RESUMO
BACKGROUND: Previous evidence suggests that early life complications (ELCs) interact with polygenic risk for schizophrenia (SCZ) in increasing risk for the disease. However, no studies have investigated this interaction on neurobiological phenotypes. Among those, anomalous emotion-related brain activity has been reported in SCZ, even if evidence of its link with SCZ-related genetic risk is not solid. Indeed, it is possible this relationship is influenced by non-genetic risk factors. Thus, this study investigated the interaction between SCZ-related polygenic risk and ELCs on emotion-related brain activity. METHODS: 169 healthy participants (HP) in a discovery and 113 HP in a replication sample underwent functional magnetic resonance imaging (fMRI) during emotion processing, were categorized for history of ELCs and genome-wide genotyped. Polygenic risk scores (PRSs) were computed using SCZ-associated variants considering the most recent genome-wide association study. Furthermore, 75 patients with SCZ also underwent fMRI during emotion processing to verify consistency of their brain activity patterns with those associated with risk factors for SCZ in HP. RESULTS: Results in the discovery and replication samples indicated no effect of PRSs, but an interaction between PRS and ELCs in left ventrolateral prefrontal cortex (VLPFC), where the greater the activity, the greater PRS only in presence of ELCs. Moreover, SCZ had greater VLPFC response than HP. CONCLUSIONS: These results suggest that emotion-related VLPFC response lies in the path from genetic and non-genetic risk factors to the clinical presentation of SCZ, and may implicate an updated concept of intermediate phenotype considering early non-genetic factors of risk for SCZ.
Assuntos
Emoções , Imageamento por Ressonância Magnética , Herança Multifatorial , Esquizofrenia , Humanos , Esquizofrenia/fisiopatologia , Esquizofrenia/genética , Esquizofrenia/diagnóstico por imagem , Masculino , Feminino , Adulto , Emoções/fisiologia , Adulto Jovem , Estudo de Associação Genômica Ampla , Fatores de Risco , Predisposição Genética para Doença , Córtex Pré-Frontal/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Encéfalo/fisiopatologia , Encéfalo/diagnóstico por imagem , Voluntários Saudáveis , Pessoa de Meia-Idade , Estratificação de Risco GenéticoRESUMO
Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. Ursini et al., Nat. Med. 24, 792-801 (2018)]. Here, we analyze whether fractionated genomic risk scores for schizophrenia and other developmental disorders and traits, based on placental gene-expression loci (PlacGRSs), are linked with early neurodevelopmental outcomes in individuals with a history of ELCs. We found that schizophrenia's PlacGRSs are negatively associated with neonatal brain volume in singletons and offspring of multiple pregnancies and, in singletons, with cognitive development at 1 y and, less strongly, at 2 y, when cognitive scores become more sensitive to other factors. These negative associations are stronger in males, found only with GRSs fractionated by placental gene expression, and not found in PlacGRSs for other developmental disorders and traits. The relationship of PlacGRSs with brain volume persists as an anlage of placenta biology in adults with schizophrenia, again selectively in males. Higher placental genomic risk for schizophrenia, in the presence of ELCs and particularly in males, alters early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia.
Assuntos
Encéfalo/anatomia & histologia , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Placenta/metabolismo , Esquizofrenia/genética , Transcriptoma , Encéfalo/fisiologia , Cognição , Feminino , Loci Gênicos , Humanos , Lactente , Recém-Nascido , Masculino , Tamanho do Órgão/genética , GravidezRESUMO
Psychiatric disorders are associated with accelerated aging and enhanced risk for neurodegenerative disorders. Brain aging is associated with molecular, cellular, and structural changes that are robust on the group level, yet show substantial inter-individual variability. Here we assessed deviations in gene expression from normal age-dependent trajectories, and tested their validity as predictors of risk for major mental illnesses and neurodegenerative disorders. We performed large-scale gene expression and genotype analyses in postmortem samples of two frontal cortical brain regions from 214 control subjects aged 20-90 years. Individual estimates of "molecular age" were derived from age-dependent genes, identified by robust regression analysis. Deviation from chronological age was defined as "delta age". Genetic variants associated with deviations from normal gene expression patterns were identified by expression quantitative trait loci (cis-eQTL) of age-dependent genes or genome-wide association study (GWAS) on delta age, combined into distinct polygenic risk scores (PRScis-eQTL and PRSGWAS), and tested for predicting brain disorders or pathology in independent postmortem expression datasets and clinical cohorts. In these validation datasets, molecular ages, defined by 68 and 76 age-related genes for two brain regions respectively, were positively correlated with chronological ages (r = 0.88/0.91), elevated in bipolar disorder (BP) and schizophrenia (SCZ), and unchanged in major depressive disorder (MDD). Exploratory analyses in independent clinical datasets show that PRSs were associated with SCZ and MDD diagnostics, and with cognition in SCZ and pathology in Alzheimer's disease (AD). These results suggest that older molecular brain aging is a common feature of severe mental illnesses and neurodegeneration.
Assuntos
Transtorno Depressivo Maior , Transtornos Mentais , Encéfalo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Transtornos Mentais/genéticaAssuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/isolamento & purificação , Feminino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Transtornos do Neurodesenvolvimento/virologia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/diagnóstico , Desenvolvimento Infantil , Complicações Infecciosas na Gravidez/virologia , Recém-Nascido , Criança , Dinâmica não Linear , LactenteRESUMO
The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.awy004media15749593779001.
Assuntos
Hipocampo/fisiopatologia , Herança Multifatorial/genética , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Hipocampo/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Inteligência/fisiologia , Imageamento por Ressonância Magnética , Masculino , Oxigênio/sangue , Adulto JovemRESUMO
Psychological distress is a known feature of generalized joint hypermobility (gJHM), as well as of its most common syndromic presentation, namely Ehlers-Danlos syndrome, hypermobility type (a.k.a. joint hypermobility syndrome - JHS/EDS-HT), and significantly contributes to the quality of life of affected individuals. Most published articles dealt with the link between gJHM (or JHS/EDS-HT) and anxiety-related conditions, and a novel generation of studies is emerging aimed at investigating the psychopathologic background of such an association. In this paper, literature review was carried out with a semi-systematic approach spanning the entire spectrum of psychopathological findings in gJHM and JHS/EDS-HT. Interestingly, in addition to the confirmation of a tight link between anxiety and gJHM, preliminary connections with depression, attention deficit (and hyperactivity) disorder, autism spectrum disorders, and obsessive-compulsive personality disorder were also found. Few papers investigated the relationship with schizophrenia with contrasting results. The mind-body connections hypothesized on the basis of available data were discussed with focus on somatotype, presumed psychopathology, and involvement of the extracellular matrix in the central nervous system. The hypothesis of positive Beighton score and alteration of interoceptive/proprioceptive/body awareness as possible endophenotypes in families with symptomatic gJHM or JHS/EDS-HT is also suggested. Concluding remarks addressed the implications of the psychopathological features of gJHM and JHS/EDS-HT in clinical practice.
Assuntos
Tecido Conjuntivo/fisiopatologia , Síndrome de Ehlers-Danlos/fisiopatologia , Instabilidade Articular/congênito , Estresse Psicológico , Ansiedade/genética , Ansiedade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Depressão/genética , Depressão/fisiopatologia , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/psicologia , Humanos , Instabilidade Articular/genética , Instabilidade Articular/fisiopatologia , Instabilidade Articular/psicologia , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
The D2/AKT1/GSK-3ß signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3ß proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3ß, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.
Assuntos
Antipsicóticos/farmacologia , Atenção/fisiologia , Benzodiazepinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Transdução de Sinais/fisiologia , Antipsicóticos/uso terapêutico , Atenção/efeitos dos fármacos , Benzodiazepinas/uso terapêutico , AMP Cíclico/metabolismo , Epistasia Genética , Genótipo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Imageamento por Ressonância Magnética , Olanzapina , Fosforilação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Receptores de Dopamina D2/genética , Esquizofrenia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Epigenetic modifications influenced by environmental exposures are molecular sources of phenotypic heterogeneity found in schizophrenia and bipolar disorder and may contribute to shared etiopathogenetic mechanisms of these two disorders. Newborns who experienced perinatal asphyxia have suffered reduced oxygen delivery to the brain around the time of birth, which increases the risk of later psychiatric diagnosis. This study aimed to investigate DNA methylation in blood cells for associations with a history of perinatal asphyxia, a neurologically harmful condition occurring within the biological environment of birth. We utilized prospective data from the Medical Birth Registry of Norway to identify incidents of perinatal asphyxia in 643 individuals with schizophrenia or bipolar disorder and 676 healthy controls. We performed an epigenome wide association study to distinguish differentially methylated positions associated with perinatal asphyxia. We found an interaction between methylation and exposure to perinatal asphyxia on case-control status, wherein having a history of perinatal asphyxia was associated with an increase of methylation in healthy controls and a decrease of methylation in patients on 4 regions of DNA important for brain development and function. The differentially methylated regions were observed in genes involved in oligodendrocyte survival and axonal myelination and functional recovery (LINGO3); assembly, maturation and maintenance of the brain (BLCAP;NNAT and NANOS2) and axonal transport processes and neural plasticity (SLC2A14). These findings are consistent with the notion that an opposite epigenetic response to perinatal asphyxia, in patients compared with controls, may contribute to molecular mechanisms of risk for schizophrenia and bipolar disorder.
Assuntos
Transtorno Bipolar , Transtornos Mentais , Recém-Nascido , Feminino , Gravidez , Humanos , Asfixia , Estudos Prospectivos , Transtorno Bipolar/genética , Epigênese GenéticaRESUMO
Primary human trophoblast stem cells (TSCs) and TSCs derived from human pluripotent stem cells (hPSCs) can potentially model placental processes in vitro. Yet, the pluripotent states and factors involved in the differentiation of hPSCs to TSCs remain poorly understood. In this study, we demonstrate that the primed pluripotent state can generate TSCs by activating pathways such as Epidermal Growth Factor (EGF) and Wingless-related integration site (WNT), and by suppressing tumor growth factor beta (TGFß), histone deacetylases (HDAC), and Rho-associated protein kinase (ROCK) signaling pathways, all without the addition of exogenous Bone morphogenetic protein 4 (BMP4)-a condition we refer to as the TS condition. We characterized this process using temporal single-cell RNA sequencing to compare TS conditions with differentiation protocols involving BMP4 activation alone or BMP4 activation in conjunction with WNT inhibition. The TS condition consistently produced a stable, proliferative cell type that closely mimics first-trimester placental cytotrophoblasts, marked by the activation of endogenous retroviral genes and the absence of amnion expression. This was observed across multiple cell lines, including various primed induced pluripotent stem cell (iPSC) and embryonic stem cell (ESC) lines. Primed-derived TSCs can proliferate for over 30 passages and further specify into multinucleated syncytiotrophoblasts and extravillous trophoblast cells. Our research establishes that the differentiation of primed hPSCs to TSC under TS conditions triggers the induction of TMSB4X, BMP5/7, GATA3, and TFAP2A without progressing through a naive state. These findings propose that the primed hPSC state is part of a continuum of potency with the capacity to differentiate into TSCs through multiple routes.
Assuntos
Células-Tronco Pluripotentes Induzidas , Células-Tronco Pluripotentes , Humanos , Feminino , Gravidez , Placenta , Diferenciação Celular/genética , Trofoblastos/metabolismo , Proteína Morfogenética Óssea 5/metabolismoRESUMO
Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. However, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, is not fully understood. Here, we report that in mice, adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in a model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings suggest the microglial Cnr1 may contribute to adverse effect of cannabis exposure in genetically vulnerable individuals.
Assuntos
Dronabinol , Microglia , Animais , Camundongos , Agonistas de Receptores de Canabinoides , Variações do Número de Cópias de DNA , Dronabinol/efeitos adversos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/genética , Receptores de Canabinoides/genéticaRESUMO
The placenta plays a role in fetal brain development, and pregnancy and birth complications can be signs of placental dysfunction. Birth asphyxia is associated with smaller head size and higher risk of developing schizophrenia (SZ), but whether birth asphyxia and placental genomic risk factors associated with SZ are related and how they might impact brain development is unclear. 433 adult patients with SZ and 870 healthy controls were clinically evaluated and underwent brain magnetic resonance imaging. Pregnancy and birth information were obtained from the Medical Birth Registry of Norway. Polygenic risk scores (PRS) from the latest genome-wide association study in SZ were differentiated into placental PRS (PlacPRS) and non-placental PRS. If the interaction between PRSs and birth asphyxia on case-control status was significant, neonatal head circumference (nHC) and adult intracranial volume (ICV) were further evaluated with these variables using multiple regression. PlacPRS in individuals with a history of birth asphyxia was associated with a higher likelihood of being a patient with SZ (t = 2.10, p = 0.018). We found a significant interaction between PlacPRS and birth asphyxia on nHC in the whole sample (t = -2.43, p = 0.008), with higher placental PRS for SZ associated with lower nHC in those with birth asphyxia. This relationship was specific to males (t = -2.71, p = 0.005) and also found with their adult ICV (t = -1.97, p = 0.028). These findings suggest that placental pathophysiology and birth asphyxia may affect early and late trajectories of brain development, particularly in males with a higher vulnerability to SZ. This knowledge might lead to new strategies of treatment and prevention in SZ.
Assuntos
Placenta , Esquizofrenia , Gravidez , Adulto , Masculino , Recém-Nascido , Humanos , Feminino , Asfixia , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Genômica , Encéfalo/diagnóstico por imagemRESUMO
Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. Nonetheless, until now, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, has been unexplored. Here, we report that adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in the mouse model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings highlight the importance of microglial Cnr1 to produce the adverse effect of cannabis exposure in genetically vulnerable individuals.
RESUMO
Our earlier work has shown that genomic risk for schizophrenia converges with early life complications in affecting risk for the disorder and sex-biased neurodevelopmental trajectories. Here, we identify specific genes and potential mechanisms that, in placenta, may mediate such outcomes. We performed TWAS in healthy term placentae (N = 147) to derive candidate placental causal genes that we confirmed with SMR; to search for placenta and schizophrenia-specific associations, we performed an analogous analysis in fetal brain (N = 166) and additional placenta TWAS for other disorders/traits. The analyses in the whole sample and stratifying by sex ultimately highlight 139 placenta and schizophrenia-specific risk genes, many being sex-biased; the candidate molecular mechanisms converge on the nutrient-sensing capabilities of placenta and trophoblast invasiveness. These genes also implicate the Coronavirus-pathogenesis pathway and showed increased expression in placentae from a small sample of SARS-CoV-2-positive pregnancies. Investigating placental risk genes for schizophrenia and candidate mechanisms may lead to opportunities for prevention that would not be suggested by study of the brain alone.
Assuntos
COVID-19 , Esquizofrenia , Gravidez , Feminino , Humanos , Placenta/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , COVID-19/metabolismo , SARS-CoV-2 , Trofoblastos/metabolismoRESUMO
Schizophrenia (SZ) and bipolar disorder (BP) are highly heritable major psychiatric disorders that share a substantial portion of genetic risk as well as their clinical manifestations. This raises a fundamental question of whether, and how, common neurobiological pathways translate their shared polygenic risks into shared clinical manifestations. This study shows the miR-124-3p-AMPAR pathway as a key common neurobiological mediator that connects polygenic risks with behavioral changes shared between these two psychotic disorders. We discovered the upregulation of miR-124-3p in neuronal cells and the postmortem prefrontal cortex from both SZ and BP patients. Intriguingly, the upregulation is associated with the polygenic risks shared between these two disorders. Seeking mechanistic dissection, we generated a mouse model that upregulates miR-124-3p in the medial prefrontal cortex. We demonstrated that the upregulation of miR-124-3p increases GRIA2-lacking calcium-permeable AMPARs and perturbs AMPAR-mediated excitatory synaptic transmission, leading to deficits in the behavioral dimensions shared between SZ and BP.
Assuntos
Transtorno Bipolar , MicroRNAs , Esquizofrenia , Camundongos , Animais , Esquizofrenia/genética , Esquizofrenia/metabolismo , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Herança Multifatorial , Córtex Pré-Frontal/metabolismoRESUMO
DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val(158) allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide. We report that methylation of the Val(158) allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT in prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val(158) allele with stress, gene expression, WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, these results demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation.
Assuntos
Catecol O-Metiltransferase/genética , Cognição/fisiologia , Metilação de DNA , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiologia , Estresse Psicológico/fisiopatologia , Adulto , Alelos , Animais , Western Blotting , Catecol O-Metiltransferase/metabolismo , Feminino , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Polimorfismo Genético , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: The authors sought to study the transcriptomic and genomic features of completed suicide by parsing the method chosen, to capture molecular correlates of the distinctive frame of mind of individuals who die by suicide, while reducing heterogeneity. METHODS: The authors analyzed gene expression (RNA sequencing) from postmortem dorsolateral prefrontal cortex of patients who died by suicide with violent compared with nonviolent means, nonsuicide patients with the same psychiatric disorders, and a neurotypical group (total N=329). They then examined genomic risk scores (GRSs) for each psychiatric disorder included, and GRSs for cognition (IQ) and for suicide attempt, testing how they predict diagnosis or traits (total N=888). RESULTS: Patients who died by suicide by violent means showed a transcriptomic pattern remarkably divergent from each of the other patient groups but less from the neurotypical group; consistently, their genomic profile of risk was relatively low for their diagnosed illness as well as for suicide attempt, and relatively high for IQ: they were more similar to the neurotypical group than to other patients. Differentially expressed genes (DEGs) associated with patients who died by suicide by violent means pointed to purinergic signaling in microglia, showing similarities to a genome-wide association study of Drosophila aggression. Weighted gene coexpression network analysis revealed that these DEGs were coexpressed in a context of mitochondrial metabolic activation unique to suicide by violent means. CONCLUSIONS: These findings suggest that patients who die by suicide by violent means are in part biologically separable from other patients with the same diagnoses, and their behavioral outcome may be less dependent on genetic risk for conventional psychiatric disorders and be associated with an alteration of purinergic signaling and mitochondrial metabolism.
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Suicídio Consumado , Encéfalo , Estudo de Associação Genômica Ampla , Humanos , Transcriptoma/genética , Violência/psicologiaRESUMO
OBJECTIVE: Pre-synaptic D2 receptors regulate striatal dopamine release and DAT activity, key factors for modulation of motor pathways. A functional SNP of DRD2 (rs1076560 G>T) is associated with alternative splicing such that the relative expression of D2S (mainly pre-synaptic) vs. D2L (mainly post-synaptic) receptor isoforms is decreased in subjects with the T allele with a putative increase of striatal dopamine levels. To evaluate how DRD2 genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans, we have investigated the association of rs1076560 with BOLD fMRI activity during a motor task. To further evaluate the relationship of this circuitry with dopamine signaling, we also explored the correlation between genotype based differences in motor brain activity and pre-synaptic striatal DAT binding measured with [(123)I] FP-CIT SPECT. METHODS: Fifty healthy subjects, genotyped for DRD2 rs1076560 were studied with BOLD-fMRI at 3T while performing a visually paced motor task with their right hand; eleven of these subjects also underwent [(123)I]FP-CIT SPECT. SPM5 random-effects models were used for statistical analyses. RESULTS: Subjects carrying the T allele had greater BOLD responses in left basal ganglia, thalamus, supplementary motor area, and primary motor cortex, whose activity was also negatively correlated with reaction time at the task. Moreover, left striatal DAT binding and activity of left supplementary motor area were negatively correlated. INTERPRETATION: The present results suggest that DRD2 genetic variation was associated with focusing of responses in the whole motor network, in which activity of predictable nodes was correlated with reaction time and with striatal pre-synaptic dopamine signaling. Our results in humans may help shed light on genetic risk for neurobiological mechanisms involved in the pathophysiology of disorders with dysregulation of striatal dopamine like Parkinson's disease.
Assuntos
Mapeamento Encefálico , Dopamina/metabolismo , Atividade Motora/genética , Córtex Motor/fisiologia , Receptores de Dopamina D2/genética , Transdução de Sinais/genética , Corpo Estriado/fisiologia , Feminino , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Polimorfismo de Nucleotídeo Único , Tempo de Reação , Tomografia Computadorizada de Emissão de Fóton Único , Adulto JovemRESUMO
Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D(2) receptors (encoded by DRD(2)) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D(2) proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD(2) polymorphism (rs1076560) causing reduced presynaptic D(2) receptor expression and the DAT 3'-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging (MRI) during memory tasks and structural MRI. Results indicated a significant DRD(2)/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD(2) allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a nonlinear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D(2) knock-out animals (D2R(-/-)) indicate that DAT and D(2) proteins interact in vivo. Together, our results demonstrate that the interaction between genetic variants in DRD(2) and DAT critically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.
Assuntos
Corpo Estriado/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D2/genética , Adulto , Análise de Variância , Animais , Mapeamento Encefálico , Corpo Estriado/irrigação sanguínea , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Lateralidade Funcional , Genótipo , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imunoprecipitação/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Knockout , Repetições Minissatélites/genética , Vias Neurais/irrigação sanguínea , Vias Neurais/fisiologia , Testes Neuropsicológicos , Oxigênio/sangue , Polimorfismo de Nucleotídeo Único/genética , Córtex Pré-Frontal/irrigação sanguínea , Receptores de Dopamina D2/deficiência , Receptores de Dopamina D2/metabolismo , Reconhecimento Psicológico/fisiologia , Análise de Regressão , Adulto JovemRESUMO
Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D(2) receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D(2) receptor gene (DRD2) (rs1076560, guanine > thymine or G > T) shifts splicing of the two protein isoforms (D(2) short, mainly presynaptic, and D(2) long) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced "emotion control" compared with GT subjects. Functional magnetic resonance imaging in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D(2) signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.
Assuntos
Encéfalo/metabolismo , Dopamina/metabolismo , Emoções/fisiologia , Vias Neurais/metabolismo , Polimorfismo Genético/genética , Receptores de Dopamina D2/genética , Adulto , Sintomas Afetivos/genética , Sintomas Afetivos/metabolismo , Sintomas Afetivos/fisiopatologia , Tonsila do Cerebelo/anatomia & histologia , Tonsila do Cerebelo/metabolismo , Encéfalo/anatomia & histologia , Análise Mutacional de DNA , Inteligência Emocional/genética , Feminino , Marcadores Genéticos/genética , Testes Genéticos , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/anatomia & histologia , Testes Neuropsicológicos , Personalidade , Córtex Pré-Frontal/anatomia & histologia , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , Inquéritos e Questionários , Adulto JovemRESUMO
The brain-derived neurotrophic factor (BDNF) is a secretory growth factor that promotes neuronal proliferation and survival, synaptic plasticity and long-term potentiation in the central nervous system. Brain-derived neurotrophic factor biosynthesis and secretion are chrono-topically regulated processes at the cellular level, accounting for specific localizations and functions. Given its role in regulating brain development and activity, BDNF represents a potentially relevant gene for schizophrenia, and indeed BDNF and its non-synonymous functional variant, rs6265 (C â T, Val â Met) have been widely studied in psychiatric genetics. Human and animal studies have indicated that brain-derived neurotrophic factor is relevant for schizophrenia-related phenotypes, and that: (1) fine-tuned regulation of brain-derived neurotrophic factor secretion and activity is necessary to guarantee brain optimal development and functioning; (2) the Val â Met substitution is associated with impaired activity-dependent secretion of brain-derived neurotrophic factor; (3) disruption of brain-derived neurotrophic factor signaling is associated with altered synaptic plasticity and neurodevelopment. However, genome-wide association studies failed to associate the BDNF locus with schizophrenia, even though a sub-threshold association exists. Here, we will review studies focused on the relationship between the genetic variation of BDNF and schizophrenia, trying to fill the gap between genetic risk per se and insights from molecular biology. A deeper understanding of brain-derived neurotrophic factor biology and of the epigenetic regulation of brain-derived neurotrophic factor and its interactome during development may help clarifying the potential role of this gene in schizophrenia, thus informing development of brain-derived neurotrophic factor-based strategies of prevention and treatment of this disorder.