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1.
Artigo em Inglês | MEDLINE | ID: mdl-32179874

RESUMO

Inflammatory markers like C-reactive protein (CRP) have been associated with post-traumatic stress disorder (PTSD) and traumatic experiences, but the underlying mechanisms are unclear. We investigated the relationship among serum CRP, PTSD, and traits related to traumatic events and social support using genetic association data from the Psychiatric Genomics Consortium (23,185 PTSD cases and 151,309 controls), the UK Biobank (UKB; up to 117,900 individuals), and the CHARGE study (Cohorts for Heart and Aging Research in Genomic Epidemiology, 148,164 individual). Linkage disequilibrium score regression, polygenic risk scoring, and two-sample Mendelian randomization (MR) analyses were used to investigate genetic overlap and causal relationships. Genetic correlations of CRP were observed with PTSD (rg = 0.16, p = 0.026) and traits related to traumatic events, and the presence of social support (-0.28 < rg < 0.20; p < 0.008). We observed a bidirectional association between CRP and PTSD (CRP → PTSD: ß = 0.065, p = 0.015; PTSD → CRP: ß = 0.008, p = 0.009). CRP also showed a negative association with the "felt loved as a child" trait (UKB, ß = -0.017, p = 0.008). Owing to the known association of socioeconomic status (SES) on PTSD, a multivariable MR was performed to investigate SES as potential mediator. We found that household income (univariate MR: ß = -0.22, p = 1.57 × 10-7; multivariate MR: ß = -0.17, p = 0.005) and deprivation index (univariate MR: ß = 0.38, p = 1.63 × 10-9; multivariate MR: ß = 0.27, p = 0.016) were driving the causal estimates of "felt loved as a child" and CRP on PTSD. The present findings highlight a bidirectional genetic association between PTSD and CRP, also suggesting a potential role of SES in the interplay between childhood support and inflammatory processes with respect to PTSD risk.

2.
Clin Epigenetics ; 12(1): 46, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171335

RESUMO

BACKGROUND: Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). METHODS: In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). RESULTS: The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10-7, padj = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10-6), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10-5, padj = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 × 10-6, padj = 0.042). CONCLUSIONS: The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.

3.
Psychol Addict Behav ; 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32191043

RESUMO

Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) frequently co-occur, highlighting the importance of understanding the etiology of these comorbid conditions. Although AUD and PTSD are moderately heritable with modest overlap in genetic risk as estimated from family studies, there has been a paucity of work using molecular genetic data to estimate shared genetic effects on these conditions. This study used large-scale genomewide molecular data to examine shared genetic risk for AUD, specifically alcohol dependence (AD), and PTSD through cross-trait linkage disequilibrium (LD) score regression (LDSC; also known as LDSR). Summary statistics came from the Psychiatric Genomics Consortium (PGC) PTSD Workgroup Freeze 2 European ancestry (EA) participants (N = 174,659) and AD summary statistics in EA participants (N = 38,686) came from the PGC Substance Use Disorders (SUD) Workgroup. We performed LDSC to estimate genetic correlation between AD and PTSD using HapMap3 variants and LD scores from the 1000 Genomes project. A moderate, significant correlation was observed between AD and PTSD (rg = .35, p = .02), with sex differences identified through stratified analyses. Our results are the first to demonstrate evidence of a shared molecular genetic etiology for AD and PTSD. Further research is needed to better understand possible sex differences in shared heritability and extend these results to additional populations. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

4.
Transl Psychiatry ; 10(1): 38, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32066696

RESUMO

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h2snp), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h2snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10-8, FOXP1; rs10262462, p = 3.24 × 10-8, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h2snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r2 = 0.0025; p = 1.8 × 10-15). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (rg = 0.70, p = 4.65 × 10-40), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

5.
Clin Epigenetics ; 12(1): 11, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931860

RESUMO

BACKGROUND: Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis. RESULTS: Stage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10-08) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region. CONCLUSIONS: This study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD.

6.
J Am Geriatr Soc ; 68(2): 288-296, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31930739

RESUMO

OBJECTIVES: Although elevated lipid levels predict increased risk of coronary heart disease and death in middle-aged women and men, evidence is mixed if lipid levels measured in later life predict survival to very old ages. We examined lipid levels and survival to age 90 with or without intact mobility in a large cohort of older women. DESIGN: Prospective cohort. SETTING: Laboratory collection at a Women's Health Initiative (WHI) center and longitudinal follow-up via mail. PARTICIPANTS: Women aged 68 to 81 years at baseline. MEASUREMENTS: Serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were collected at baseline. Participant survival status and self-reported mobility was compared across lipid levels. RESULTS: HDL and LDL levels were not associated with survival to age 90 after adjustment for cardiovascular risk factors (HDL: quartile (Q) 2: odds ratio [OR] = 1.14 [95% confidence interval [CI] = .94-1.38]; Q3 OR = 1.08 [95% CI = .88-1.33]; Q4 OR = 1.09 [95% CI = .88-1.35]; LDL: Q2 OR = 1.07 [95% CI = .88-1.31]; Q3 OR = 1.27 [95% CI = 1.04-1.55]; Q4 OR = 1.07 [95% CI = .88-1.31]). Similarly, no associations were observed between HDL and LDL levels and survival to age 90 with mobility disability. High HDL was not associated with survival to age 90 with intact mobility after adjustment for other cardiovascular risk factors. Compared with the lowest LDL quartile, the three upper LDL quartiles were associated with greater odds of survival to age 90 with intact mobility (LDL: Q2 OR = 1.31 [95% CI = .99-1.74]; Q3 OR = 1.43 [95% CI = 1.07-1.92]; Q4 OR = 1.35 [95% CI = 1.01-1.80]; P = .05). CONCLUSION: Neither higher HDL nor lower LDL levels predicted survival to age 90, but higher LDL predicted healthy survival. These findings suggest the need for reevaluation of healthy LDL levels in older women. J Am Geriatr Soc 68:288-296, 2020.

7.
Genet Epidemiol ; 44(2): 148-158, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31737926

RESUMO

Recent technological and methodological developments have enabled the use of array-based DNA methylation data to call copy number variants (CNVs). ChAMP, Conumee, and cnAnalysis450k are popular methods currently used to call CNVs using methylation data. However, so far, no studies have analyzed the reliability of these methods using real samples. Data from a cohort of individuals with genotype and DNA methylation data generated using the HumanMethylation450 and MethylationEPIC BeadChips were used to assess the consistency between the CNV calls generated by methylation and genotype data. We also took advantage of repeated measures of methylation data collected from the same individuals to compare the reliability of CNVs called by ChAMP, Conumee, and cnAnalysis450k for both the methylation arrays. ChAMP identified more CNVs than Conumee and cnAnalysis450k for both the arrays and, as a consequence, had a higher overlap (~62%) with the calls from the genotype data. However, all methods had relatively low reliability. For the MethylationEPIC array, Conumee had the highest reliability (57.6%), whereas for the HumanMethylation450 array, cnAnalysis450k had the highest reliability (43.0%). Overall, the MethylationEPIC array provided significant gains in reliability for CNV calling over the HumanMethylation450 array but not for overlap with CNVs called using genotype data.

8.
Sleep ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31802129

RESUMO

STUDY OBJECTIVES: Sleep problems are common, serving as both a predictor and symptom of posttraumatic stress disorder (PTSD), with these bidirectional relationships well established in the literature. While both sleep phenotypes and PTSD are moderately heritable, there has been a paucity of investigation into potential genetic overlap between sleep and PTSD. Here, we estimate genetic correlations between multiple sleep phenotypes (including insomnia symptoms, sleep duration, daytime sleepiness, and chronotype) and PTSD, using results from the largest genome-wide association study (GWAS) to date of PTSD, as well as publicly available GWAS results for sleep phenotypes within UK Biobank data (23 variations, encompassing four main phenotypes). METHODS: Genetic correlations were estimated utilizing linkage disequilibrium score regression (LDSC), an approach that uses GWAS summary statistics to compute genetic correlations across traits, and Mendelian randomization (MR) analyses were conducted to follow up on significant correlations. RESULTS: Significant, moderate genetic correlations were found between insomnia symptoms (rg range 0.36-0.49), oversleeping (rg range 0.32-0.44), undersleeping (rg range 0.48-0.49), and PTSD. In contrast, there were mixed results for continuous sleep duration and daytime sleepiness phenotypes, and chronotype was not correlated with PTSD. MR analyses did not provide evidence for casual effects of sleep phenotypes on PTSD. CONCLUSION: Sleep phenotypes, particularly insomnia symptoms and extremes of sleep duration, have shared genetic etiology with PTSD, but causal relationships were not identified. This highlights the importance of further investigation into the overlapping influences on these phenotypes as sample sizes increase and new methods to investigate directionality and causality become available.

9.
Eur J Psychotraumatol ; 10(1): 1679964, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31723377

RESUMO

Background: Insomnia is common in service members and associated with many mental and physical health problems. Recently, longitudinal data have been used to assess the impact of disturbed sleep on mental health outcomes. These studies have consistently shown relationships between sleep disturbance and development of mental illness. Objective: The present study examined the longitudinal relationship between sleep disturbance and PTSD symptomatology in a cohort of Marines and Navy Corpsmen deployed to Iraq and Afghanistan (n = 2,404) assessed prior to deployment, as well as at -3 and 6 months post-deployment. Additionally, we aimed to investigate the extent to which these relationships are moderated by combat-stress severity, and to what extent these findings are replicated in a second, separate cohort of Marines and Navy corpsmen (n = 938) assessed with identical measures prior to deployment and within 3 months of return. Method: The present study employed latent variable path models to examine the relationships between pre-deployment sleep disturbance and post-deployment re-experiencing symptoms. Initial cross-lagged path models were conducted on discovery and replication samples to validate the hypothesized predictive relationships. Follow up moderation path models were then conducted to include the effect of combat-stress severity on these relationships. Results: Initial cross-lagged models supported a significant relationship between pre-deployment sleep disturbance and future re-experiencing PTSD symptoms at all time points. Initial moderation models showed a small moderator effect of combat-stress severity, though the main predictive relationship between pre-deployment sleep disturbance and PTSD symptoms remained significant. The moderator effect was not significant in the replication sample. Conclusions: The results of this study support pre-deployment sleep disturbance as a risk factor for development of post-deployment PTSD symptoms. Interventions aimed at normalizing sleep may be important in preventive measures for PTSD.

10.
JAMA Psychiatry ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31596458

RESUMO

Importance: The Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration. Objective: To build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs). Design, Setting, and Participants: A total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis. Data for COGS-1 were collected from January 6, 2003, to August 6, 2008; data for COGS-2, from June 30, 2010, to February 14, 2014. Data were analyzed from October 28, 2016, to May 4, 2018. Main Outcomes and Measures: A genome-wide association study was performed to evaluate association for 11 neurophysiological and neurocognitive endophenotypes targeting key domains of schizophrenia related to inhibition, attention, vigilance, learning, working memory, executive function, episodic memory, and social cognition. Results: The final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. In total, 7 genome-wide significant regions (P < 5 × 10-8) and 2 nearly significant regions (P < 9 × 10-8) containing several genes of interest, including NRG3 and HCN1, were identified for 7 endophenotypes. For each of the 11 endophenotypes, enrichment analyses performed at the level of P < 10-4 compared favorably with previous association results in the COGS-1 families and showed extensive overlap with regions identified for schizophrenia diagnosis. Conclusions and Relevance: These analyses identified several genomic regions of interest that require further exploration and validation. These data seem to demonstrate the utility of endophenotypes for resolving the genetic architecture of schizophrenia and characterizing the underlying biological dysfunctions. Understanding the molecular basis of these endophenotypes may help to identify novel treatment targets and pave the way for precision-based medicine in schizophrenia and related psychotic disorders.

11.
Nat Commun ; 10(1): 4558, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594949

RESUMO

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Transtornos de Estresse Pós-Traumáticos/genética , Ubiquitina-Proteína Ligases/genética , Grupo com Ancestrais do Continente Africano/genética , Conjuntos de Dados como Assunto , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fatores Sexuais , Veteranos/estatística & dados numéricos
12.
Mol Neuropsychiatry ; 5(2): 115-124, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31192224

RESUMO

Bipolar disorder (BD) is characterized by recurrent mood episodes, and circadian rhythm disturbances. Past studies have identified calcium channel genes as risk loci for BD. CACNA1C encodes an L-type calcium channel (LTCC) involved in the entrainment of circadian rhythms to light. Another calcium channel, i.e., the ryanodine receptor (RYR), is involved in -circadian phase delays. It is unknown whether variants in CACNA1C or other calcium channels contribute to the circadian phenotype in BD. We hypothesized that, by using temperature cycles, we could model circadian entrainment in fibroblasts from BD patients and controls to interrogate the circadian functions of LTCCs. Using Per2-luc, a bioluminescent reporter, we verified that cells entrain to temperature rhythms in vitro. Under constant temperature conditions, the LTCC antagonist verapamil shortened the circadian period, and the RYR antagonist dantrolene lengthened the period. However, neither drug affected temperature entrainment. Fibroblasts from BD patients and controls also entrained to temperature. In cells from BD patients, the rhythm amplitude was lower under entrained, but not constant, conditions. Temperature entrainment was otherwise similar between BD and control cells. However, the CACNA1C genotype among BD cells predicted the degree to which cells entrained. We conclude that assessment of rhythms under entrained conditions reveals additional rhythm abnormalities in BD that are not observable under constant temperature conditions.

13.
Am J Med Genet B Neuropsychiatr Genet ; 180(5): 310-319, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31081985

RESUMO

Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genome-wide association studies (GWASs) of self-assessed (by questionnaire) and outcome-based (incident mental disorders from predeployment to postdeployment) resilience among European (EUR) ancestry soldiers in the Army study to assess risk and resilience in servicemembers. Self-assessed resilience (N = 11,492) was found to have significant common-variant heritability (h2 = 0.162, se = 0.050, p = 5.37 × 10-4 ), and to be significantly negatively genetically correlated with neuroticism (rg = -0.388, p = .0092). GWAS results from the EUR soldiers revealed a genome-wide significant locus on an intergenic region on Chr 4 upstream from doublecortin-like kinase 2 (DCLK2) (four single nucleotide polymorphisms (SNPs) in LD; top SNP: rs4260523 [p = 5.65 × 10-9 ] is an eQTL in frontal cortex), a member of the doublecortin family of kinases that promote survival and regeneration of injured neurons. A second gene, kelch-like family member 36 (KLHL36) was detected at gene-wise genome-wide significance [p = 1.89 × 10-6 ]. A polygenic risk score derived from the self-assessed resilience GWAS was not significantly associated with outcome-based resilience. In very preliminary results, genome-wide significant association with outcome-based resilience was found for one locus (top SNP: rs12580015 [p = 2.37 × 10-8 ]) on Chr 12 downstream from solute carrier family 15 member 5 (SLC15A5) in subjects (N = 581) exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress-related psychopathology and point to new avenues for therapeutic intervention.

14.
JAMA Netw Open ; 2(5): e193447, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31050786

RESUMO

Importance: There is a well-established negative association of educational attainment (EA) and other traits related to cognitive ability with posttraumatic stress disorder (PTSD), but the underlying mechanisms are poorly understood. Objectives: To investigate the association of PTSD with traits related to EA. Design, Setting, and Participants: Genetic correlation, polygenic risk scoring, and mendelian randomization (MR) were conducted including 23 185 individuals with PTSD and 151 309 control participants from the Psychiatric Genomics Consortium for PTSD and up to 1 131 881 individuals assessed for EA and related traits from UK Biobank, 23andMe, and the Social Science Genetic Association Consortium. Data were analyzed from July 3 through November 19, 2018. Main Outcomes and Measures: Genetic correlation obtained from linkage disequilibrium score regression, phenotypic variance explained by polygenic risk scores, and association estimates from MR. Results: Summary association data from multiple genome-wide association studies were available for a total of 1 180 352 participants (634 391 [53.7%] women). Posttraumatic stress disorder showed negative genetic correlations with EA (rg = -0.26; SE = 0.05; P = 4.60 × 10-8). Mendelian randomization analysis, conducting considering a random-effects inverse-variance weighted method, indicated that EA has a negative association with PTSD (ß = -0.23; 95% CI, -0.07 to -0.39; P = .004). Investigating potential mediators of the EA-PTSD association, propensity for trauma exposure and risk-taking behaviors were observed as risk factors for PTSD independent of EA (trauma exposure: ß = 0.37; 95% CI, 0.19 to 0.52; P = 2.57 × 10-5; risk-taking: ß = 0.76; 95% CI, 0.38 to 1.13; P = 1.13 × 10-4), while income may mediate the association of EA with PSTD (MR income: ß = -0.18; 95% CI, -0.29 to -0.07; P = .001; MR EA: ß = -0.23; 95% CI, -0.39 to -0.07; P = .004; multivariable MR income: ß = -0.32; 95% CI, -0.57 to 0.07; P = .02; multivariable MR EA: ß = -0.04; 95% CI, -0.29 to 0.21; SE, 0.13; P = .79). Conclusions and Relevance: Large-scale genomic data sets add further evidence to the negative association of EA with PTSD, also supporting the role of economic status as a mediator in the association observed.


Assuntos
Cognição/fisiologia , Status Econômico , Escolaridade , Análise da Randomização Mendeliana/métodos , Transtornos de Estresse Pós-Traumáticos/psicologia , Estudos Transversais , Humanos , Polimorfismo de Nucleotídeo Único , Assunção de Riscos , Transtornos de Estresse Pós-Traumáticos/genética
15.
J Affect Disord ; 252: 350-357, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30999091

RESUMO

BACKGROUND: Post-traumatic stress disorder (PTSD) is a complex psychiatric disorder that occurs with relatively high frequency after deployment to warzones (∼10%). While twin studies have estimated the heritability to be up to 40%, thus indicating a considerable genetic component in the etiology, the biological mechanisms underlying risk and development of PTSD remain unknown. METHODS: Here, we conduct a genome-wide association study (GWAS; N = 2,481) to identify genome regions that associate with PTSD in a highly homogenous, trauma-exposed sample of Danish soldiers deployed to war and conflict zones. We perform integrated analyses of our results with gene-expression and chromatin-contact datasets to prioritized genes. We also leverage on other large GWAS (N>300,000) to investigate genetic correlations between PTSD and other psychiatric disorders and traits. RESULTS: We discover, but do not replicate, one region, 4q31, close to the IL15 gene, which is genome-wide significantly associated with PTSD. We demonstrate that gene-set enrichment, polygenic risk score and genetic correlation analyses show consistent and significant genetic correlations between PTSD and depression, insomnia and schizophrenia. LIMITATIONS: The limited sample size, the lack of replication, and the PTSD case definition by questionnaire are limitations to the study. CONCLUSIONS: Our results suggest that genetic perturbations of inflammatory response may contribute to the risk of PTSD. In addition, shared genetic components contribute to observed correlations between PTSD and depression, insomnia and schizophrenia.


Assuntos
Militares/psicologia , Doenças Profissionais/genética , Doenças Profissionais/psicologia , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto , Depressão/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial , Esquizofrenia/genética , Distúrbios do Início e da Manutenção do Sono/genética , Distúrbios do Início e da Manutenção do Sono/psicologia
16.
Neuropsychopharmacology ; 44(3): 620-628, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30487653

RESUMO

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/fisiopatologia , Ritmo Circadiano , Fibroblastos , Compostos de Lítio/farmacologia , Adulto , Animais , Transtorno Bipolar/genética , Células Cultivadas , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Técnicas de Genotipagem , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Medições Luminescentes , Camundongos , Células NIH 3T3 , Proteínas Circadianas Period , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
17.
Biol Psychol ; 134: 72-79, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29471015

RESUMO

In order to decrease the risk of developing stress-related disorders after military deployment, biological vulnerability factors should be identified. Neuropeptide Y (NPY) is a peptide neurotransmitter that is associated with modulation of the stress response. Using the data of two longitudinal prospective cohort studies (N = 892 and N = 2427), plasma NPY (pNPY) was assessed as a possible susceptibility biomarker for the development of PTSD symptoms over time. Data collection started prior to deployment and follow-up assessments were completed up to two years after deployment. In pNPY levels, measured before and shortly after deployment, three distinct trajectories were identified. In both cohorts, these trajectories were not related to the level of reported PTSD symptoms over time and neither were pre-deployment pNPY levels. Whereas previous research suggested that high NPY levels might be a marker for resilience, the current findings suggest limited usefulness of peripherally measured NPY in the development of PTSD.


Assuntos
Distúrbios de Guerra/sangue , Neuropeptídeo Y/sangue , Transtornos de Estresse Pós-Traumáticos/sangue , Adolescente , Adulto , Campanha Afegã de 2001- , Distúrbios de Guerra/psicologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Militares , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Resiliência Psicológica , Transtornos de Estresse Pós-Traumáticos/psicologia , Inquéritos e Questionários , Adulto Jovem
18.
Psychoneuroendocrinology ; 92: 123-134, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29452766

RESUMO

BACKGROUND: Recent studies examining the association between posttraumatic stress disorder (PTSD) and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed chronological age, have yielded mixed results. METHODS: We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity in association with accelerated DNA methylation age using data from 9 cohorts contributing to the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N = 2186). Associations between demographic and cellular variables and accelerated DNA methylation age were also examined, as was the moderating influence of demographic variables. RESULTS: Meta-analysis of regression coefficients from contributing cohorts revealed that childhood trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps = 0.028 and 0.016, respectively). Sex, CD4T cell proportions, and natural killer cell proportions were also significantly associated with accelerated DNA methylation age (all ps < 0.02). PTSD diagnosis and lifetime trauma exposure were not associated with advanced DNA methylation age. There was no evidence of moderation of the trauma or PTSD variables by demographic factors. CONCLUSIONS: Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD.


Assuntos
Metilação de DNA , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Estudos de Coortes , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/psicologia , Índices de Gravidade do Trauma
19.
Neuropsychopharmacology ; 43(3): 469-481, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28925389

RESUMO

Transcriptome-wide screens of peripheral blood during the onset and development of posttraumatic stress disorder (PTSD) indicate widespread immune dysregulation. However, little is known as to whether biological sex and the type of traumatic event influence shared or distinct biological pathways in PTSD. We performed a combined analysis of five independent PTSD blood transcriptome studies covering seven types of trauma in 229 PTSD and 311 comparison individuals to synthesize the extant data. Analyses by trauma type revealed a clear pattern of PTSD gene expression signatures distinguishing interpersonal (IP)-related traumas from combat-related traumas. Co-expression network analyses integrated all data and identified distinct gene expression perturbations across sex and modes of trauma in PTSD, including one wound-healing module downregulated in men exposed to combat traumas, one IL-12-mediated signaling module upregulated in men exposed to IP-related traumas, and two modules associated with lipid metabolism and mitogen-activated protein kinase activity upregulated in women exposed to IP-related traumas. Remarkably, a high degree of sharing of transcriptional dysregulation across sex and modes of trauma in PTSD was also observed converging on common signaling cascades, including cytokine, innate immune, and type I interferon pathways. Collectively, these findings provide a broad view of immune dysregulation in PTSD and demonstrate inflammatory pathways of molecular convergence and specificity, which may inform mechanisms and diagnostic biomarkers for the disorder.


Assuntos
Transtornos de Estresse Pós-Traumáticos/sangue , Transcriptoma , Feminino , Humanos , Masculino , Caracteres Sexuais , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/imunologia
20.
Depress Anxiety ; 35(1): 32-42, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28833952

RESUMO

BACKGROUND: Risk for posttraumatic stress disorder (PTSD) is thought to be mediated by gene × environment (G × E) interactions that affect core cognitive processes such as fear learning. The catechol-O-methyltransferase (COMT) val158met polymorphism has been associated with risk for PTSD and impaired fear inhibition. We used a large, relatively homogenous population to (1) replicate previous findings of poor fear inhibition in COMT Met/Met carriers with PTSD; (2) determine if COMT association with fear inhibition is moderated by childhood trauma (CT), an environmental risk factor for PTSD; and (3) determine if COMT is associated with altered fear processes after recent exposure to combat trauma. METHODS: Male Marines and Navy Corpsmen of European-American ancestry were assessed prior to (n = 714) and 4-6 months after deployment to Afghanistan (n = 452). Acquisition and extinction of fear-potentiated startle, childhood and combat trauma history, and PTSD diagnosis were assessed at both time points. RESULTS: Before deployment, Met/Met genotype was associated with fear inhibition deficits in participants with current PTSD; however, this association was dependent on CT exposure. After deployment, combat trauma was associated with a modest reduction in fear extinction in Met/Met compared with Val/Val carriers. There were no associations of COMT genotype with fear extinction within healthy and non-traumatized individuals. CONCLUSIONS: These findings support the hypothesis that G × E interactions underlie associations of COMT val158met with fear inhibition deficits. These studies confirm that Met/Met carriers with PTSD have poor fear inhibition, and support further research in understanding how this polymorphism might impact response to extinction-based therapies.


Assuntos
Adultos Sobreviventes de Eventos Adversos na Infância , Catecol O-Metiltransferase/genética , Extinção Psicológica/fisiologia , Medo/fisiologia , Interação Gene-Ambiente , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adulto , Humanos , Masculino , Militares , Polimorfismo Genético , Adulto Jovem
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