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1.
Psychiatry Res ; 270: 775-779, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30551324

RESUMO

Several studies have established that Major depressive disorder is associated with excess inflammation with an elevation of both pro and anti-inflammatory cytokines in major depressive disorder. In addition, individuals with major depressive disorder are at higher risk of developing coronary artery disease. The role of innate immunity and NFκB-mediated inflammation in depression and its increased association with coronary artery disease is yet to be fully elucidated. Polymorphisms in the Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat and Pyrin Domain Containing 12 (NLRP12), are associated with depression and coronary artery disease in trauma exposed individuals. In a cohort of Vietnam War veterans (n = 299) NLRP12 polymorphisms were analysed for association with depression and coronary calcium scores. The NLRP12 polymorphism, rs34436714 was associated with a higher DASS21 Score for depression (p = 0.037). NLRP12 polymorphisms rs34971363 and rs6509825 (p = 0.022 and p = 0.020) were associated with raised coronary calcium score. To our knowledge, this is the first time rs34436714 has been investigated in Vietnam veterans identifying AC as a risk genotype for depression in Caucasian cohorts. It is also the first time the rs34971363 (CG) and rs6509825 (CT) genotype have been associated with raised coronary calcium score.


Assuntos
Distúrbios de Guerra/genética , Doença da Artéria Coronariana/genética , Transtorno Depressivo Maior/genética , Genótipo , Inflamassomos/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Veteranos , Estudos de Coortes , Distúrbios de Guerra/imunologia , Doença da Artéria Coronariana/imunologia , Transtorno Depressivo Maior/imunologia , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Inflamassomos/imunologia , Masculino , NF-kappa B/genética , Polimorfismo Genético , Fatores de Risco
2.
Acta Psychiatr Scand ; 136(5): 493-505, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28795405

RESUMO

OBJECTIVE: Epigenetic modifications such as DNA methylation may play a key role in the aetiology and serve as biomarkers for post-traumatic stress disorder (PTSD). We performed a genomewide analysis to identify genes whose DNA methylation levels are associated with PTSD. METHOD: A total of 211 individuals comprising Australian male Vietnam War veterans (n = 96) and males from a general population belonging to the Grady Trauma Project (n = 115) were included. Genomewide DNA methylation was performed from peripheral blood using the Illumina arrays. Data analysis was performed using generalized linear regression models. RESULTS: Differential DNA methylation of 17 previously reported PTSD candidate genes was associated with PTSD symptom severity. Genomewide analyses revealed CpG sites spanning BRSK1, LCN8, NFG and DOCK2 genes were associated with PTSD symptom severity. We replicated the findings of DOCK2 in an independent cohort. Pathway analysis revealed that among the associated genes, genes within actin cytoskeleton and focal adhesion molecular pathways were enriched. CONCLUSION: These data highlight the role of DNA methylation as biomarkers of PTSD. The results support the role of previous candidates and uncover novel genes associated with PTSD, such as DOCK2. This study contributes to our understanding of the biological underpinnings of PTSD.


Assuntos
Distúrbios de Guerra/genética , Metilação de DNA/genética , Transtornos de Estresse Pós-Traumáticos/genética , Veteranos , Idoso , Austrália , Biomarcadores/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Masculino , Guerra do Vietnã
3.
Sci Rep ; 7(1): 4375, 2017 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-28663541

RESUMO

Telomere length has been suggested to be a cellular marker for age-related diseases as well as psychosocial stress. The present study investigated whether telomere length is associated with post-traumatic stress disorder (PTSD) among veterans exposed to combat trauma in the Vietnam War. The potentially associated factors on cellular aging were considered. Korean male veterans with (n = 122) and without (n = 120) PTSD were included and leukocyte telomere length was measured with a quantitative PCR-based technique. As a whole, no significant difference in telomere length was found between PTSD and non-PTSD groups. In linear regression analysis stratified by trauma levels, among veterans exposed to severe combat (n = 45), PTSD status (B = -1.176, t = -2.259, p = 0.029), antidepressant use (B = 0.168, t = 2.528, p = 0.015), and education level (B = 0.019, t = 2.369, p = 0.023) affected telomere length. However, among veterans with light-to-moderate combat exposure (n = 197), only age (B = -0.007, t = -2.434, p = 0.016) and education level (B = 0.010, t = 2.295, p = 0.023) were associated with telomere length. In the Post-hoc analysis, antidepressant use was associated with longer telomere length in subjects exposed to severe combat. Our exploratory results suggest that PTSD status in combination with severe trauma may be associated with accelerated telomere shortening, and that antidepressant use may have a protective effect on telomere dynamics.


Assuntos
Distúrbios de Guerra/genética , Transtornos de Estresse Pós-Traumáticos/genética , Homeostase do Telômero/genética , Telômero/genética , Idoso , Distúrbios de Guerra/epidemiologia , Humanos , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Fatores Socioeconômicos , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Estresse Fisiológico , Estresse Psicológico , Veteranos
4.
Compr Psychiatry ; 74: 125-133, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28160694

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with increased inflammation and comorbid medical conditions. However, study findings for individual inflammatory marker levels have been inconsistent. Some research suggests that resilience may play a role in decreased inflammation. A polymorphism in the promoter region of the tumor necrosis factor α gene (TNFα), TNFA -308 (rs1800629) is associated with psychiatric illness but its role in PTSD is yet to be elucidated. OBJECTIVE: This study investigates a key inflammatory marker, TNFα, for its role in PTSD severity. METHOD: In a cohort of trauma-exposed Vietnam War veterans (n=299; 159 cases, 140 controls) TNF α serum levels and TNFα polymorphism rs1800629 were correlated with PTSD severity and resilience scores. RESULTS: The polymorphism was associated with PTSD severity (p=0.045). There were significant group differences between cases and controls with regards to serum TNFα levels (p=0.036). Significant correlations were found between PTSD severity and elevated TNFα levels (r=0.153; p=0.009), and between resilience and decreased TNFα levels at a trend level (p=0.08) across the entire cohort. These relationships were non-significant after controlling for covariates. In the PTSD diagnostic group, a correlation of TNFα and PTSD severity was observed on a trend level (p=0.06), the relationship between TNFα and resilience remained non-significant. CONCLUSIONS: To our knowledge, this is the first time rs1800629 has been investigated in PTSD contributing to a growing body of literature that identifies the GG as a risk genotype for psychiatric disorders in Caucasian cohorts. However, more research is needed to replicate our results in larger, equally well-characterized cohorts. The relationship between serum TNFα levels and PTSD severity and resilience requires further investigation.


Assuntos
Transtornos de Estresse Pós-Traumáticos/sangue , Transtornos de Estresse Pós-Traumáticos/genética , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Veteranos , Guerra do Vietnã , Idoso , Austrália/epidemiologia , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Distúrbios de Guerra/sangue , Distúrbios de Guerra/epidemiologia , Distúrbios de Guerra/genética , Marcadores Genéticos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Índice de Gravidade de Doença , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Veteranos/psicologia
5.
Psychiatry Res ; 251: 261-265, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28222310

RESUMO

Posttraumatic stress disorder (PTSD) affects many returning combat veterans, but underlying biological mechanisms remain unclear. In order to compare circulating micro RNA (miRNA) of combat veterans with and without PTSD, peripheral blood from 24 subjects was collected following deployment, and isolated miRNA was sequenced. PTSD was associated with 8 differentially expressed miRNA. Pathway analysis shows that PTSD is related to the axon guidance and Wnt signaling pathways, which work together to support neuronal development through regulation of growth cones. PTSD is associated with miRNAs that regulate biological functions including neuronal activities, suggesting that they play a role in PTSD symptomatology.


Assuntos
MicroRNA Circulante/genética , Distúrbios de Guerra/genética , Distúrbios de Guerra/psicologia , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/psicologia , Veteranos/psicologia , Adulto , Orientação de Axônios/genética , Estudos de Coortes , Feminino , Marcadores Genéticos/genética , Cones de Crescimento/fisiologia , Humanos , Masculino , Fatores de Risco , Análise de Sequência de RNA , Via de Sinalização Wnt/genética
6.
Acta Psychiatr Scand ; 135(2): 170-179, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27886370

RESUMO

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) plays a crucial role in modulating resilience and vulnerability to stress. The aim of this study was to investigate whether epigenetic regulation of the BDNF gene is a biomarker of post-traumatic stress disorder (PTSD) development among veterans exposed to combat in the Vietnam War. METHODS: Using the Clinician-Administered PTSD Scale, combat veterans were grouped into those with (n = 126) and without (n = 122) PTSD. DNA methylation levels at four CpG sites within the BDNF promoter I region were quantified in the peripheral blood using pyrosequencing. The effects of BDNF DNA methylation levels and clinical variables on the diagnosis of PTSD were tested using binary logistic regression analysis. RESULTS: Subjects with PTSD showed a higher DNA methylation of four CpG sites at the BDNF promoter compared with those without PTSD. High methylation levels at the BDNF promoter CpG site, high combat exposure, and alcohol problems were significantly associated with PTSD diagnosis. CONCLUSIONS: This study demonstrated an association between higher DNA methylation of the BDNF promoter and PTSD diagnosis in combat-exposed individuals. Our findings suggest that altered BDNF methylation may be a valuable biomarker of PTSD after trauma exposure.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Distúrbios de Guerra/diagnóstico , Metilação de DNA , Regiões Promotoras Genéticas , Idoso , Distúrbios de Guerra/genética , Ilhas de CpG , Epigênese Genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica
7.
Transl Psychiatry ; 6(11): e954, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27845777

RESUMO

Post-traumatic stress disorder (PTSD) is a mental disorder occurring in about 2-9% of individuals after their exposure to life-threatening events, such as severe accidents, sexual abuse, combat or a natural catastrophe. Because PTSD patients are exposed to trauma, it is likely that epigenetic modifications have an important role in disease development and prognosis. For the past two decades, abnormal expression of the epigenetic regulators microRNAs (miRs) and miR-mediated gene regulation have been given importance in a variety of human diseases, such as cancer, heart disease and viral infection. Emerging evidence supports a role for miR dysregulation in psychiatric and neurological disorders, including schizophrenia, bipolar disorder, anxiety, major depressive disorder, autism spectrum disorder and Tourette's syndrome. Recently mounting of evidence supports the role of miR both in preclinical and clinical settings of psychiatric disorders. Abnormalities in miR expression can fine-tune the expression of multiple genes within a biological network, suggesting that miR dysregulation may underlie many of the molecular changes observed in PTSD pathogenesis. This provides strong evidence that miR not only has a critical role in PTSD pathogenesis, but can also open up new avenues for the development of diagnostic tools and therapeutic targets for the PTSD phenotype. In this review, we revisit some of the recent evidence associated with miR and PTSD in preclinical and clinical settings. We also discuss the possible clinical applications and future use of miRs in PTSD therapy.


Assuntos
Epigênese Genética/genética , MicroRNAs/genética , Transtornos de Estresse Pós-Traumáticos/genética , Animais , Distúrbios de Guerra/diagnóstico , Distúrbios de Guerra/genética , Distúrbios de Guerra/terapia , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Ratos , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/terapia , Veteranos/psicologia
8.
Psychiatry Res ; 244: 376-81, 2016 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-27525827

RESUMO

Since both posttraumatic stress disorder (PTSD) and depression are associated with disturbances in the serotoninergic system, the aim of the study was to determine the association between severity of PTSD symptoms, serotonin transporter polymorphism (5-HTTLPR) and platelet serotonin (5-HT) concentration, in male combat veterans with PTSD (n = 325), who were subdivided according to presence of comorbid depression. The methodological approach included the psychiatric diagnostic interviews and rating scales (SCID for DSM-IV, HDRS, CAPS), polymerase chain reaction for 5-HTTLPR genotyping and spectrophotofluorometric method for measuring the platelet 5-HT concentration. PTSD veterans without depression had more severe PTSD symptoms, and less severe depressive symptoms, than PTSD veterans with depression. 5-HTTLPR genotype frequencies did not differ between veterans with mild, moderate and severe PTSD symptoms, and between depressed and non-depressed PTSD veterans. No significant association was found between the severity of PTSD symptoms and 5-HTTLPR genotype. Platelet 5-HT concentration was similar in PTSD veterans, with or without comorbid depression, and between two groups subdivided according to the severity of PTSD symptoms or 5-HTTLPR genotype. The study confirmed, on ethnically homogenous groups of veterans with matched combat experience, a lack of association between the PTSD symptoms severity and 5-HTTLPR or platelet 5-HT concentration.


Assuntos
Distúrbios de Guerra/genética , Depressão/genética , Polimorfismo Genético/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transtornos de Estresse Pós-Traumáticos/genética , Veteranos , Adulto , Distúrbios de Guerra/epidemiologia , Distúrbios de Guerra/psicologia , Comorbidade , Estudos Transversais , Depressão/epidemiologia , Depressão/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Serotonina/genética , Índice de Gravidade de Doença , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Inquéritos e Questionários , Veteranos/psicologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-26404173

RESUMO

This study evaluated the degree of mixed-handedness in predominantly right-handed Vietnam combat veteran twins and their identical, combat-unexposed cotwins. The "high-risk" cotwins of combat veterans with combat-related posttraumatic stress disorder (PTSD) had more mixed-handedness (i.e., less right-handedness) than the "low-risk" cotwins of combat veterans without PTSD. Self-reported combat exposure in combat-exposed twins was a mediator of the association between handedness in their unexposed cotwins and PTSD in the twins themselves. We conclude that mixed-handedness is a familial risk factor for combat-related PTSD. This risk may be mediated in part by a proclivity for mixed-handed soldiers and Marines to experience heavier combat.


Assuntos
Lateralidade Funcional/genética , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/psicologia , Gêmeos Monozigóticos/genética , Veteranos/psicologia , Guerra do Vietnã , Distúrbios de Guerra/diagnóstico , Distúrbios de Guerra/genética , Distúrbios de Guerra/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/diagnóstico
10.
J Anxiety Disord ; 36: 78-83, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26454231

RESUMO

BACKGROUND: Cholecystokinin (CCK) is a neuropeptide that has been implicated in understanding the acquisition and extinction of fear. Research on CCK in anxiety has primarily focused on understanding panic attacks and panic disorder. Emerging data suggests that CCK may also hold promise in understanding the development and maintenance of posttraumatic stress disorder (PTSD). METHOD: The present study examined whether a single nucleotide polymorphism in the promoter region of the CCK gene (C>T; rs1799923) was associated with an increased prevalence of PTSD as well as with severity of PTSD symptoms among a sample of 457 combat veterans. RESULTS: Results demonstrated that participants with either the heterozygous or homozygous T allele had an increased prevalence of PTSD relative to participants with the CC genotype (OR=2.17; 95% CI [1.37-3.43]). LIMITATIONS: The relatively small sample size precluded examination of racial/ethnic differences. Findings were also limited by the absence of a systematic assessment of comorbid anxiety psychopathology. CONCLUSIONS: These data offer preliminary evidence supporting an association between the rs1799923 polymorphism in the CCK gene and PTSD. Additional research is needed to better understand the nature of this relationship.


Assuntos
Colecistocinina/genética , Distúrbios de Guerra/genética , Polimorfismo Genético/genética , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Alelos , Transtornos de Ansiedade/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/genética , Regiões Promotoras Genéticas , Veteranos/psicologia
11.
Psychoneuroendocrinology ; 51: 506-12, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25129579

RESUMO

Several studies have reported an association between traumatic stress and telomere length suggesting that traumatic stress has an impact on ageing at the cellular level. A newly derived tool provides an additional means to investigate cellular ageing by estimating epigenetic age based on DNA methylation profiles. We therefore hypothesise that in a longitudinal study of traumatic stress both indicators of cellular ageing will show increased ageing. We expect that particularly in individuals that developed symptoms of post-traumatic stress disorder (PTSD) increases in these ageing parameters would stand out. From an existing longitudinal cohort study, ninety-six male soldiers were selected based on trauma exposure and the presence of symptoms of PTSD. All military personnel were deployed in a combat zone in Afghanistan and assessed before and 6 months after deployment. The Self-Rating Inventory for PTSD was used to measure the presence of PTSD symptoms, while exposure to combat trauma during deployment was measured with a 19-item deployment experiences checklist. These groups did not differ for age, gender, alcohol consumption, cigarette smoking, military rank, length, weight, or medication use. In DNA from whole blood telomere length was measured and DNA methylation levels were assessed using the Illumina 450K DNA methylation arrays. Epigenetic ageing was estimated using the DNAm age estimator procedure. The association of trauma with telomere length was in the expected direction but not significant (B=-10.2, p=0.52). However, contrary to our expectations, development of PTSD symptoms was associated with the reverse process, telomere lengthening (B=1.91, p=0.018). In concordance, trauma significantly accelerated epigenetic ageing (B=1.97, p=0.032) and similar to the findings in telomeres, development of PTSD symptoms was inversely associated with epigenetic ageing (B=-0.10, p=0.044). Blood cell count, medication and premorbid early life trauma exposure did not confound the results. Overall, in this longitudinal study of military personnel deployed to Afghanistan we show an acceleration of ageing by trauma. However, development of PTSD symptoms was associated with telomere lengthening and reversed epigenetic ageing. These findings warrant further study of a perhaps dysfunctional compensatory cellular ageing reversal in PTSD.


Assuntos
Senescência Celular/genética , Distúrbios de Guerra/genética , Epigênese Genética , Militares/psicologia , Transtornos de Estresse Pós-Traumáticos/genética , Telômero , Adolescente , Adulto , Campanha Afegã de 2001- , Distúrbios de Guerra/psicologia , Humanos , Masculino , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto Jovem
12.
Psychoneuroendocrinology ; 51: 472-94, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25311155

RESUMO

The etiology of post-traumatic stress disorder (PTSD) likely involves the interaction of numerous genes and environmental factors. Similarly, gene-expression levels in peripheral blood are influenced by both genes and environment, and expression levels of many genes show good correspondence between peripheral blood and brain tissues. In that context, this pilot study sought to test the following hypotheses: (1) post-trauma expression levels of a gene subset in peripheral blood would differ between Marines with and without PTSD; (2) a diagnostic biomarker panel of PTSD among high-risk individuals could be developed based on gene-expression in readily assessable peripheral blood cells; and (3) a diagnostic panel based on expression of individual exons would surpass the accuracy of a model based on expression of full-length gene transcripts. Gene-expression levels in peripheral blood samples from 50 U.S. Marines (25 PTSD cases and 25 non-PTSD comparison subjects) were determined by microarray following their return from deployment to war-zones in Iraq or Afghanistan. The original sample was carved into training and test subsets for construction of support vector machine classifiers. The panel of peripheral blood biomarkers achieved 80% prediction accuracy in the test subset based on the expression of just two full-length transcripts (GSTM1 and GSTM2). A biomarker panel based on 20 exons attained an improved 90% accuracy in the test subset. Though further refinement and replication of these biomarker profiles are required, these preliminary results provide proof-of-principle for the diagnostic utility of blood-based mRNA-expression in PTSD among trauma-exposed individuals.


Assuntos
Distúrbios de Guerra/diagnóstico , Expressão Gênica , Militares , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Adolescente , Adulto , Campanha Afegã de 2001- , Biomarcadores/sangue , Distúrbios de Guerra/sangue , Distúrbios de Guerra/genética , Humanos , Guerra do Iraque 2003-2011 , Acontecimentos que Mudam a Vida , Masculino , Projetos Piloto , Transtornos de Estresse Pós-Traumáticos/sangue , Transtornos de Estresse Pós-Traumáticos/genética , Adulto Jovem
13.
Psychoneuroendocrinology ; 51: 459-71, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25456346

RESUMO

BACKGROUND: Research on the etiology of post-traumatic stress disorder (PTSD) has rapidly matured, moving from candidate gene studies to interrogation of the entire human genome in genome-wide association studies (GWAS). Here we present the results of a GWAS performed on samples from combat-exposed U.S. Marines and Sailors from the Marine Resiliency Study (MRS) scheduled for deployment to Iraq and/or Afghanistan. The MRS is a large, prospective study with longitudinal follow-up designed to identify risk and resiliency factors for combat-induced stress-related symptoms. Previously implicated PTSD risk loci from the literature and polygenic risk scores across psychiatric disorders were also evaluated in the MRS cohort. METHODS: Participants (N=3494) were assessed using the Clinician-Administered PTSD Scale and diagnosed using the DSM-IV diagnostic criterion. Subjects with partial and/or full PTSD diagnosis were called cases, all other subjects were designated controls, and study-wide maximum CAPS scores were used for longitudinal assessments. Genomic DNA was genotyped on the Illumina HumanOmniExpressExome array. Individual genetic ancestry was determined by supervised cluster analysis for subjects of European, African, Hispanic/Native American, and other descent. To test for association of SNPs with PTSD, logistic regressions were performed within each ancestry group and results were combined in meta-analyses. Measures of childhood and adult trauma were included to test for gene-by-environment (GxE) interactions. Polygenic risk scores from the Psychiatric Genomic Consortium were used for major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ). RESULTS: The array produced >800K directly genotyped and >21M imputed markers in 3494 unrelated, trauma-exposed males, of which 940 were diagnosed with partial or full PTSD. The GWAS meta-analysis identified the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) as a genome-wide significant PTSD locus (rs6482463; OR=1.47, SE=0.06, p=2.04×10(-9)), with a similar effect across ancestry groups. Association of PRTFDC1 with PTSD in an independent military cohort showed some evidence for replication. Loci with suggestive evidence of association (n=25 genes, p<5×10(-6)) further implicated genes related to immune response and the ubiquitin system, but these findings remain to be replicated in larger GWASs. A replication analysis of 25 putative PTSD genes from the literature found nominally significant SNPs for the majority of these genes, but associations did not remain significant after correction for multiple comparison. A cross-disorder analysis of polygenic risk scores from GWASs of BPD, MDD, and SCZ found that PTSD diagnosis was associated with risk sores of BPD, but not with MDD or SCZ. CONCLUSIONS: This first multi-ethnic/racial GWAS of PTSD highlights the potential to increase power through meta-analyses across ancestry groups. We found evidence for PRTFDC1 as a potential novel PTSD gene, a finding that awaits further replication. Our findings indicate that the genetic architecture of PTSD may be determined by many SNPs with small effects, and overlap with other neuropsychiatric disorders, consistent with current findings from large GWAS of other psychiatric disorders.


Assuntos
Distúrbios de Guerra/genética , Predisposição Genética para Doença , Hipoxantina Fosforribosiltransferase/genética , Resiliência Psicológica , Transtornos de Estresse Pós-Traumáticos/genética , Adolescente , Adulto , Distúrbios de Guerra/psicologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Militares/psicologia , Polimorfismo de Nucleotídeo Único , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto Jovem
14.
J Anxiety Disord ; 28(8): 902-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25445080

RESUMO

Candidate gene studies have yet to investigate the glutamate system, the primary excitatory neurotransmitter of the HPA-axis related to PTSD risk. We investigated 13 SNPs in the glutamate transporter gene (SLC1A1) in relation to PTSD among combat-exposed veterans. Participants (n=418) completed a diagnostic interview and provided a blood sample for DNA isolation and genotyping. A subset of participants (n=391) had severity and combat exposure data available. In the primary logistic regression gender and rs10739062 were significant predictors of PTSD diagnosis (OR=0.50; OR=1.43). In the linear regression analysis, combat exposure was the only significant predictor (ß=0.16) of severity. A computed genetic risk sum score was significant in relation to PTSD diagnosis (OR=1.15) and severity scores (ß=0.14) above and beyond the effects of combat exposure. This study provides preliminary support for the relationship of glutamate transporter polymorphisms to PTSD risk and the need for further genetic studies within this system.


Assuntos
Distúrbios de Guerra/genética , Transportador 3 de Aminoácido Excitatório/genética , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único/genética , Análise de Regressão , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Veteranos
15.
Am J Med Genet B Neuropsychiatr Genet ; 162B(7): 762-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24132908

RESUMO

Factors determining who develops PTSD following trauma are not well understood. The €4 allele of the apolipoprotein E (apoE) gene is associated with dementia and unfavorable outcome following brain insult. PTSD is also associated with dementia. Given evidence that psychological trauma adversely affects the brain, we hypothesized that the apoE genotype moderates effects of psychological trauma on PTSD pathogenesis. To investigate the moderation of the relationship between PTSD symptoms and combat exposure, we used 172 participants with combat trauma sustained during the Vietnam War. PTSD symptoms were the dependent variable and number of combat experiences, apoE genotype, and the combat experiences × apoE genotype interaction were predictors. We also examined the outcome of a diagnosis of PTSD (n = 39) versus no PTSD diagnosis (n = 131). The combat × apoE genotype interaction was significant for both PTSD symptoms (P = .014) and PTSD diagnosis (P = .009). ApoE genotype moderates the relationship between combat exposure and PTSD symptoms. Although the pathophysiology of PTSD is not well understood, the €4 allele is related to reduced resilience of the brain to insult. Our results are consistent with the €4 allele influencing the effects of psychological trauma on the brain, thereby affecting the risk of PTSD.


Assuntos
Apolipoproteínas E/genética , Distúrbios de Guerra/genética , Interação Gene-Ambiente , Transtornos de Estresse Pós-Traumáticos/genética , Envelhecimento/genética , Genótipo , Inquéritos Epidemiológicos , Humanos , Pessoa de Meia-Idade , Análise de Regressão , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Gêmeos/genética , Vietnã
16.
Depress Anxiety ; 30(12): 1194-201, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23761065

RESUMO

BACKGROUND: The symptomatology of posttraumatic stress disorder (PTSD) is related not only to the intensity of the causative trauma, but also to alcohol use and genetic factors. Among the many candidate genes, the apolipoprotein E gene (APOE) is thought to be associated with stress reactivity. METHODS: Korean veterans of the Vietnam War with (n = 128) or without (n = 128) PTSD participated in this study. The Clinician-Administered PTSD Scale and Combat Exposure Scale were administered, and the severity of alcohol use was assessed among these veterans. The APOE polymorphism and clinical variables of the subjects were compared, and associations between PTSD and potential explanatory variables were tested using logistic regression analysis. RESULTS: Higher frequencies of APOE ε2 alleles and a greater number of individuals with the ε2 allele were found in the PTSD group. Among patients with PTSD, ε2-allele noncarriers consumed alcohol in greater amounts and more frequently than did ε2-allele carriers. Regression analysis revealed a significant interactional effect between harmful drinking and the absence of the ε2 allele associated with PTSD risk. CONCLUSIONS: These results suggest that the APOE ε2 allele operates as a susceptibility gene for combat-related PTSD, with the relationship between alcohol use and PTSD differing according to the ε2-allele status. Future studies should determine the role of the APOE in adaptation to extreme stress, the development of PTSD, and comorbid alcohol-related disorders.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Apolipoproteína E2/genética , Distúrbios de Guerra/genética , Interação Gene-Ambiente , Transtornos de Estresse Pós-Traumáticos/genética , Veteranos/psicologia , Idoso , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco
17.
Mol Med Rep ; 8(1): 238-44, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23673673

RESUMO

Post-traumatic stress disorder (PTSD) is a common, debilitating and complex disorder. Numerous genetic and environmental factors are important in the genesis and maintenance of PTSD. Thus, gene expression analysis (GEA) is a critical technology for PTSD research since it detects essential genetic output affected by gene-environment interactions. Quality control methods are rarely reported in gene expression studies. The present study aimed to identify reliably expressed genes in whole blood samples from subjects with combat-induced PTSD (n=6) and, secondly, to investigate the expression of genes that may be differentially expressed in PTSD compared with an appropriate control group (n=11). Strict quality control methods were used. From a theoretically driven set of 42 genes, 17 were reliably detected using quantitative PCR on samples from 17 combat-exposed veterans. Four of these 17 genes were consistently and modestly correlated with clinical phenotypes and had significant expression effects on phenotypes. These genes regulate inflammatory systems and are regulated by the adrenergic system, consistent with peripheral markers important in PTSD. Inflammatory disinhibition may be involved in combat-induced PTSD, and may be responsible for the increased prevalence of inflammatory­related illnesses observed in PTSD. This is a preliminary study with a small sample size. A number of genes are not reliably detected by the current methodology. Improved detection methods are important to extend the current study and to further understand mechanisms in PTSD.


Assuntos
Distúrbios de Guerra/genética , Perfilação da Expressão Gênica , Transtornos de Estresse Pós-Traumáticos/genética , Veteranos , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Distúrbios de Guerra/complicações , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Controle de Qualidade , Transtornos de Estresse Pós-Traumáticos/complicações , Adulto Jovem
18.
Biol Psychiatry ; 73(11): 1103-10, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23434412

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) has been linked to increased morbidity. An inflexibility of the autonomic nervous system might be the underlying mechanism. We aimed to assess whether PTSD and combat trauma exposure are associated with lower heart rate variability (HRV), a measure of autonomic function and a predictor of death. METHODS: We measured HRV by power spectral analysis on 24-hour ambulatory electrocardiogram in 459 middle-aged veteran male twins. Combat trauma was assessed with the combat exposure scale, and current and remitted PTSD was assessed with the Structured Clinical Interview for Psychiatry Disorders. Mixed-effects regression models were used to test associations of PTSD and HRV between and within twin pairs. RESULTS: Of all twins, 211 had combat exposure, 31 had current PTSD, and 43 had remitted PTSD. Current PTSD was inversely associated with very-low-frequency and low-frequency HRV both in individual twins and within 20 pairs discordant for current PTSD. Twins with current PTSD had a 49% lower low-frequency HRV than their brothers without PTSD (p<.001). Remitted PTSD was not associated with HRV. Results were robust to adjustment for depression and other risk factors. Combat exposure was inversely associated with most HRV frequencies, but this association mostly diminished after adjustment for current PTSD. CONCLUSION: In middle-aged veteran men, combat exposure and current PTSD are associated with measures of autonomic inflexibility previously shown to have prognostic significance. The negative health impact of combat exposure on autonomic function is mediated largely through PTSD and might reverse with remission of PTSD.


Assuntos
Distúrbios de Guerra/fisiopatologia , Frequência Cardíaca/fisiologia , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Distúrbios de Guerra/genética , Doenças em Gêmeos , Eletrocardiografia Ambulatorial , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Análise de Regressão , Veteranos/psicologia
19.
J Affect Disord ; 147(1-3): 87-93, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23146198

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) and depressive disorder are over represented in combat veterans. Veterans with both disorders have an increased risk of suicide. The nitric oxide synthase 1 adaptor protein (NOS1AP) gene, which modulates stress-evoked N-methyl-d-aspartate (NMDA) activity, was investigated in combat veterans. METHODS: A comprehensive genetic analysis of NOS1AP and its association with PTSD was investigated in Vietnam combat veterans with PTSD (n=121) and a group of healthy control individuals (n=237). PTSD patients were assessed for symptom severity and level of depression using the Mississippi Scale for Combat-Related PTSD and the Beck Depression Inventory-II (BDI). RESULTS: The G allele of NOS1AP SNP rs386231 was significantly associated with PTSD (p=0.002). Analysis of variance revealed significant differences in BDI-II and Mississippi scores between genotypes for rs386231 with the GG genotype associated with increased severity of depression (p=0.002 F=6.839) and higher Mississippi Scale for Combat-Related PTSD scores (p=0.033). Haplotype analysis revealed that the C/G haplotype (rs451275/rs386231) was significantly associated with PTSD (p=0.001). LIMITATIONS: The sample sizes in our study were not sufficient to detect SNP associations with very small effects. In addition the study was limited by its cross sectional design. CONCLUSIONS: This is the first study reporting that a variant of the NOS1AP gene is associated with PTSD. Our data also suggest that a genetic variant in NOS1AP may increase the susceptibility to severe depression in patients with PTSD and increased risk for suicide.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Distúrbios de Guerra/genética , Depressão/genética , Transtorno Depressivo/genética , Transtornos de Estresse Pós-Traumáticos/genética , Veteranos/psicologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Distúrbios de Guerra/metabolismo , Depressão/metabolismo , Transtorno Depressivo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , N-Metilaspartato/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/psicologia , Guerra do Vietnã
20.
Transl Psychiatry ; 2: e75, 2012 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-22832737

RESUMO

The past few years have seen an increase in the clinical awareness of post-traumatic stress disorder (PTSD), one of the most disabling and least understood behavioral disorders. Although the biological bases of PTSD are poorly understood, fatty-acid amide hydrolase (FAAH) activity has been linked with arousability and aversive-memories extinction, that is, two key features of PTSD. In this study, we investigated the association between the FAAH genetic polymorphisms and PTSD development and maintenance. We assessed PTSD frequency in a group of male Vietnam war veterans who suffered combat-related penetrating traumatic brain injury, that is, a relatively homogeneous population regarding the nature of the events that led to PTSD. We showed that rs2295633, a single-nucleotide polymorphism of FAAH, was significantly associated with PTSD diagnosis in subjects without lesions in the ventromedial prefrontal cortex. Moreover, the presence of the C allele was associated with more severe re-experiencing of trauma and more negative reported childhood experiences. In conclusion, our data suggest that FAAH has an important role in PTSD through modulation of aversive memories and point to both a novel therapeutic target and a possible risk marker for this condition.


Assuntos
Alelos , Amidoidrolases/genética , Distúrbios de Guerra/genética , Predisposição Genética para Doença/genética , Traumatismos Cranianos Penetrantes/genética , Polimorfismo Genético/genética , Polimorfismo de Nucleotídeo Único/genética , Transtornos de Estresse Pós-Traumáticos/genética , Veteranos/psicologia , Guerra do Vietnã , Adolescente , Adulto , Idoso , Criança , Maus-Tratos Infantis/psicologia , Distúrbios de Guerra/diagnóstico , Distúrbios de Guerra/epidemiologia , Distúrbios de Guerra/psicologia , Estudos Transversais , Mecanismos de Defesa , Genótipo , Traumatismos Cranianos Penetrantes/diagnóstico , Traumatismos Cranianos Penetrantes/epidemiologia , Humanos , Interpretação de Imagem Assistida por Computador , Acontecimentos que Mudam a Vida , Masculino , Rememoração Mental/fisiologia , Pessoa de Meia-Idade , Córtex Pré-Frontal/lesões , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Tomografia Computadorizada por Raios X
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