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Dysregulation of excitatory and inhibitory signaling is commonly observed in major psychiatric disorders, including schizophrenia, depression, and bipolar disorder, and is often targeted by psychological and pharmacological treatment methods. The balance of excitation and inhibition is highly sensitive to severe psychological stress, one of the strongest risk factors for psychiatric disorders. The role of astrocytes in regulating excitatory and inhibitory signaling is now widely recognized; however, the specific involvement of astrocytes in the context of psychiatric disorders with a history of significant stress exposure remains unclear. In this review, we summarize how astrocytes regulate the balance of excitation and inhibition in the context of stress exposure and severe psychopathology, with a focus on the PFC, a brain area highly implicated in psychopathology. We first focus on preclinical models to demonstrate that the duration of stress (particularly acute vs chronic stress) is key to shaping astrocyte function and downstream behavior. We then provide a hypothesis for how astrocytes are involved in stress-associated cortical signaling imbalance, discuss how this directly contributes to phenotypes of psychopathologies, and provide suggestions for future research. We highlight that astrocytes are a key target to understand and treat the dysregulation of cortical signaling associated with stress-related psychiatric disorders.
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Transtornos Mentais , Esquizofrenia , Humanos , Astrócitos/fisiologia , Transdução de Sinais , Inibição PsicológicaRESUMO
BACKGROUND: Acid sphingomyelinase (ASM) catalyses the hydrolysis of sphingomyelin into ceramide, which acts as a lipid messenger that regulates important cellular functions. Deregulated ASM activity has been reported for different common diseases, but the mechanisms regulating ASM activity are still debated. ASM contains an exceptional signal peptide which is polymorphic due to a variable number of a hexanucleotide sequence that determines the length of the hydrophobic core. We investigated the impact of the signal peptide polymorphism on the regulation of ASM activity and secretion in vivo and in vitro. METHODS AND RESULTS: Subjects homozygous for the rare 4-repeat allele displayed significantly lower secreted ASM activity than subjects homozygous for the common 6-repeat allele. In vitro, overexpression of ASM variants encoded by 2, 8 or 9 repeats resulted in a significantly lowered ASM secretion rate. Treatment of ASM-overexpressing cells with tumour necrosis factor α induced secretion of ASM, and the secretion rate was highest for the most common ASM variant encoding 6 repeats compared to other naturally occurring variants. CONCLUSION: We provide evidence that the polymorphic ASM signal peptide regulates ASM secretion. It might be an evolutionary mechanism to increase ASM secretion potential, whereas an increase in lysosomal ASM activity is limited due to deleterious cellular effects.
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Polimorfismo Genético/genética , Sinais Direcionadores de Proteínas/genética , Esfingomielina Fosfodiesterase/genética , Esfingomielina Fosfodiesterase/metabolismo , Alelos , Células Cultivadas , Humanos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Acid sphingomyelinase (ASM) is a key regulator of ceramide-dependent signalling pathways. Among others, activation of ASM can be induced by CD95 or cytokine signalling and by cellular stress resulting from inflammation or infection. Increased ASM activity was observed in a variety of human diseases including inflammatory and neuropsychiatric disorders. We hypothesized that basal ASM activity might influence the susceptibility for common human diseases. METHODS: The general health condition of 100 young people was assessed using a questionnaire. The ASM polymorphism rs1050239 (c.1522G>A; encoding p.G508R) was determined from genomic DNA. Activities of secretory (S-) and lysosomal (L-) ASM were measured in blood plasma and peripheral blood cells respectively. RESULTS: The polymorphism rs1050239 was significantly associated with self-reported allergy (p=4.68×10(-4); adjusted p-value for multiple testing 0.007). Allergy was more prevalent in carriers of the minor A allele compared to non-carriers (p=0.00015; odds ratio=6.5, 95% CI 2.15-21.7). S-ASM activity was significantly associated with rs1050239 (p=5.3×10(-7)) and decreased with the number of A alleles in a gene-dosage dependent manner. In allergic patients, S-ASM activity was moderately decreased (p=0.034). L-ASM activity was significantly lower in subjects homozygous for the minor A allele (p=0.025) but not different between allergic and non-allergic subjects (p=0.318). CONCLUSION: Our analysis provides evidence for an involvement of ASM in the pathophysiology of allergy, which is in line with previous reports addressing the role of sphingolipids in this disorder. Further studies should clarify the mechanism linking rs1050239 to allergy. The ASM pathway might be useful for predicting allergic disposition and disease course and as a therapeutic target.
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Hipersensibilidade/enzimologia , Polimorfismo de Nucleotídeo Único , Esfingomielina Fosfodiesterase/genética , Adulto , Alelos , Células Sanguíneas/enzimologia , Feminino , Genótipo , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/patologia , Lisossomos/enzimologia , Masculino , Prevalência , Esfingomielina Fosfodiesterase/metabolismo , Adulto JovemRESUMO
The influence of genetic factors in the development of schizophrenia has been convincingly demonstrated by family, twin, and adoption studies. The statistical construct of heritability is generally used for estimating the liability due to genetic factors. Heritability estimates for schizophrenia are reported to be between 60 and 80 %. Due to the technical achievements in whole genome-wide association studies, dissection of the underlying genetic factors was intensified recently, resulting in the conclusion that schizophrenia is essentially a polygenic, complex disorder. Most likely more than 100 genes, each with small effect size, contribute to disease risk. A most recent multi-stage genome-wide association study (Ripke et al. in Nat Genet 2013) identified 22 risk loci and estimated that 8,300 independent single-nucleotide polymorphisms contributed to the risk accounting collectively for 32 % in liability. In addition to this polygenic, complex inheritance, there is also strong indication that in some patients a deletion or insertion of a larger chromosomal region [so-called copy number variation (CNV)] might play a crucial role in pathogenesis. This could be specifically important in sporadic cases with schizophrenia, since a higher frequency of de novo mutations has been associated with these CNVs. Further studies, combining much larger sample sizes as well as application of newer technology, such as deep sequencing technologies will be necessary in order to obtain a more comprehensive understanding of the genetic foundations of schizophrenia.
Assuntos
Estudo de Associação Genômica Ampla , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Alelos , Predisposição Genética para Doença , Variação Genética , Humanos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , RiscoRESUMO
Studying the gut microbiome can provide valuable insights into animal health and inform the conservation management of threatened wildlife. Gut microbiota play important roles in regulating mammalian host physiology, including digestion, energy metabolism and immunity. Dysbiosis can impair such physiological processes and compromise host health, so it is essential that the gut microbiome be considered in conservation planning. The southern greater glider (Petauroides volans) is an endangered arboreal marsupial that faced widespread habitat fragmentation and population declines following the 2019-2020 Australian bushfire season. This study details baseline data on the gut microbiome of this species. The V3-V4 region of the 16S rRNA gene was amplified from scats collected from individuals inhabiting burnt and unburnt sites across southeastern Australia and sequenced to determine bacterial community composition. Southern greater glider gut microbiomes were characterised by high relative abundances of Firmicutes and Bacteroidota, which is consistent with that reported for other marsupial herbivores. Significant differences in gut microbial diversity and community structure were detected among individuals from different geographic locations. Certain microbiota and functional orthologues were also found to be significantly differentially abundant between locations. The role of wildfire in shaping southern greater glider gut microbiomes was shown, with some significant differences in the diversity and abundance of microbiota detected between burnt and unburnt sites. Overall, this study details the first data on greater glider (Petauroides) gut microbiomes, laying the foundation for future studies to further explore relationships between microbial community structure, environmental stressors and host health.
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Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10-6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.
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Transtorno Autístico , Esquizofrenia , Humanos , Esquizofrenia/genética , Transtorno Autístico/genética , Alelos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodosRESUMO
After finishing my pharmacy studies, I became interested in undertaking a PhD in the genetics of psychiatric disorders, specifically, the genetics of schizophrenia. At this time in 1990, only limited information about the human genome was available. Still, the research soon picked up some speed with introduction of the polymerase chain reaction (PCR) into research laboratories and the growing knowledge about the structure of the human genome. In my research, I aim to identify altered genes that increase the susceptibility to schizophrenia. The idea was that identifying these genes allows an understanding of the underlying biochemistry, therefore facilitating the development of targeted pharmacotherapies. While we have come closer to achieving this aim, the complexity of the identified genetic architecture and the phenotypes implies that there is still much research to be completed before we can achieve this aim.
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Esquizofrenia , Humanos , Esquizofrenia/genética , Predisposição Genética para Doença/genética , Fenótipo , Variação Genética/genética , Ligação Genética , Estudo de Associação Genômica AmplaRESUMO
In academia and related industry, particularly in the medical sciences, some individuals are noticed for their ability to attract others towards their ideas, theories and objectives. They are often referred to as the "thought leaders" of the field. Noticeably, individuals who are labeled as "thought leaders" appear more often to be males than females. Moreover, this is not a racially or ethnically diverse group. In this special issue, we intend to challenge that bias. As we look world-wide at the incredibly important contributions of women in both psychiatry and related neuroscience, it was a logical step to ask these 'thought leaders' to write commentaries on their most important work, how they got there, and what they predict for the future. When compiling a list of "thought leaders" for future academic and industry workshops, these scientists are certain to enrich and advance the discourse.
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Liderança , Psiquiatria , Feminino , Humanos , MasculinoRESUMO
Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.
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Estudo de Associação Genômica Ampla , Transtornos Relacionados ao Uso de Opioides , Furina/genética , Predisposição Genética para Doença , Humanos , Transtornos Relacionados ao Uso de Opioides/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores Opioides mu/genéticaRESUMO
Variant rs2522833 of the Piccolo-encoding gene PCLO has recently been found to be associated with major depressive disorder (MDD). PCLO encodes a presynaptic cytomatrix protein which influences monoamine neurotransmitter release. Piccolo could therefore play an important role in treatment response to antidepressant therapy and the improvement of alterations in HPA system reactivity. We investigated the influence of the coding variant rs2522833 in the PCLO gene on treatment response in 205 in-patients with unipolar depression. Treatment response was measured (1) at the level of psychopathology using the Hamilton Depression Rating Scale (HAMD) and (2) with the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, which is a refined tool for showing dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system, a neurobiological finding in depression. While we did not find an association between variation in PCLO and HAMD scores, HPA dysregulation was less pronounced in carriers of the AA genotype than in carriers of one or two C alleles. HPA activity of individuals with the AA genotype only marginally changed during 4-wk antidepressant treatment, whereas C allele carriers showed a higher hormonal secretion at admission than carriers of the AA genotype but lower responsivity to the Dex/CRH challenge after 4 wk. Our results point to a moderating role of PCLO SNP rs2522833 on HPA regulation during antidepressant treatment, which may represent a neurobiological feature of stability of clinical response.
Assuntos
Antidepressivos/uso terapêutico , Proteínas do Citoesqueleto/genética , Transtorno Depressivo Maior/tratamento farmacológico , Sistema Hipotálamo-Hipofisário/metabolismo , Neuropeptídeos/genética , Sistema Hipófise-Suprarrenal/metabolismo , Hormônio Adrenocorticotrópico/sangue , Fatores Etários , Alelos , Área Sob a Curva , Hormônio Liberador da Corticotropina , Proteínas do Citoesqueleto/metabolismo , Transtorno Depressivo Maior/metabolismo , Dexametasona , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Neuropeptídeos/metabolismo , Polimorfismo de Nucleotídeo Único , Escalas de Graduação PsiquiátricaRESUMO
The use of genetic information in conservation biology has become more widespread with genetic information more readily available for non-model organisms. It has also been recognized that genetic information from invasive species can inform their management and control. The red fox poses a significant threat to Australian native fauna and the agricultural industry. Despite this, there are few recently published studies investigating the population genetics of foxes in Australia. This study investigated the population genetics of 94 foxes across the Illawarra and Shoalhaven regions of New South Wales, Australia. Diversity Array sequencing technology was used to genotype a large number of single nucleotide polymorphisms (N = 33,375). Moderate genetic diversity and relatedness were observed across the foxes sampled. Low to moderate levels of inbreeding, high-levels of identity-by-state values, as well as high identity-by-descent values were also found. There was limited evidence for population genetic structure among the foxes across the landscape sampled, supporting the presence of a single population across the study area. This indicates that there may be no barriers hindering fox dispersal across the landscape.
Assuntos
Raposas/genética , Polimorfismo de Nucleotídeo Único , Distribuição Animal , Animais , Austrália , Espécies Introduzidas , LinhagemRESUMO
Severe stress is among the most robust risk factors for the development of psychiatric disorders. Imaging studies indicate that life stress is integral to shaping the human brain, especially regions involved in processing the stress response. Although this is likely underpinned by changes to the cytoarchitecture of cellular networks in the brain, we are yet to clearly understand how these define a role for stress in human psychopathology. In this review, we consolidate evidence of macro-structural morphometric changes and the cellular mechanisms that likely underlie them. Focusing on stress-sensitive regions of the brain, we illustrate how stress throughout life may lead to persistent remodelling of the both neurons and glia in cellular networks and how these may lead to psychopathology. We support that greater translation of cellular alterations to human cohorts will support parsing the psychological sequalae of severe stress and improve our understanding of how stress shapes the human brain. This will remain a critical step for improving treatment interventions and prevention outcomes.
Assuntos
Transtornos Mentais , Córtex Pré-Frontal , Encéfalo , Forma Celular , Humanos , Estresse PsicológicoRESUMO
Displacement of people from their homes, families and countries is a current global crisis, with over 70 million people forcibly on the move. A substantial proportion of these people will end up in regions with a different language and culture, where they are registered as refugees or asylum seekers. Due to the underlying reasons for displacement (including conflicts, persecution or violation of human rights), displaced people are severely stress-exposed, which continues into their post-migration life and increases risk for developing psychiatric disorders such as post-traumatic stress disorder and other anxiety disorders and mood disorders. While landmark studies have illustrated the increased prevalence of psychopathology in asylum seeker and refugee populations following pre-/post-displacement stress, few studies add to our understanding of the basic biological mechanisms underpinning risk to psychiatric disorders in these populations. Additionally, the mechanisms underlying resilience despite significant adversity remain unclear. Understanding the molecular mechanisms underpinning the development of psychiatric disorders in refugees can propel treatments (both drug and non-drug) that are capable of influencing biology at the molecular level, and the design of interventions. In the following review, we summarise the status quo of research investigating the pathophysiology of psychiatric disorders in refugees, and propose new ways to address gaps in knowledge with multidisciplinary research.
Assuntos
Transtornos Mentais/epidemiologia , Saúde Mental/etnologia , Trauma Psicológico/etnologia , Psicopatologia , Refugiados/psicologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/etnologia , Transtornos de Ansiedade , Humanos , Hidrocortisona/sangue , Masculino , Transtornos do Humor , Prevalência , Trauma Psicológico/diagnóstico , Trauma Psicológico/psicologia , Refugiados/estatística & dados numéricos , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/etnologia , Estresse Psicológico/diagnóstico , Estresse Psicológico/psicologiaRESUMO
FKBP5 is a glucocorticoid receptor-regulating co-chaperone of hsp-90 and, therefore, is suggested to play a role in the regulation of the hypothalamic-pituitary-adrenocortical system and the pathophysiology of depression. Previously, three studies identified single nucleotide polymorphisms (SNPs) in the FKBP5 gene associated with response to antidepressants, and one study found an association with diagnosis of depression. We selected five markers from the region of interest. A case-control sample comprising 268 German in-patients with recurrent unipolar depression, and 284 German controls recruited from the general population were available. Association of the selected FKBP5 sequence variants with clinical depression were analysed. In addition, we explored association with treatment response by (a) the Hamilton Depression Rating Scale and (b) the dexamethasone/corticotrophin-releasing hormone (Dex/CRH) test, as well as association with hippocampal volumes in a subpopulation of 110 patients. For three of the five investigated SNPs we were able to show association with the diagnosis of depression. In the subpopulation of 110 patients, diagnosis-related alleles were also associated with the reduction of cortisol secretion in the Dex/CRH test during a 4-wk treatment period, while psychopathological changes were not associated. Furthermore, diagnosis-related alleles were associated with reduction of the hippocampal volume. This study extends the replicated association of a promoter SNP with antidepressant response on a biological level by demonstrating normalization of the cortisol response under Dex/CRH stimulation during treatment. Furthermore, several of the investigated SNPs were associated with the disease status and the intermediate phenotype of hippocampal volume.
Assuntos
Alelos , Sequência de Bases/genética , Transtorno Depressivo/genética , Variação Genética/genética , Proteínas de Ligação a Tacrolimo/genética , Adolescente , Adulto , Estudos de Casos e Controles , Citalopram/uso terapêutico , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/patologia , Feminino , Ligação Genética/genética , Marcadores Genéticos/genética , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Adulto JovemRESUMO
The genetic factors determining the progression of prodromal syndromes to first episode schizophrenia have remained enigmatic to date. In a unique prospective multicentre trial, we assessed whether variants at the D-amino acid oxidase activator (DAOA)/G72 locus influence progression to psychosis. Young subjects with a prodromal syndrome were observed prospectively for up to 2 years to assess the incidence of progression to schizophrenia or first episode psychosis. Of the 82 probands with a prodromal syndrome, 21 probands experienced progression to psychosis within the observation period. Assessment of nine common variants in the DAOA/G72 locus yielded two variants with the predictive value for symptom progression: all four probands with the rs1341402 CC genotype developed psychosis compared with 17 out of 78 probands with the TT or CT genotypes (chi(2) = 12.348; df = 2; p = 0.002). The relative risk for progression to psychosis was significantly increased in the CC genotype: RR = 4.588 (95% CI = 2.175-4.588). Similarly, for rs778294, 50% of probands with the AA genotype, but only 22% of probands with a GG or GA genotype progressed to psychosis (chi(2) = 7.027; df = 2; p = 0.030). Moreover, haplotype analysis revealed a susceptibility haplotype for progression to psychosis. This is one of the first studies to identify a specific genetic factor for the progression of prodromal syndromes to schizophrenia, and further underscores the importance of the DAOA/G72 gene for schizophrenia.
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Proteínas de Transporte/genética , Predisposição Genética para Doença , Transtornos Psicóticos/genética , Adolescente , Adulto , Análise de Variância , Distribuição de Qui-Quadrado , Progressão da Doença , Feminino , Frequência do Gene , Testes Genéticos , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/diagnóstico , Adulto JovemRESUMO
Severe stress exposure causes the loss of dendritic spines on cortical pyramidal neurons and induces psychiatric-like symptoms in rodent models. These effects are strongest following early-life stress and are most persistent on apical dendrites. However, the long-term impacts and temporal effects of stress exposure on the human brain remain poorly understood. Using a novel postmortem cohort of psychiatric cases with severe stress experienced in childhood, adulthood, or no severe stress, and matched controls, we aimed to determine the impact of stress timing on pyramidal neuron structure in the human orbitofrontal cortex (OFC). We performed Golgi Cox staining and manually measured the morphology and density of over 22,000 dendritic spines on layer-specific pyramidal neuron apical dendrites. We also quantified glucocorticoid receptor mRNA and protein as a marker of stress dysregulation. Both childhood and adulthood stress were associated with large reductions in mature mushroom spine density (up to 56% loss) in both the superficial (II/III) and deeper layers (V) of the OFC. However, childhood stress caused more substantial reductions to both total and mature mushroom spines. No difference in glucocorticoid receptor mRNA and protein were seen between groups, although both negatively correlated with total spine density within the whole cohort. These findings indicate that severe stress, especially when experienced during childhood, persistently affects the fine morphological properties of neurons in the human OFC. This may impact on cell connectivity in this brain area, and at least partly explain the social and emotional symptoms that originate in the OFC in psychiatric disorders.
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We previously reported genome-wide significant linkage to chromosome 3p in a sib-pair family sample from Indonesia. A promising candidate gene within the linked region is the metabotropic glutamate receptor subtype 7 (GRM7), involved in glutamatergic neurotransmission. We genotyped 18 single nucleotide polymorphisms in GRM7 in the sample of 124 Indonesian sib-pair families that had provided the significant linkage finding. Transmission disequilibrium analysis revealed nominally significant transmission distortion of rs17031835 in intron 1 of GRM7 (p=0.004, before correction for multiple testing), along with haplotypes containing rs17031835. No other single marker was found to be significantly associated with schizophrenia in our sample. The results from our study provide support for the idea that glutamatergic neurotransmission and specifically the GRM7 gene might be relevant to the development of schizophrenia. Further studies supporting this finding are warranted.
Assuntos
Povo Asiático/genética , Cromossomos Humanos Par 3 , Polimorfismo de Nucleotídeo Único , Receptores de Glutamato Metabotrópico/genética , Esquizofrenia/genética , Análise Mutacional de DNA , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Indonésia , Íntrons , Desequilíbrio de Ligação , Linhagem , Esquizofrenia/etnologiaRESUMO
The Neuregulin (NRG1) gene has been associated with schizophrenia, but its functional implications are largely unknown. Our aim was to assess differential brain activation between patients carrying an at-risk allele on the Neuregulin 1 gene and patients without this genetic risk. Neural signal changes between 14 first episode schizophrenia patients with the at risk allele (SNP8NRG221533) from the Icelandic core haplotype and 14 without were measured with fMRI during a working memory task. Patients without the at risk allele showed greater activations (P < 0.05; corrected) in the left hippocampus, precuneus and cerebellum, as well as the right anterior cingulate. Brain regions previously associated with the pathology of Schizophrenia are differentially affected in those with a genetic at risk status in the NRG1 gene. Heterogeneity of structural and functional measures within patients characterized by clinical phenotypes may be in part due to this genetic variation.
Assuntos
Córtex Cerebral/fisiopatologia , Haplótipos/genética , Neuregulina-1/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Adulto , Cerebelo/fisiopatologia , Córtex Cerebral/patologia , Feminino , Lobo Frontal/fisiopatologia , Lateralidade Funcional/genética , Predisposição Genética para Doença/genética , Giro do Cíngulo/fisiopatologia , Hipocampo/fisiopatologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Esquizofrenia/diagnóstico , Lobo Temporal/fisiopatologia , Adulto JovemRESUMO
OBJECTIVES: Susceptibility to heroin dependence is strongly influenced by genetic factors with heritability estimates as high as 0.7. A number of genes, as well as environmental factors, are likely to contribute to its etiology. Not all individuals who have ever tried heroin at some stage during their lifetime become dependent on heroin. It has been suggested that genetic factors might be more important in the transition stage to heroin dependence rather than in environmental exposures and experimenting with heroin. As the features of substance dependence and memory formation have been found to be strikingly similar, we have focused on a key enzyme involved in long-term potentiation and synaptic plasticity, namely the calcium-dependent/calmodulin-dependent protein kinase IIα (CAMKIIa). We hypothesized, that CamK2A genetic variation may play a role in the transition from occasional to regular heroin use. MATERIALS AND METHODS: Using quantitative trait association analysis, we addressed this hypothesis by correlating the self-reported time interval between occasional and regular heroin use with the frequency of 12 single nucleotide polymorphisms located within the genomic region of the CamK2A gene. A sample of 570 Caucasian patients was available for analysis. RESULTS: Single marker association analysis (rs10066581, P=0.007), as well as haplotype analysis (global P=0.005), suggested an association with the quantitative trait 'time interval from occasional to regular heroin use.' CONCLUSION: Our results propose that genetic variants located in the genomic region of the CamK2A gene may be involved in transition time from occasional to regular heroin use.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Dependência de Heroína/genética , Adolescente , Adulto , Austrália , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Variação Genética/genética , Genótipo , Haplótipos/genética , Heroína/efeitos adversos , Humanos , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Adulto JovemRESUMO
Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.