophrenia. In this review, we highlight the interplays between GWAS-SNPs and miRNAs in four perspectives: SNP in miRNA gene; miRNA located in the host gene; SNP located in the miRNA's seed sequence; SNP located in the miRNA's binding site. We also speculate on the future research on the role of miRNA in the development of schizophrenia.


Assuntos
MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Sítios de Ligação , Estudo de Associação Genômica Ampla , Humanos
9.
Genet Epidemiol ; 43(7): 730-741, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31328830

RESUMO

The heritability of most complex traits is driven by variants throughout the genome. Consequently, polygenic risk scores, which combine information on multiple variants genome-wide, have demonstrated improved accuracy in genetic risk prediction. We present a new two-step approach to constructing genome-wide polygenic risk scores from meta-GWAS summary statistics. Local linkage disequilibrium (LD) is adjusted for in Step 1, followed by, uniquely, long-range LD in Step 2. Our algorithm is highly parallelizable since block-wise analyses in Step 1 can be distributed across a high-performance computing cluster, and flexible, since sparsity and heritability are estimated within each block. Inference is obtained through a formal Bayesian variable selection framework, meaning final risk predictions are averaged over competing models. We compared our method to two alternative approaches: LDPred and lassosum using all seven traits in the Welcome Trust Case Control Consortium as well as meta-GWAS summaries for type 1 diabetes (T1D), coronary artery disease, and schizophrenia. Performance was generally similar across methods, although our framework provided more accurate predictions for T1D, for which there are multiple heterogeneous signals in regions of both short- and long-range LD. With sufficient compute resources, our method also allows the fastest runtimes.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Área Sob a Curva , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 1/genética , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Curva ROC , Fatores de Risco , Esquizofrenia/genética
10.
Genome Biol ; 20(1): 135, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288836

RESUMO

BACKGROUND: The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls. RESULTS: The methylomes of the two cell types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder. CONCLUSIONS: Our results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. This data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. We further show reduced cell type epigenetic distinction in schizophrenia.


Assuntos
Encéfalo/metabolismo , Metilação de DNA , Epigênese Genética , Esquizofrenia/genética , Encéfalo/citologia , Estudos de Casos e Controles , Humanos , Esquizofrenia/metabolismo
11.
Nat Commun ; 10(1): 3043, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292440

RESUMO

There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age.


Assuntos
Testes Genéticos , Modelos Genéticos , Idade Paterna , Adulto , Fatores Etários , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Criança , Dinamarca/epidemiologia , Epilepsia/epidemiologia , Epilepsia/genética , Feminino , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Incidência , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prevalência , Sistema de Registros/estatística & dados numéricos , Medição de Risco/métodos , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Sequenciamento Completo do Exoma
12.
Nat Neurosci ; 22(7): 1066-1074, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209380

RESUMO

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.


Assuntos
Abuso de Maconha/genética , Proteínas do Tecido Nervoso/fisiologia , Receptores Nicotínicos/fisiologia , Idade de Início , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/metabolismo , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Cognição/fisiologia , Estudos de Coortes , Dinamarca , Escolaridade , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia , Masculino , Herança Multifatorial , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/genética , Esquizofrenia/genética , Fumar/genética , Transcriptoma
13.
BMC Bioinformatics ; 20(Suppl 12): 313, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31216978

RESUMO

BACKGROUND: Schizophrenia and autism are examples of polygenic diseases caused by a multitude of genetic variants, many of which are still poorly understood. Recently, both diseases have been associated with disrupted neuron motility and migration patterns, suggesting that aberrant cell motility is a phenotype for these neurological diseases. RESULTS: We formulate the POLYGENIC DISEASE PHENOTYPE Problem which seeks to identify candidate disease genes that may be associated with a phenotype such as cell motility. We present a machine learning approach to solve this problem for schizophrenia and autism genes within a brain-specific functional interaction network. Our method outperforms peer semi-supervised learning approaches, achieving better cross-validation accuracy across different sets of gold-standard positives. We identify top candidates for both schizophrenia and autism, and select six genes labeled as schizophrenia positives that are predicted to be associated with cell motility for follow-up experiments. CONCLUSIONS: Candidate genes predicted by our method suggest testable hypotheses about these genes’ role in cell motility regulation, offering a framework for generating predictions for experimental validation.


Assuntos
Movimento Celular/genética , Doença/genética , Redes Reguladoras de Genes , Herança Multifatorial/genética , Algoritmos , Transtorno Autístico/genética , Estudos de Associação Genética , Humanos , Aprendizado de Máquina , Fenótipo , Curva ROC , Reprodutibilidade dos Testes , Esquizofrenia/genética
14.
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
15.
Neuron ; 103(2): 203-216.e8, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31174959

RESUMO

The hippocampus formation, although prominently implicated in schizophrenia pathogenesis, has been overlooked in large-scale genomics efforts in the schizophrenic brain. We performed RNA-seq in hippocampi and dorsolateral prefrontal cortices (DLPFCs) from 551 individuals (286 with schizophrenia). We identified substantial regional differences in gene expression and found widespread developmental differences that were independent of cellular composition. We identified 48 and 245 differentially expressed genes (DEGs) associated with schizophrenia within the hippocampus and DLPFC, with little overlap between the brain regions. 124 of 163 (76.6%) of schizophrenia GWAS risk loci contained eQTLs in any region. Transcriptome-wide association studies in each region identified many novel schizophrenia risk features that were brain region-specific. Last, we identified potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia and offer new insights into potentially causative biology.


Assuntos
Lobo Frontal , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipocampo , Esquizofrenia/genética , Esquizofrenia/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Lobo Frontal/embriologia , Lobo Frontal/crescimento & desenvolvimento , Lobo Frontal/metabolismo , Ontologia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipocampo/embriologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Proc Jpn Acad Ser B Phys Biol Sci ; 95(5): 179-197, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080187

RESUMO

The adult human brain consists of approximately a hundred billion neurons, which are connected via synapses. The pattern and strength of the synaptic connections are constantly changing (synaptic plasticity), and these changes are considered to underlie learning, memory, and personality. Many psychiatric disorders have been related to disturbances in synaptogenesis and subsequent plasticity. In this review, we summarize findings of synaptic disturbance and its involvement in the pathogenesis and/or pathophysiology of psychiatric disorders. We will focus on schizophrenia, because this condition has a high proven heritability, which offers more unambiguous insights into the biological origins of not only schizophrenia but also related psychiatric disorders. To demonstrate the involvement of synaptopathy in psychiatric disorders, we discuss what knowledge is missing at the circuits level, and what new technologies are needed to achieve a comprehensive understanding of synaptopathy in psychiatric disorders.


Assuntos
Esquizofrenia/genética , Esquizofrenia/patologia , Sinapses/patologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Optogenética , Esquizofrenia/diagnóstico por imagem
17.
Dis Markers ; 2019: 8062397, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061683

RESUMO

Recent research has shown that prenatal famine exposure may be one of the risk factors for schizophrenia and that people born in famine years may be at an increased risk of schizophrenia due to alteration of the DNA methylation of genes. In this study, the association of rs2283291/rs4648635 and the incidence of schizophrenia and prenatal famine exposure at the genetic level were investigated to provide clues to the pathogenesis of schizophrenia. A total of 960 participants were recruited, comprising 473 prenatal famine-exposed individuals (225 patients and 248 controls) and 487 prenatal non-famine-exposed individuals (220 patients and 267 controls). The association of prenatal famine, schizophrenia, and their interaction with DNA methylation levels was analyzed using SPSS and GMDR software. Gender stratification analysis revealed a significant association between the rs2283291 genotype and schizophrenia in male patients (P = 0.017), and difference still existed after correction by the Bonferroni method. It was also found that an increasing risk of schizophrenia was associated with rs2283291 in males (OR: 1.62, 95% CI: 1.13-2.33, P = 0.0086, AIC = 669.7) in an overdominant model. The results of gene-environment interaction and gene-gene interaction revealed no association with the risk of schizophrenia. This study reported for the first time that rs2283291 was associated with schizophrenia in Chinese males.


Assuntos
Canais de Cálcio Tipo L/genética , Desnutrição/epidemiologia , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , China , Feminino , Interação Gene-Ambiente , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/epidemiologia , Fatores Sexuais
18.
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
19.
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
20.
Artigo em Russo | MEDLINE | ID: mdl-31089096

RESUMO

AIM: To search for genetic variants associated with premorbid personality in patients with schizophrenia. MATERIAL AND METHODS: The sample included 272 men diagnosed with schizophrenia or schizoaffective disorder. Patients were divided into 3 groups based on premorbid personality difficulties: mild (group 1, n=110), moderate (group 2, n=113), marked (group 3, n=49). The following polymorphisms were genotyped: 5-HTR2A (T102C), 5-HTTLPR, BDNF (Val66Met), CRP (-717A>G). RESULTS: A significant increase in the frequency of the CC (5-HTR2A T102C), LL (5-HTTLPR) and Met/Met (BDNF Val66Met) genotypes was identified in group 3 compared to group 1. Frequencies of CC and LL genotypes were significantly higher in group 2 compared to group 1 as well. The differences between group 2 and group 3 were found only for the Met/Met genotype. There were no between-group differences in the frequencies of CRP (-717A>G) genotypes. CONCLUSION: 5-HTR2A (T102C), 5-HTTLPR, BDNF (Val66Met) polymorphisms previously reported to modify schizophrenia course are also associated with premorbid personality in schizophrenic patients.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Serina Peptidase 2 de Requerimento de Alta Temperatura A , Personalidade , Transtornos Psicóticos , Esquizofrenia , Proteínas da Membrana Plasmática de Transporte de Serotonina , Fator Neurotrófico Derivado do Encéfalo/genética , Genótipo , Serina Peptidase 2 de Requerimento de Alta Temperatura A/genética , Humanos , Masculino , Personalidade/genética , Polimorfismo Genético , Receptor 5-HT2A de Serotonina , Esquizofrenia/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
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