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1.
Medicine (Baltimore) ; 98(11): e14838, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30882674

RESUMO

The aim of the present case-control study was to explore the association between BDNF Val66Met (rs6265) polymorphism and generalized anxiety disorder in Mexican individuals, and whether this polymorphism plays a role in the symptomatology of anxiety.A total of 212 subjects were included in the study. Around 75 patients with generalized anxiety disorder were diagnosed by psychiatrists based on the DSM-IV instrument and 137 unrelated subjects psychiatrically healthy were used as comparison group. The subclinical symptomatology in patients was assessed with the State-Trait Anxiety Inventory. BDNF rs6265 genotypes were analyzed using the polymerase chain reaction end-point method.The association between BDNF Val66Met with the risk for generalized anxiety disorder was evaluated using 4 inheritance models. The present study showed that carrying the Met allele confers increased risk for the presence of generalized anxiety disorder (χ = 4.7, P = .03; OR (95%) 1.96 (1.05-3.56)) when patients with generalized anxiety disorder were compared with the comparison group.Our results provide evidence of an association between the Val66Met polymorphism of the BDNF gene and generalized anxiety disorder in a Mexican population. However, no association was observed between this polymorphism and the symptomatology of anxiety.


Assuntos
Transtornos de Ansiedade , Fator Neurotrófico Derivado do Encéfalo/genética , Adulto , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/psicologia , Sintomas Comportamentais/diagnóstico , Correlação de Dados , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Predisposição Genética para Doença , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica
2.
Cell Tissue Res ; 377(1): 21-43, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30778732

RESUMO

The increasing number of individuals with comorbidities poses an urgent need to improve the management of patients with multiple co-existing diseases. Among these comorbidities, chronic pain and mood disorders, two long-lasting disabling conditions that significantly reduce the quality of life, could be cited first. The recent development of animal models accelerated the studies focusing on the underlying mechanisms of the chronic pain and depression/anxiety comorbidity. This review provides an overview of clinical and pre-clinical studies performed over the past two decades addressing the molecular aspects of the comorbid relationship of chronic pain and depression. We thus focused on the studies that investigated the molecular characteristics of the comorbid relationship between chronic pain and mood disorders, especially major depressive disorders, from the genetic and epigenetic point of view to key neuromodulators which have been shown to play an important role in this comorbidity.


Assuntos
Dor Crônica/epidemiologia , Dor Crônica/genética , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Animais , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Monoaminas Biogênicas/farmacologia , Monoaminas Biogênicas/uso terapêutico , Dor Crônica/tratamento farmacológico , Comorbidade , Transtorno Depressivo Maior/tratamento farmacológico , Modelos Animais de Doenças , Epigênese Genética , Humanos , Camundongos , Qualidade de Vida , Ratos , Fatores de Transcrição/metabolismo
3.
J Affect Disord ; 245: 885-896, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30699873

RESUMO

BACKGROUND: There have been considerable recent advances in understanding the genetic architecture of anxiety disorders and posttraumatic stress disorder (PTSD), as well as the underlying neurocircuitry of these disorders. However, there is little work on the concordance of genetic variations that increase risk for these conditions, and that influence subcortical brain structures. We undertook a genome-wide investigation of the overlap between the genetic influences from single nucleotide polymorphisms (SNPs) on volumes of subcortical brain structures and genetic risk for anxiety disorders and PTSD. METHOD: We obtained summary statistics of genome-wide association studies (GWAS) of anxiety disorders (Ncases = 7016, Ncontrols = 14,745), PTSD (European sample; Ncases = 2424, Ncontrols = 7113) and of subcortical brain structures (N = 13,171). SNP Effect Concordance Analysis (SECA) and Linkage Disequilibrium (LD) Score Regression were used to examine genetic pleiotropy, concordance, and genome-wide correlations respectively. SECAs conditional false discovery was used to identify specific risk variants associated with anxiety disorders or PTSD when conditioning on brain related traits. RESULTS: For anxiety disorders, we found evidence of significant concordance between increased anxiety risk variants and variants associated with smaller amygdala volume. Further, by conditioning on brain volume GWAS, we identified novel variants that associate with smaller brain volumes and increase risk for disorders: rs56242606 was found to increase risk for anxiety disorders, while two variants (rs6470292 and rs683250) increase risk for PTSD, when conditioning on the GWAS of putamen volume. LIMITATIONS: Despite using the largest available GWAS summary statistics, the analyses were limited by sample size. CONCLUSIONS: These preliminary data indicate that there is genome wide concordance between genetic risk factors for anxiety disorders and those for smaller amygdala volume, which is consistent with research that supports the involvement of the amygdala in anxiety disorders. It is notable that a genetic variant that contributes to both reduced putamen volume and PTSD plays a key role in the glutamatergic system. Further work with GWAS summary statistics from larger samples, and a more extensive look at the genetics underlying brain circuits, is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/psicologia , Variação Genética/genética , Vias Neurais/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/psicologia , Tonsila do Cerebelo/diagnóstico por imagem , Transtornos de Ansiedade/fisiopatologia , Encéfalo/diagnóstico por imagem , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/fisiopatologia
4.
Twin Res Hum Genet ; 22(1): 48-55, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30698127

RESUMO

This study uses novel approaches to examine genetic and environmental influences shared between childhood behavioral inhibition (BI) and symptoms of preadolescent anxiety disorders. Three hundred and fifty-two twin pairs aged 9-13 and their mothers completed questionnaires about BI and anxiety symptoms. Biometrical twin modeling, including a direction-of-causation design, investigated genetic and environmental risk factors shared between BI and social, generalized, panic and separation anxiety. Social anxiety shared the greatest proportion of genetic (20%) and environmental (16%) variance with BI with tentative evidence for causality. Etiological factors underlying BI explained little of the risk associated with the other anxiety domains. Findings further clarify etiologic pathways between BI and anxiety disorder domains in children.


Assuntos
Transtornos de Ansiedade/genética , Interação Gene-Ambiente , Inibição (Psicologia) , Inquéritos e Questionários , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adolescente , Transtornos de Ansiedade/psicologia , Criança , Feminino , Humanos , Masculino , Gêmeos Dizigóticos/psicologia , Gêmeos Monozigóticos/psicologia
5.
Transl Psychiatry ; 9(1): 23, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655507

RESUMO

Prenatal stress defines long-term phenotypes through epigenetic programming of the offspring. These effects are potentially mediated by glucocorticoid release and by sex. We hypothesized that the glucocorticoid receptor (Gr, Nr3c1) fashions the DNA methylation profile of offspring. Consistent with this hypothesis, fetal Nr3c1 heterozygosity leads to altered DNA methylation landscape in fetal placenta in a sex-specific manner. There was a significant overlap of differentially methylated genes in fetal placenta and adult frontal cortex in Nr3c1 heterozygotes. Phenotypically, Nr3c1 heterozygotes show significantly more anxiety-like behavior than wildtype. DNA methylation status of fetal placental tissue is significantly correlated with anxiety-like behavior of the same animals in adulthood. Thus, placental DNA methylation might predict behavioral phenotypes in adulthood. Our data supports the hypothesis that Nr3c1 influences DNA methylation at birth and that DNA methylation in placenta correlates with adult frontal cortex DNA methylation and anxiety-like phenotypes.


Assuntos
Transtornos de Ansiedade/genética , Comportamento Animal , Metilação de DNA , Placenta , Receptores de Glucocorticoides/deficiência , Fatores Sexuais , Animais , Ilhas de CpG , Modelos Animais de Doenças , Epigênese Genética , Feminino , Feto , Masculino , Camundongos , Camundongos Knockout , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
6.
Transl Psychiatry ; 9(1): 18, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655508

RESUMO

Anxiety disorders are among the leading health issues in human medicine. The complex phenotypic and allelic nature of these traits as well as the challenge of establishing reliable measures of the heritable component of behaviour from the associated environmental factors hampers progress in their molecular aetiology. Dogs exhibit large natural variation in fearful and anxious behaviour and could facilitate progress in the molecular aetiology due to their unique genetic architecture. We have performed a genome-wide association study with a canine high-density SNP array in a cohort of 330 German Shepherds for two phenotypes, fear of loud noises (noise sensitivity) and fear of strangers or in novel situations. Genome-widely significant loci were discovered for the traits on chromosomes 20 and 7, respectively. The regions overlap human neuropsychiatric loci, including 18p11.2, with physiologically relevant candidate genes that contribute to glutamatergic and dopaminergic neurotransmission in the brain. In addition, the noise-sensitivity locus includes hearing-related candidate genes. These results indicate a genetic contribution for canine fear and suggest a shared molecular aetiology of anxiety across species. Further characterisation of the identified loci will pave the way to molecular understanding of the conditions as a prerequisite for improved therapy.


Assuntos
Transtornos de Ansiedade/genética , Comportamento Animal , Mapeamento Cromossômico , Medo , Estudos de Associação Genética , Alelos , Animais , Cruzamento , Cães , Estudo de Associação Genômica Ampla , Genômica , Humanos , Polimorfismo de Nucleotídeo Único
8.
Artigo em Inglês | MEDLINE | ID: mdl-30201454

RESUMO

BACKGROUND: Depression, anxiety and somatoform disorders are all more prevalent in women than in men. However, specific biological mechanisms contributing to such sex differences remain unknown. Serotonergic pathways are involved in mood and behavior regulation and thus have been suggested to be altered in several psychiatric disorders. The serotonin transporter (SERT), encoded by SLC6A4 gene, has received major attention due to its crucial role in serotonergic transmission. METHODS: 148 monozygotic twin subjects were assessed for (i) lifetime categorical diagnosis of anxious-depressive disorders, following SCID-I-based DSM-IV criteria, and (ii) current psychiatric symptomatology, from a dimensional approach, by means of the Brief Symptom Inventory (BSI). SLC6A4 gene methylation was analyzed by means of Infinium HumanMethylation450 in a subset of the sample. CpG-specific methylation at the promoter region of SLC6A4 gene was further analyzed by means of pyrosequencing technology in the total sample. RESULTS: SLC6A4 methylation was found to be significantly higher in women when compared to men independent of DSM-IV diagnosis. SLC6A4 methylation was further associated with the BSI-derived somatization dimension. CONCLUSIONS: Female hypermethylation of a discrete region located within SLC6A4 promoter region could underlie differential SERT expression in women when compared to men and could be one of the causative mechanisms by which women exhibit increased prevalence of somatic symptoms.


Assuntos
Metilação de DNA , Epigênese Genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Caracteres Sexuais , Transtornos Somatoformes/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/metabolismo , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Ilhas de CpG , Transtorno Depressivo/genética , Transtorno Depressivo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Escalas de Graduação Psiquiátrica , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transtornos Somatoformes/genética , Gêmeos Monozigóticos , Adulto Jovem
9.
J Affect Disord ; 243: 552-558, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30078664

RESUMO

BACKGROUND: Converging lines of evidence suggest that Brain-Derived Neurotrophic Factor (BDNF) may play a central role in the pathogenesis of Bipolar Disorder (BD), thus representing a valid biomarker of the disease. A common genetic variation in the BDNF gene, the Val66Met, is associated with reduced maturation and secretion of BDNF and therefore it has been related to specific mood, cognitive and neuroanatomical alterations in BD. However, so far, only a handful of studies have investigated the association between Val66Met polymorphism and cognitive functioning in BD. METHODS: We performed a bibliographic search on PUBMED of all genetic studies investigating Val66Met modulation on cognitive performances in BD subjects. The inclusion criteria were met by nine studies, including a total amount of 897 BD subjects and 803 healthy controls. RESULTS: From the analysis of the existing literature emerged that a) Val allele in BD adults, but not in BD adolescents, was associated with better performances in selective cognitive domains including executive functions, verbal learning and memory; b) Met allele may negatively modulate the association between childhood trauma and performances in memory, verbal ability and verbal fluency tasks; c) Met allele may also negatively regulate structural abnormalities in cognitive cerebral structures; d) Val/Met carriers showed greater improvements in cognitive functions compared to Val/Val and Met/Met carriers. LIMITATIONS: Few genetic studies exploring the impact of Val66Met on cognition in BD. CONCLUSIONS: Val66Met polymorphism likely modulates cognitive functions in BD patients with complex gene-environment interactions and through potential modulations of cerebral structures. Further and larger genetic studies are required in order to detect association between BDNF polymorphism, BDNF levels, brain abnormalities and cognition in BD.


Assuntos
Transtorno Bipolar/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos do Humor/genética , Polimorfismo Genético , Adolescente , Adulto , Alelos , Transtornos de Ansiedade/genética , Transtorno Bipolar/metabolismo , Criança , Função Executiva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/metabolismo , Polimorfismo de Nucleotídeo Único
10.
Nat Commun ; 9(1): 5400, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30573727

RESUMO

Abnormalities in synaptic inhibition play a critical role in psychiatric disorders, and accordingly, it is essential to understand the molecular mechanisms linking components of the inhibitory postsynapse to psychiatrically relevant neural circuits and behaviors. Here we study the role of IgSF9b, an adhesion protein that has been associated with affective disorders, in the amygdala anxiety circuitry. We show that deletion of IgSF9b normalizes anxiety-related behaviors and neural processing in mice lacking the synapse organizer Neuroligin-2 (Nlgn2), which was proposed to complex with IgSF9b. This normalization occurs through differential effects of Nlgn2 and IgSF9b at inhibitory synapses in the basal and centromedial amygdala (CeM), respectively. Moreover, deletion of IgSF9b in the CeM of adult Nlgn2 knockout mice has a prominent anxiolytic effect. Our data place IgSF9b as a key regulator of inhibition in the amygdala and indicate that IgSF9b-expressing synapses in the CeM may represent a target for anxiolytic therapies.


Assuntos
Tonsila do Cerebelo/metabolismo , Transtornos de Ansiedade/genética , Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Sinapses/metabolismo , Tonsila do Cerebelo/fisiologia , Animais , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/fisiologia , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Interferência de RNA , Transmissão Sináptica/genética
11.
Psychiatry Res ; 270: 780-785, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30551325

RESUMO

The aim of the study is to explore the impact of Generalized Anxiety Disorder (GAD) comorbidity in children with Attention Deficit Hyperactivity Disorder (ADHD). Six hundred children with ADHD (mean age = 9.12 years), recruited from 2013 to 2017, participated in the study. A total of 96 (16%) children with ADHD displayed a comorbidity with GAD. ADHD + GAD were compared to 504 ADHD children without GAD in terms of cognitive and psychiatric profile, ADHD subtype and family psychiatric history. The ADHD + GAD, predominantly represented from ADHD combined (72.6%), displayed higher psychiatry comorbidity, in particular with depressive disorders, and were associated with higher rates of maternal depression, of ADHD in fathers, and bipolar disorders in second degree relatives. Moreover, younger preschool-primary school age children with ADHD + GAD showed significant higher frequency of depressive disorders versus younger preschool-primary children with ADHD without GAD. ADHD + GAD comorbidity represents a more complex clinical condition compared to ADHD without GAD, characterized by the higher frequency of multiple comorbidities and by a psychiatric family with higher rates of mood and disruptive disorders.


Assuntos
Transtornos de Ansiedade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Adolescente , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Criança , Pré-Escolar , Comorbidade , Estudos Transversais , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/genética , Transtorno Depressivo/psicologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Prevalência
12.
BMC Neurosci ; 19(1): 79, 2018 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-30537945

RESUMO

BACKGROUND: Development of anxiety- and depression-like states under chronic social defeat stress in mice has been shown by many experimental studies. In this article, the differentially expressed Slc25* family genes encoding mitochondrial carrier proteins were analyzed in the brain of depressive (defeated) mice versus aggressive mice winning in everyday social confrontations. The collected samples of brain regions were sequenced at JSC Genoanalytica ( http://genoanalytica.ru/ , Moscow, Russia). RESULTS: Changes in the expression of the 20 Slc25* genes in the male mice were brain region- and social experience (positive or negative)-specific. In particular, most Slc25* genes were up-regulated in the hypothalamus of defeated and aggressive mice and in the hippocampus of defeated mice. In the striatum of defeated mice and in the ventral tegmental area of aggressive mice expression of mitochondrial transporter genes changed specifically. Significant correlations between expression of most Slc25* genes and mitochondrial Mrps and Mrpl genes were found in the brain regions. CONCLUSION: Altered expression of the Slc25* genes may serve as a marker of mitochondrial dysfunction in brain, which accompanies the development of many neurological and psychoemotional disorders.


Assuntos
Transtornos de Ansiedade/metabolismo , Encéfalo/metabolismo , Transtorno Depressivo/metabolismo , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Agressão/fisiologia , Processamento Alternativo , Animais , Transtornos de Ansiedade/genética , Transtorno Depressivo/genética , Modelos Animais de Doenças , Dominação-Subordinação , Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Análise de Sequência de RNA , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Transcriptoma
13.
J Youth Adolesc ; 47(9): 1799-1812, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29704085

RESUMO

The single nucleotide polymorphism rs53576 of the oxytocin receptor (OXTR) gene is involved in forming and maintaining relationships in various social contexts. However, this has not been studied in the childhood peer context. The present study followed 359 children (51.6% girls) from age 9 to 12 to explore associations between OXTR rs53576 genotype (i.e., AA, AG or GG genotype) and three indicators of children's relationships with peers: likability and dis-likability among, and friendship with, classroom peers. Our results showed that OXTR rs53576 was associated with likability among boys, but not with dis-likability and friendship or among girls. Boys with an A and a G allele (i.e., AG genotype) became increasingly more liked by their peers across the four-year studied period than those with two A alleles or two G alleles (i.e., AA and GG genotype). This study indicates that OXTR rs53576 genotype might influence children's peer relationships, particularly their likeability among peers. Associations between OXTR rs53576 and peer relationships may differ depending on children's sex and the specific type of peer-relationship under scrutiny.


Assuntos
Transtornos de Ansiedade/genética , Amigos , Polimorfismo de Nucleotídeo Único , Receptores de Ocitocina/genética , Alelos , Criança , Feminino , Genótipo , Humanos , Relações Interpessoais , Estudos Longitudinais , Masculino , Grupo Associado
14.
J Affect Disord ; 234: 105-108, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29525350

RESUMO

BACKGROUND: Genetic studies have been consistent that bipolar disorder type I (BPI) runs in families and that this familial aggregation is strongly influenced by genes. In a preliminary study, we proved that anxiety trait meets endophenotype criteria for BPI. METHODS: We assessed 619 individuals from the Central Valley of Costa Rica (CVCR) who have received evaluation for anxiety following the same methodological procedure used for the initial pilot study. Our goal was to conduct a multipoint quantitative trait linkage analysis to identify quantitative trait loci (QTLs) related to anxiety trait in subjects with BPI. We conducted the statistical analyses using Quantitative Trait Loci method (Variance-components models), implemented in Sequential Oligogenic Linkage Analysis Routines (SOLAR), using 5606 single nucleotide polymorphism (SNPs). RESULTS: We identified a suggestive linkage signal with a LOD score of 2.01 at chromosome 2 (2q13-q14). LIMITATIONS: Since confounding factors such as substance abuse, medical illness and medication history were not assessed in our study, these conclusions should be taken as preliminary. CONCLUSIONS: We conclude that region 2q13-q14 may harbor a candidate gene(s) with an important role in the pathophysiology of BPI and anxiety.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/psicologia , Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Locos de Características Quantitativas/genética , Adolescente , Adulto , Idoso , Costa Rica , Endofenótipos , Feminino , Ligação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
15.
Behav Brain Res ; 341: 91-97, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29288745

RESUMO

There have been important advances in our understanding of the genetic architecture of anxiety disorders. At the same time, relatively few genes have reached genome wide significance in anxiety disorders, and there is relatively little work on how exposure to an adverse environment impacts on gene expression in either animal models or human clinical populations. Here we assessed differential expression of genes of the dorsal striatum involved in synaptic transmission in an animal models of early adversity (maternal separation followed by restraint stress), and investigated whether variants in these genes were associated with risk for anxiety disorders, particularly in the presence of environmental stressors. Fifty-two male Sprague Dawley rats underwent maternal separation, and gene expression was studied using array technology. The human homologues of the differentially expressed genes were screened and analysed in a DSM-IV anxiety disorders cohort, and healthy controls (patients, n = 92; controls, n = 194), using blood. Two candidate genes (Mmp9 and Bdnf) were aberrantly expressed in the experimental rodent group relative to controls. Four single nucleotide polymorphisms (SNPs) in the human homologues of these genes were significantly associated with susceptibility for anxiety disorders (MMP9: rs3918242 and BDNF: rs6265, rs10835210 and rs11030107). Three of these (BDNF: rs6265, rs10835210, rs11030107) were found to interact significantly with childhood trauma severity resulting in increased likelihood of an anxiety disorder diagnosis. This study provides insights into the utility of rat models for identifying molecular candidates for anxiety disorders in humans.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Adultos Sobreviventes de Eventos Adversos na Infância/psicologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estudos de Coortes , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Expressão Gênica , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Masculino , Privação Materna , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Polimorfismo de Nucleotídeo Único , Ratos Sprague-Dawley , Estresse Psicológico/genética , Estresse Psicológico/metabolismo
16.
Eur Child Adolesc Psychiatry ; 27(5): 615-624, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29110074

RESUMO

This family study investigated (1) the prevalence of anxiety disorders (ADs) in parents and siblings of children (n = 144) aged 8-18 years with ADs compared to control children (n = 49), and (2) the specificity of relationships between child-mother, child-father, and child-sibling ADs. Clinical interviews were used to assess current DSM-IV-TR ADs in children and siblings, and lifetime and current ADs in parents. Results showed that children with ADs were two to three times more likely to have at least one parent with current and lifetime ADs than the control children (odds ratio (OR) = 2.04 and 3.14). Children with ADs were more likely to have mothers with current ADs (OR = 2.51), fathers with lifetime ADs (OR = 2.84), but not siblings with ADs (OR = 0.75). Specific relationships between mother-child ADs were found for Social Anxiety Disorder (SAD, OR = 3.69) and Generalized Anxiety Disorder (OR = 3.47). Interestingly, all fathers and siblings with SAD came from families of children with SAD. Fathers of children with SAD were more likely to have lifetime ADs themselves (OR = 2.86). Findings indicate that children with ADs more often have parents with ADs, and specifically SAD is more prevalent in families of children with SAD. Influence of parent's (social) ADs should be considered when treating children with ADs.


Assuntos
Transtornos de Ansiedade/genética , Pai/psicologia , Mães/psicologia , Irmãos/psicologia , Adolescente , Transtornos de Ansiedade/epidemiologia , Criança , Feminino , Humanos , Masculino , Prevalência
17.
Z Kinder Jugendpsychiatr Psychother ; 46(2): 155-167, 2018 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-28256157

RESUMO

Besides typical physical and hormonal changes during pregnancy, this life period is often associated with an increased emotional and mental stress for women. For the child, the time in utero is regarded as a critical developmental period since adverse stimuli during pregnancy can have lasting consequences for the fetal and postnatal health and development. Thus, prenatal depression, anxiety and stress are considered as risk factors for developmental delay, emotional and behavioral problems. Epigenetic modifications, especially modifications in DNA methylation, are discussed as a possible biological mechanism that could explain the association between prenatal emotional stress and altered developmental and health outcomes of the child. This review summarizes evidence for DNA methylation changes related to prenatal emotional stress from studies with a candidate-gene approach as well as epigenome-wide association studies. Problematic issues are discussed and recommendations for future research are presented.


Assuntos
Transtornos de Ansiedade/complicações , Transtornos de Ansiedade/genética , Período Crítico (Psicologia) , Transtorno Depressivo/complicações , Transtorno Depressivo/genética , Epigênese Genética/genética , Complicações na Gravidez/genética , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico/complicações , Estresse Psicológico/genética , Sintomas Afetivos/genética , Sintomas Afetivos/psicologia , Transtornos de Ansiedade/psicologia , Transtornos do Comportamento Infantil/genética , Transtornos do Comportamento Infantil/psicologia , Metilação de DNA/genética , Transtorno Depressivo/psicologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/psicologia , Feminino , Humanos , Recém-Nascido , Gravidez , Fatores de Risco , Estresse Psicológico/psicologia
18.
J Psychiatr Res ; 96: 100-107, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28992526

RESUMO

The objective of this study was to evaluate the effect of pharmacogenetics-guided treatment on patients diagnosed with depression and/or anxiety, in a diverse set of clinical settings, as compared to the standard of care. The trial design followed a prospective, randomized, subject- and rater-blinded approach enrolling 685 patients from clinical providers specializing in Psychiatry, Internal Medicine, Obstetrics & Gynecology, and Family Medicine. The NeuroIDgenetix® test uses a genetic variant panel of ten genes, along with concomitant medications, to make medication management recommendations based on gene-drug and drug-drug interactions for over 40 medications used in the treatment of depression and anxiety. Pharmacogenetic testing was performed at the initial screening visit and baseline patient assessments were determined using the 17-item Hamilton Rating Scale for Depression (HAM-D17) and the Hamilton Rating Scale for Anxiety (HAM-A). Following enrollment and randomization, pharmacogenetic results for subjects assigned to the experimental group were provided to physicians to guide treatment selection, while control subjects were treated according to the usual standard of care. HAM-D17 and HAM-A assessments were collected at 4 weeks, 8 weeks, and 12 weeks after baseline to assess the efficacy of therapeutic selection. In patients diagnosed with depression, response rates (p = 0.001; OR: 4.72 [1.93-11.52]) and remission rates (p = 0.02; OR: 3.54 [1.27-9.88]) were significantly higher in the pharmacogenetics-guided group as compared to the control group at 12 weeks. In addition, patients in the experimental group diagnosed with anxiety showed a meaningful improvement in HAM-A scores at both 8 and 12 weeks (p = 0.02 and 0.02, respectively), along with higher response rates (p = 0.04; OR: 1.76 [1.03-2.99]). From these results, we conclude that pharmacogenetic-guided medication selection significantly improves outcomes of patients diagnosed with depression or anxiety, in a variety of healthcare settings.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Medicina de Precisão , Ansiolíticos/efeitos adversos , Ansiolíticos/uso terapêutico , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Tomada de Decisão Clínica , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Escalas de Graduação Psiquiátrica , Fatores de Tempo , Resultado do Tratamento
19.
Curr Top Behav Neurosci ; 35: 467-498, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28812274

RESUMO

In the present chapter, we review the literature focusing on oxytocin (OT)-centered research in anxiety spectrum conditions, comprising separation anxiety disorder, specific phobias, social anxiety disorder (SAD), panic disorder, generalized anxiety disorder, and anxiety-related endophenotypes (e.g., trust behavior, behavioral inhibition, neuroticism, and state/trait anxiety). OT receptor gene (OXTR) polymorphisms have been implicated in gene-environment interactions with attachment style and childhood maltreatment and to influence clinical outcomes, including SAD intensity and limbic responsiveness. Epigenetic OXTR DNA methylation patterns have emerged as a link between categorical, dimensional, neuroendocrinological, and neuroimaging SAD correlates, highlighting them as potential peripheral surrogates of the central oxytocinergic tone. A pathophysiological framework of OT integrating the dynamic nature of epigenetic biomarkers and the summarized genetic and peripheral evidence is proposed. Finally, we emphasize opportunities and challenges of OT as a key network node of social interaction and fear learning in social contexts. In conjunction with multi-level investigations incorporating a dimensional understanding of social affiliation and avoidance in anxiety spectrum disorders, these concepts will help to promote research for diagnostic, state, and treatment response biomarkers of the OT system, advancing towards indicated preventive interventions and personalized treatment approaches.


Assuntos
Transtornos de Ansiedade/etiologia , Interação Gene-Ambiente , Relações Interpessoais , Ocitocina/genética , Receptores de Ocitocina/genética , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/psicologia , Metilação de DNA , Medo/psicologia , Humanos , Meio Social
20.
Genes Brain Behav ; 17(3): e12423, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28873274

RESUMO

The pathogenesis of anxiety disorders is multifactorial, involving complex interactions between biological factors, environmental influences and psychological mechanisms. Recent advances have highlighted the role of epigenetics in bridging the gap between multiple contributing risk factors toward an increased understanding of the pathomechanisms underlying anxiety. In this review, we present an overview of the current state of knowledge regarding putative risk mechanisms in the pathogenesis of anxiety disorders, placing a particular focus on the role of protective factors serving to buffer a risk factor constellation and the role of epigenetic processes functioning as a potent turnstile changing passage direction toward disorder risk or resilience. We discuss promising future directions in epigenetic research regarding the prediction, prevention and personalized treatment of anxiety disorders.


Assuntos
Transtornos de Ansiedade/genética , Ansiedade/genética , Interação Gene-Ambiente , Animais , Ansiedade/fisiopatologia , Ansiedade/psicologia , Transtornos de Ansiedade/fisiopatologia , Transtornos de Ansiedade/psicologia , Metilação de DNA , Epigênese Genética , Histonas/genética , Humanos , Resiliência Psicológica , Fatores de Risco
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