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1.
BMC Med Genet ; 21(1): 184, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32957930

RESUMO

BACKGROUND: Two important aspects for the development of anxiety disorders are genetic predisposition and alterations in the hypothalamic-pituitary-adrenal (HPA) axis. In order to identify genetic risk-factors for anxiety, the aim of this exploratory study was to investigate possible relationships between genetic polymorphisms in genes important for the regulation and activity of the HPA axis and self-assessed anxiety in healthy individuals. METHODS: DNA from 72 healthy participants, 37 women and 35 men, were included in the analyses. Their DNA was extracted and analysed for the following Single Nucleotide Polymorphisms (SNP)s: rs41423247 in the NR3C1 gene, rs1360780 in the FKBP5 gene, rs53576 in the OXTR gene, 5-HTTLPR in SLC6A4 gene and rs6295 in the HTR1A gene. Self-assessed anxiety was measured by the State and Trait Anxiety Inventory (STAI) questionnaire. RESULTS: Self-assessed measure of both STAI-S and STAI-T were significantly higher in female than in male participants (p = 0.030 and p = 0.036, respectively). For SNP rs41423247 in the NR3C1 gene, there was a significant difference in females in the score for STAI-S, where carriers of the G allele had higher scores compared to the females that were homozygous for the C allele (p < 0.01). For the SNP rs53576 in the OXTR gene, there was a significant difference in males, where carriers of the A allele had higher scores in STAI-T compared to the males that were homozygous for the G allele (p < 0.01). CONCLUSION: This study shows that SNP rs41423247 in the NR3C1 gene and SNP rs53576 in the OXTR gene are associated with self-assessed anxiety in healthy individuals in a gender-specific manner. This suggests that these SNP candidates are possible genetic risk-factors for anxiety.


Assuntos
Transtornos de Ansiedade/genética , Predisposição Genética para Doença/genética , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de Glucocorticoides/genética , Receptores de Ocitocina/genética , Adulto , Alelos , Ansiedade/psicologia , Transtornos de Ansiedade/psicologia , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
2.
Depress Anxiety ; 37(6): 540-548, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32369878

RESUMO

BACKGROUND: Internalizing disorders (IDs), consisting of syndromes of anxiety and depression, are common, debilitating conditions often beginning early in life. Various trait-like psychological constructs are associated with IDs. Our prior analysis identified a tripartite model of Fear/Anxiety, Dysphoria, and Positive Affect among symptoms of anxiety and depression and the following constructs in youth: anxiety sensitivity, fearfulness, behavioral activation and inhibition, irritability, neuroticism, and extraversion. The current study sought to elucidate their overarching latent genetic and environmental risk structure. METHODS: The sample consisted of 768 juvenile twin subjects ages 9-14 assessed for the nine, abovementioned measures. We compared two multivariate twin models of this broad array of phenotypes. RESULTS: A hypothesis-driven, common pathway twin model reflecting the tripartite structure of the measures were fit to these data. However, an alternative independent pathway model provided both a better fit and more nuanced insights into their underlying genetic and environmental risk factors. CONCLUSIONS: Our findings suggest a complex latent genetic and environmental structure to ID phenotypes in youth. This structure, which incorporates both clinical symptoms and various psychological traits, informs future phenotypic approaches for identifying specific genetic and pathophysiological mechanisms underlying ID risk.


Assuntos
Transtornos de Ansiedade , Psicopatologia , Adolescente , Ansiedade , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Criança , Medo , Humanos , Neuroticismo
3.
Cell Mol Life Sci ; 77(21): 4347-4364, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32409861

RESUMO

Neuropsychiatric disorders, including autism spectrum disorders (ASD) and anxiety disorders are characterized by a complex range of symptoms, including social behaviour and cognitive deficits, depression and repetitive behaviours. Although the mechanisms driving pathophysiology are complex and remain largely unknown, advances in the understanding of gene association and gene networks are providing significant clues to their aetiology. In recent years, small noncoding RNA molecules known as microRNA (miRNA) have emerged as a new gene regulatory layer in the pathophysiology of mental illness. These small RNAs can bind to the 3'-UTR of mRNA thereby negatively regulating gene expression at the post-transcriptional level. Their ability to regulate hundreds of target mRNAs simultaneously predestines them to control the activity of entire cellular pathways, with obvious implications for the regulation of complex processes such as animal behaviour. There is growing evidence to suggest that numerous miRNAs are dysregulated in pathophysiology of neuropsychiatric disorders, and there is strong genetic support for the association of miRNA genes and their targets with several of these conditions. This review attempts to cover the most relevant microRNAs for which an important contribution to the control of social and anxiety-related behaviour has been demonstrated by functional studies in animal models. In addition, it provides an overview of recent expression profiling and genetic association studies in human patient-derived samples in an attempt to highlight the most promising candidates for biomarker discovery and therapeutic intervention.


Assuntos
Transtornos de Ansiedade/genética , Ansiedade/genética , Transtorno do Espectro Autista/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Animais , Redes Reguladoras de Genes , Humanos , RNA Mensageiro/genética
5.
Am J Psychiatry ; 177(3): 214-222, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32114783

RESUMO

Anxiety and fear-related disorders are common and disabling, and they significantly increase risk for suicide and other causes of morbidity and mortality. However, there is tremendous potential for translational neuroscience to advance our understanding of these disorders, leading to novel and powerful interventions and even to preventing their initial development. This overview examines the general circuits and processes thought to underlie fear and anxiety, along with the promise of translational research. It then examines some of the data-driven "next-generation" approaches that are needed for discovery and understanding but that do not always fit neatly into established models. From one perspective, these disorders offer among the most tractable problems in psychiatry, with a great deal of accumulated understanding, across species, of neurocircuit, behavioral, and, increasingly, genetic mechanisms, of how dysregulation of fear and threat processes contributes to anxiety-related disorders. One example is the progressively sophisticated understanding of how extinction underlies the exposure therapy component of cognitive-behavioral therapy approaches, which are ubiquitously used across anxiety and fear-related disorders. However, it is also critical to examine gaps in our understanding between reasonably well-replicated examples of successful translation, areas of significant deficits in knowledge, and the role of large-scale data-driven approaches in future progress and discovery. Although a tremendous amount of progress is still needed, translational approaches to understanding, treating, and even preventing anxiety and fear-related disorders offer great opportunities for successfully bridging neuroscience discovery to clinical practice.


Assuntos
Transtornos de Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Medo/fisiologia , Transtornos de Ansiedade/genética , Extinção Psicológica/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Vias Neurais/fisiopatologia
6.
J Abnorm Psychol ; 129(3): 237-247, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32077707

RESUMO

The valine66methionine (Val66Met) polymorphism (rs6265) of the brain-derived neurotrophic factor (BDNF) gene has been shown to influence autonomic arousal pathways, which in turn predict elevated syndromal anxiety in healthy humans. We examined whether the BDNF variant is associated with an increased risk of generalized anxiety disorder (GAD), one of the most prevalent anxiety disorders, through altering parasympathetic stress/relaxation reactivity. A total of 2,250 Han Chinese adults (750 GAD patients and 1,500 healthy controls) were included in the genotyping. High-frequency heart rate variability, an index of vagal (parasympathetic) activity, was measured during the supine-standing-supine test (5 min in each position); vagal withdrawal and vagal activation were calculated as baseline supine minus standing and recovery supine minus standing, respectively. Analysis of healthy participants indicated that Val/Val homozygotes displayed significantly blunted vagal withdrawal and vagal activation compared with Met allele carriers. After analyzing the entire sample, these effects remained significant. Furthermore, both attenuated vagal response patterns were found to be significantly associated with a higher incidence of GAD. Lastly, the path analysis identified a significant indirect effect of BDNF on the risk of GAD via diminishing vagal response to either orthostatic stress or supine relaxation. Even when further testing the subsample comprising only comorbidity- and medication-free GAD patients and healthy controls to minimize the confounding bias, the results still remained. Our findings demonstrate that individuals carrying the BDNF Val/Val genotype, compared to Met-carriers, may be at higher risk of GAD due to blunted vagal reactivity in response to both stress and relaxation. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Assuntos
Transtornos de Ansiedade/genética , Ansiedade/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Genótipo , Sistema Nervoso Parassimpático/fisiopatologia , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Ansiedade/fisiopatologia , Transtornos de Ansiedade/fisiopatologia , Nível de Alerta/fisiologia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Nervo Vago/fisiopatologia
7.
Adv Exp Med Biol ; 1191: 543-559, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002945

RESUMO

Anxiety is prevalent in childhood and adolescence. Youth with maladaptive responses to common situations and stressors are at risk of having anxiety disorders. Persistent anxiety symptoms and anxiety disorders can be debilitating with long-term adverse outcomes in adulthood. Hence, decreasing the burden of anxiety disorders is an important public health priority. Development of anxiety disorders has a multifactorial etiology. There is a considerable complex interaction of genetics, temperament, parenting behavior, environmental triggers, and physiologic factors. Identification of these risk factors is key to early detection, prevention, and development of applicable management approaches. Despite several evidence-based treatments published, there are limited prevention strategies available. Effective implementation of prevention strategies is essential and can be achieved by either elimination or reduction of the negative risk factors or strengthening the protective factors on anxiety symptoms and anxiety disorders. This chapter reviews the common risk and protective factors and provides current literature on prevention strategies for pediatric and adolescent anxiety disorders.


Assuntos
Transtornos de Ansiedade/prevenção & controle , Transtornos de Ansiedade/psicologia , Adolescente , Transtornos de Ansiedade/genética , Criança , Humanos , Poder Familiar , Prevalência , Fatores de Proteção , Fatores de Risco , Temperamento
8.
Adv Exp Med Biol ; 1191: 93-102, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002924

RESUMO

Several environmental risk factors such as early adverse childhood experiences, stress, and stressful life events are associated with anxiety disorders. Current approaches such as epigenetics and gene-environment interactions were used to identify candidate biomarkers for anxiety disorders to assess determinants of disease. In this chapter, in relation to gene-environment interactions, a variety of association studies regarding anxiety disorders were surveyed. We then showed supporting results from recent association studies such as human studies and animal models in terms of the epigenetic contribution to disease susceptibility to anxiety disorders. At last, future directions and limitations are highlighted. With the advances in multi-omics technologies, innovative ideas regarding disease prevention and drug responsiveness in anxiety disorders require further research in epigenetics and gene-environment interactions.


Assuntos
Transtornos de Ansiedade/genética , Epigênese Genética , Interação Gene-Ambiente , Animais , Epigenômica , Estudos de Associação Genética , Humanos
9.
Am J Psychiatry ; 177(3): 223-232, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906708

RESUMO

OBJECTIVE: Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder. METHODS: Using one of the world's largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis. RESULTS: The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (rg=0.75), depression (rg=0.81), and neuroticism (rg=0.75). CONCLUSIONS: This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.


Assuntos
Transtornos de Ansiedade/genética , Ansiedade/genética , Loci Gênicos , Predisposição Genética para Doença , Fenótipo , Polimorfismo de Nucleotídeo Único , Idoso , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Veteranos
10.
Biol Res Nurs ; 22(2): 277-286, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31908177

RESUMO

This study aimed to (1) identify subgroups of women with breast cancer with the psychological symptom cluster (fatigue, depressive symptoms, and anxiety) during the first 18 months of adjuvant therapy and (2) explore associations between demographic and clinical characteristics and variations in genetic polymorphisms related to hypothalamic-pituitary-adrenal (HPA) axis function and predicted symptom trajectory subgroup membership. We obtained symptom data at 4 time points from baseline to 18 months of adjuvant therapy among 292 postmenopausal women with breast cancer. Genetic data were collected in a subgroup at baseline (N = 184). Group-based multitrajectory modeling was used to classify women into subgroups with similar psychological symptom cluster trajectories. Binary logistic regression was used to explore the associations between each genotypic and phenotypic predictor and predicted subgroup membership. Two distinct symptom subgroups (low and high) were identified based on the trajectories of the symptom cluster of fatigue, depressive symptoms, and anxiety over the first 18 months of adjuvant therapy. Women who were younger, less educated, and who received chemotherapy had greater likelihood of being in the high-symptom subgroup. Variation in genes regulating the HPA axis (FKBP5 rs9394309 [odds ratio (OR) = 3.98, p = .015], NR3C2 rs5525 [OR = 2.54, p = .036], and CRHR1 rs12944712 [OR = 3.99, p = .021]) was associated with membership in the high-symptom subgroup. These results may help to identify women with breast cancer who are at increased risk for psychological symptoms, facilitating the development of individualized and preemptive interventions to better manage these symptoms during adjuvant therapy.


Assuntos
Transtornos de Ansiedade/induzido quimicamente , Transtornos de Ansiedade/genética , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/efeitos adversos , Transtorno Depressivo/induzido quimicamente , Transtorno Depressivo/genética , Fadiga/induzido quimicamente , Fadiga/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Modelos Logísticos , Pessoa de Meia-Idade
11.
Depress Anxiety ; 37(6): 512-520, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31951317

RESUMO

BACKGROUND: Anxiety and depressive disorders can be classified under a bidimensional model, where depression and generalized anxiety disorder are represented by distress and the other anxiety disorders, by fear. The phenotypic structure of this model has been validated, but twin studies only show partial evidence for genetic and environmental distinctions between distress and fear. Moreover, the effects of genetic variants are mostly shared between anxiety and depression, but the genome-wide genetic distinction between distress and fear remains unexplored. This study aimed to examine the degree of common genetic variation overlap between distress and fear, and their associations with the psychosocial risk factors of loneliness and social isolation. METHODS: We used genome-wide data from 157,366 individuals in the UK Biobank who answered a mental health questionnaire. RESULTS: Genetic correlations indicated that depression and generalized anxiety had a substantial genetic overlap, and that they were genetically partially distinct from fear disorders. Associations with loneliness, but not social isolation, showed that loneliness was more strongly associated with both distress disorders than with fear. CONCLUSIONS: Our findings shed light on genetic and environmental mechanisms that are common and unique to distress and fear and contribute to current knowledge on individuals' susceptibility to anxiety and depression.


Assuntos
Bancos de Espécimes Biológicos , Depressão , Ansiedade/genética , Transtornos de Ansiedade/genética , Depressão/genética , Humanos , Reino Unido
12.
Pharmacogenomics ; 21(2): 111-123, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31957548

RESUMO

Introduction: Phenazepam therapy can often be ineffective and some patients develop dose-related adverse drug reactions. Aim. The purpose of this research was to study the effect of the CYP2C19*2 (681G>A, rs4244285) in patients with anxiety disorders and alcohol dependence taking phenazepam therapy. Materials & methods: Patients (175 males, average age: 37.16 ± 7.84 years) received phenazepam in tablet form for 5 days. Genotyping was performed by real-time polymerase chain reaction. Results: The statistically significant differences in the UKU Side-Effect Rating Scale scores on the fifth day of therapy: (CYP2C19*1/*1) 2.00 [1.00; 2.00), (CYP2C19*1/*2) 7.00 (7.00; 7.00), (CYP2C19*2/*2) 9.00 (8.00; 9.00), p < 0.001. Conclusion: This study demonstrated the different efficacy and safety of phenazepam in patients with different genotypes of CYP2C19*2.


Assuntos
Alcoolismo/genética , Transtornos de Ansiedade/tratamento farmacológico , Benzodiazepinas/administração & dosagem , Citocromo P-450 CYP2C19/genética , Adulto , Alcoolismo/patologia , Ansiolíticos/administração & dosagem , Ansiolíticos/efeitos adversos , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/patologia , Benzodiazepinas/efeitos adversos , Feminino , Genótipo , Humanos , Masculino
13.
J Affect Disord ; 260: 597-603, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541970

RESUMO

BACKGROUND: The TIA1 gene encodes a prion-related RNA-binding protein that regulates stress-dependent synaptic plasticity and fear memory in mice. It is unknown whether genetic variation in human TIA1 is associated with differences in stress- and fear-related behavior in people. METHODS: A longitudinal, population-based survey was conducted in Sweden to collect information on demographics, socioeconomic status, exposure to stressful life events and psychiatric symptoms. DNA samples were obtained from study participants to allow genotyping of single-nucleotide polymorphisms in the human TIA1 locus. RESULTS: We identified a single-nucleotide polymorphism in the human TIA1 gene that interacts with exposure to previous-year stressful life events to predict the development of pathological anxiety symptoms in a non-clinical cohort. LIMITATIONS: Sample population is limited in both size and scope, and we did not perform functional analysis of allelic variants of TIA1. CONCLUSIONS: TIA1 may represent a susceptibility locus for stress-dependent psychopathology. These studies support an evolutionarily conserved role of TIA1 in the mammalian brain, and may provide molecular and genetic insight into the development of stress-related psychiatric conditions such as PTSD and anxiety.


Assuntos
Transtornos de Ansiedade/genética , Polimorfismo de Nucleotídeo Único , Estresse Psicológico/genética , Antígeno-1 Intracelular de Células T/genética , Adulto , Alelos , Transtornos de Ansiedade/psicologia , Estudos de Coortes , Feminino , Interação Gene-Ambiente , Técnicas de Genotipagem , Humanos , Acontecimentos que Mudam a Vida , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estresse Psicológico/psicologia , Suécia , Adulto Jovem
14.
Psychoneuroendocrinology ; 111: 104480, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31707294

RESUMO

The highly conserved transcription factor LIM-only 3 (Lmo3) is involved in important neurodevelopmental processes in several brain areas including the amygdala, a central hub for the generation and regulation of emotions. Accordingly, a role for Lmo3 in the behavioral responses to ethanol and in the display of anxiety-like behavior in mice has been demonstrated while the potential involvement of Lmo3 in the control of mood-related behavior has not yet been explored. Using a mouse model of Lmo3 depletion (Lmo3z), we here report that genetic Lmo3 deficiency is associated with altered performance in behavioral paradigms assessing anxiety-like and depression-like traits and additionally accompanied by impairments in learned fear. Importantly, long-term potentiation (LTP) in the basolateral amygdala (BLA), a proposed cellular correlate of fear learning, is impaired in Lmo3z mice. RNA-Seq analysis of BLA tissue and gene set enrichment analysis (GSEA) of differentially expressed genes in Lmo3z mice reveals a significant overlap between genes overexpressed in Lmo3z mice and those enriched in the amygdala of a cohort of patients suffering from major depressive disorder. Consequently, we propose that Lmo3 may play a role in the regulation of gene networks that are relevant to the regulation of emotions. Future work may aid to further explore the role of Lmo3 in the pathophysiology of affective disorders and its genetic foundations.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Tonsila do Cerebelo/metabolismo , Proteínas com Domínio LIM/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Afeto , Tonsila do Cerebelo/fisiologia , Animais , Ansiedade/genética , Transtornos de Ansiedade/genética , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Depressão/genética , Transtorno Depressivo Maior/genética , Medo/fisiologia , Feminino , Proteínas com Domínio LIM/metabolismo , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Knockout , Fatores de Transcrição/genética
15.
Sci Rep ; 9(1): 19437, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31857655

RESUMO

Pharmacological research in mice and human genetic analyses suggest that the kallikrein-kinin system (KKS) may regulate anxiety. We examined the role of the KKS in anxiety and stress in both species. In human genetic association analysis, variants in genes for the bradykinin precursor (KNG1) and the bradykinin receptors (BDKRB1 and BDKRB2) were associated with anxiety disorders (p < 0.05). In mice, however, neither acute nor chronic stress affected B1 receptor gene or protein expression, and B1 receptor antagonists had no effect on anxiety tests measuring approach-avoidance conflict. We thus focused on the B2 receptor and found that mice injected with the B2 antagonist WIN 64338 had lowered levels of a physiological anxiety measure, the stress-induced hyperthermia (SIH), vs controls. In the brown adipose tissue, a major thermoregulator, WIN 64338 increased expression of the mitochondrial regulator Pgc1a and the bradykinin precursor gene Kng2 was upregulated after cold stress. Our data suggests that the bradykinin system modulates a variety of stress responses through B2 receptor-mediated effects, but systemic antagonists of the B2 receptor were not anxiolytic in mice. Genetic variants in the bradykinin receptor genes may predispose to anxiety disorders in humans by affecting their function.


Assuntos
Transtornos de Ansiedade/metabolismo , Bradicinina/metabolismo , Sistema Calicreína-Cinina/fisiologia , Estresse Psicológico/metabolismo , Adulto , Animais , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/patologia , Antagonistas de Receptor B1 da Bradicinina/administração & dosagem , Antagonistas de Receptor B2 da Bradicinina/administração & dosagem , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Sistema Calicreína-Cinina/efeitos dos fármacos , Cininogênios/genética , Cininogênios/metabolismo , Masculino , Camundongos , Naftalenos/administração & dosagem , Compostos Organofosforados/administração & dosagem , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Polimorfismo de Nucleotídeo Único , Receptor B1 da Bradicinina/genética , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/genética , Receptor B2 da Bradicinina/metabolismo , Especificidade da Espécie , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia , Regulação para Cima
16.
Psychiatry Res ; 282: 112640, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31727442

RESUMO

Information of the modulation effect of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) on post-traumatic stress disorder (PTSD) after earthquakes is scarce and contradictory. A cross-sectional face-to-face interview survey of a representative sample of the adults was carried out after the Lorca (Spain) earthquakes (May 11, 2011). Socio-demographic variables, DSM-IV diagnostic assessment and earthquake-related stressors were obtained from the Composite International Diagnostic Interview (CIDI). The triallelic and biallelic classification of the 5-HTTLPR polymorphism were genotyped from buccal swabs. Multivariate logistic regression models were used to predict PTSD, including interaction terms to explore gene-environment (G x E) interactions. The vast majority (83%, n = 341) of the Lorca survey respondents (n = 412, 71% response rate) were genotyped. Both classifications of the 5-HTTLPR genotype were in Hardy-Weinberg equilibrium. Prior lifetime PTSD was the only variable that remained a significant predictor after adjustments. There were no significant main effects of earthquake related stressors or 5-HTTLPR. However, G x E interactions of 5-HTTLPR with high emotional impact and prior lifetime anxiety disorders were statistically significant. These results provide new evidence of the modulation effect of the 5-HTTLPR polymorphisms on PTSD risk. This information might characterize people at higher risk of developing PTSD after an earthquake exposure.


Assuntos
Transtornos de Ansiedade/genética , Interação Gene-Ambiente , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Estudos Transversais , Terremotos , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Desastres Naturais , Fatores de Risco , Espanha , Adulto Jovem
17.
Depress Anxiety ; 36(12): 1163-1172, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31622521

RESUMO

BACKGROUND: Depression and anxiety may unfavorably impact on cardiac autonomic dysregulation. However, it is unclear whether this relationship results from a causal effect or may be attributable to confounding factors. We tested the relationship between depression and anxiety with heart rate (HR) and heart rate variability (HRV) across a 9-year follow-up (FU) period and investigated possible confounding by antidepressant use and genetic pleiotropy. METHODS: Data (no. of observations = 6,994, 65% female) were obtained from the longitudinal Netherlands Study of Depression and Anxiety, with repeated waves of data collection of HR, HRV, depression, anxiety, and antidepressant use. Summary statistics from meta-analyses of genome-wide association studies were used to derive polygenic risk scores of depression, HR, and HRV. RESULTS: Across the 9-year FU, generalized estimating equations analyses showed that the relationship between cardiac autonomic dysregulation and depression/anxiety rendered nonsignificant after adjusting for antidepressant use. A robust association was found between antidepressant use (especially tricyclic antidepressants, selective serotonin, and noradrenalin reuptake inhibitors) and unfavorable cardiac autonomic activity across all waves. However, no evidence was found for a genetic correlation of depression with HR and HRV, indicating that confounding by genetic pleiotropy is minimal. CONCLUSIONS: Our results indicate that the association between depression/anxiety and cardiac autonomic dysregulation does not result from a causal pathway or genetic pleiotropy, and these traits might therefore not be inevitably linked. Previously reported associations were likely confounded by the use of certain classes of antidepressants.


Assuntos
Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiopatologia , Fatores de Confusão Epidemiológicos , Depressão/tratamento farmacológico , Coração/inervação , Adolescente , Adulto , Idoso , Antidepressivos Tricíclicos/farmacologia , Antidepressivos Tricíclicos/uso terapêutico , Ansiedade/genética , Ansiedade/fisiopatologia , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/fisiopatologia , Depressão/genética , Depressão/fisiopatologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Transtorno Depressivo/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Países Baixos , Adulto Jovem
18.
Curr Top Behav Neurosci ; 42: 185-219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31485988

RESUMO

MicroRNAs as critical regulators of gene expression important for functions including neuronal development, synapse formation, and synaptic plasticity have been linked with the regulation of neurobiological systems that underlie anxiety processing in the brain. In this chapter, we give an update on associative evidence linking regulation of microRNAs with anxiety- and trauma-related disorders. Moving beyond correlative research, functional studies have emerged recently that explore causal relationships between microRNA expression and anxiety-like behavior. It has been demonstrated that experimental up- or downregulation of the candidate microRNAs in important nodes of the anxiety neurocircuitry can indeed modulate anxiety-related behavior in animal models. Improved methodologies for assessing microRNA-mediated modulation have aided such functional studies, revealing a number of anxiety-regulating microRNAs including miR-15a, miR-17-92, miR-34, miR-101, miR-124, miR-135, and miR-155. Important functional target genes of these identified microRNAs are associated with specific neurotransmitter/neuromodulator signaling, neurotrophin (e.g., BDNF) expression and other aspects of synaptic plasticity, as well as with stress-regulatory/hypothalamic-pituitary-axis function. Furthermore, microRNAs have been revealed that are regulated in distinct brain regions following various anxiety-attenuating strategies. These include pharmacological treatments such as antidepressants and other drugs, as well as non-pharmacological interventions such as fear extinction/exposure therapy or positive stimuli such as exposure to environmental enrichment. These are first indications for a role for microRNAs in the mechanism of action of anxiolytic treatments. As research continues, there is much hope that a deeper understanding of the microRNA-mediated mechanisms underlying anxiety-related disorders could open up possibilities for future novel biomarker and treatment strategies.


Assuntos
Transtornos de Ansiedade , Ansiedade , MicroRNAs , Animais , Ansiedade/genética , Transtornos de Ansiedade/genética , Medo , Plasticidade Neuronal
19.
Psychiatr Genet ; 29(5): 191-199, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31464999

RESUMO

In the past decades, the improving knowledge of genes implicated in the pathogenesis of psychiatric disorders together with the advancements in genetic engineering has led to the creation of mice in which one or more genes are inactivated or 'knocked out'. Knockout mice are extensively used to better investigate the molecular and cellular mechanisms underlying these diseases as well as the biological role of specific genes. Moreover, they are also useful tools for developing new therapeutic strategies. The success of using knockout mice is possible due to availability of several models used to mimic some clinical manifestations reported in psychiatric patients. In the present review, we will give an update of the most used gene knockout models in the field of psychiatric disorders including depression, anxiety, and obsessive-compulsive disorder.


Assuntos
Transtornos de Ansiedade/genética , Transtorno Depressivo/genética , Camundongos Knockout , Transtorno Obsessivo-Compulsivo/genética , Animais , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Humanos , Camundongos
20.
Int J Geriatr Psychiatry ; 34(11): 1706-1714, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31368178

RESUMO

BACKGROUND: Although the precise etiology of poststroke anxiety (PSA) has yet to be fully elucidated, it is known that brain-derived neurotrophic factor (BDNF) is important for neural plasticity and long-term potentiation, associated with the pathophysiology of anxiety. The expression of BDNF is regulated by epigenetic and genetic profiles. Thus, we investigated the association between BDNF methylation status and PSA at 2 weeks and 1 year after stroke while accounting for interactions with the BDNF Val66Met polymorphism. METHODS: The baseline sample comprised 286 patients who were assessed at 2 weeks after stroke; of these patients, 222 (78%) were followed up with at 1 year after stroke. The presence of PSA was determined using the anxiety subscale of the Hospital Anxiety and Depression Scale (HADS), and the effects of BDNF methylation status and polymorphisms on PSA status were assessed with multivariate logistic regression models. RESULTS: The prevalence of PSA was slightly lower (27 [9.4%]) at baseline, and 35 (15.8%) patients were identified as having PSA at the 1-year follow-up. Stroke patients with a higher average methylation status were more likely to have PSA at 1 year. The BDNF Val66Met polymorphism was not independently associated with PSA during either the acute or chronic phase after stroke, but there was a significant interactive effect between BDNF methylation and genotype on PSA at 2 weeks. CONCLUSIONS: In this study, BDNF methylation in combination with the met/met BDNF polymorphism (Val66Met polymorphism) was associated with PSA. These findings may help identify patients at higher risk for PSA.


Assuntos
Transtornos de Ansiedade , Fator Neurotrófico Derivado do Encéfalo , Acidente Vascular Cerebral/psicologia , Adulto , Idoso , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Metilação de DNA , Feminino , Marcadores Genéticos , Genótipo , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo Genético , Prevalência
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