Showing papers by "Israel Liberzon published in 2018"

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

Abstract: The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case–control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD—for both European- and African-American individuals—and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder.

Abstract: Post-traumatic stress disorder (PTSD) is a common, costly, and often debilitating psychiatric condition. However, the biological mechanisms underlying this disease are still largely unknown or poorly understood. Considerable evidence indicates that PTSD results from dysfunction in highly-conserved brain systems involved in stress, anxiety, fear, and reward. Pre-clinical models of traumatic stress exposure are critical in defining the neurobiological mechanisms of PTSD, which will ultimately aid in the development of new treatments for PTSD. Single prolonged stress (SPS) is a pre-clinical model that displays behavioral, molecular, and physiological alterations that recapitulate many of the same alterations observed in PTSD, illustrating its validity and giving it utility as a model for investigating post-traumatic adaptations and pre-trauma risk and protective factors. In this manuscript, we review the present state of research using the SPS model, with the goals of (1) describing the utility of the SPS model as a tool for investigating post-trauma adaptations, (2) relating findings using the SPS model to findings in patients with PTSD, and (3) indicating research gaps and strategies to address them in order to improve our understanding of the pathophysiology of PTSD.

Cognitive Flexibility Predicts PTSD Symptoms: Observational and Interventional Studies.

Abstract: Introduction: Post-Traumatic Stress Disorder (PTSD) is a prevalent, severe and tenacious psychopathological consequence of traumatic events. Neurobehavioral mechanisms underlying PTSD pathogenesis have been identified, and may serve as risk-resilience factors during the early aftermath of trauma exposure. Longitudinally documenting the neurobehavioral dimensions of early responses to trauma may help characterize survivors at risk and inform mechanism-based interventions. We present two independent longitudinal studies that repeatedly probed clinical symptoms and neurocognitive domains in recent trauma survivors. We hypothesized that better neurocognitive functioning shortly after trauma will be associated with less severe PTSD symptoms a year later, and that an early neurocognitive intervention will improve cognitive functioning and reduce PTSD symptoms. Methods: Participants in both studies were adult survivors of traumatic events admitted to two general hospitals' emergency departments (EDs) in Israel. The studies used identical clinical and neurocognitive tools, which included assessment of PTSD symptoms and diagnosis, and a battery of neurocognitive tests. The first study evaluated 181 trauma-exposed individuals one-, six-, and 14 months following trauma exposure. The second study evaluated 97 trauma survivors 1 month after trauma exposure, randomly allocated to 30 days of web-based neurocognitive intervention (n = 50) or control tasks (n = 47), and re-evaluated all subjects three- and 6 months after trauma exposure. Results: In the first study, individuals with better cognitive flexibility at 1 month post-trauma showed significantly less severe PTSD symptoms after 13 months (p = 0.002). In the second study, the neurocognitive training group showed more improvement in cognitive flexibility post-intervention (p = 0.019), and lower PTSD symptoms 6 months post-trauma (p = 0.017), compared with controls. Intervention- induced improvement in cognitive flexibility positively correlated with clinical improvement (p = 0.002). Discussion: Cognitive flexibility, shortly after trauma exposure, emerged as a significant predictor of PTSD symptom severity. It was also ameliorated by a neurocognitive intervention and associated with a better treatment outcome. These findings support further research into the implementation of mechanism-driven neurocognitive preventive interventions for PTSD.

Subthreshold PTSD and PTSD in a prospective-longitudinal cohort of military personnel: Potential targets for preventive interventions

Abstract: Background Prevention of PTSD requires identification of subpopulations contributing most to the population burden of PTSD. This study examines the relative contribution of subthreshold PTSD and probable PTSD on future PTSD in a representative military cohort. Methods We analyze data on 3,457 U.S. National Guard members from the state of Ohio, assessed by telephone annually from 2008 to 2014. At each wave, participants were classified into one of three groups based on the PTSD Checklist: probable PTSD (DSM-IV-TR criteria), subthreshold PTSD (Criterion A1, at least one symptom in each cluster, symptom lasting longer than 30 days, and functional impairment), and no PTSD. We calculated the exposure rate, risk ratio (RR), and population attributable fraction (PAF) to determine the burden of future probable PTSD attributable to subthreshold PTSD compared to probable PTSD. Results The annualized prevalence of subthreshold PTSD and probable PTSD was respectively 11.9 and 5.0%. The RR for probable PTSD was twice as great among respondents with probable PTSD the prior interview than that of those with subthreshold PTSD (7.0 vs. 3.4); however, the PAF was considerably greater in participants with subthreshold PTSD the prior interview (PAF = 35%; 95% confidence interval (CI) = 26.0-42.9%) than in those with probable PTSD (PAF = 28.0%; 95% CI = 21.8-33.8%). Results were robust to changes in subthreshold PTSD definition. Conclusions Subthreshold PTSD accounted for a substantial proportion of this population's future PTSD burden. Population-based preventive interventions, compared to an approach focused exclusively on cases of diagnosable PTSD, is likely to affect the greatest reduction in this population's future PTSD burden.

The dopamine D4 receptor gene (DRD4) modulates cultural variation in emotional experience

Abstract: Prior work suggests that people who carry a 7- or 2-repeat allele of the dopamine D4 receptor gene (DRD4) are more sensitive to environmental influences than those who do not carry this allele. Since culture is an important aspect of the environment for all humans, the carriers of this allele may be more likely to show culturally typical response patterns than non-carriers. The current work tested this hypothesis in the domain of emotional experience. Whereas European Americans typically report experiencing positive emotions more than negative emotions, this positivity bias is atypical for East Asians. Accordingly, we predicted that the positivity bias in emotional experience would be moderated by both DRD4 and culture. 194 European Americans and 204 East Asians rated the frequency of actually experiencing various positive and negative emotions in a typical week. As predicted, we found a significant culture × DRD4 interaction for emotional experience. East Asian carriers (versus non-carriers) of the 7/2R allele of DRD4 reported experiencing greater emotional balance (i.e., weaker positivity bias), than non-carriers of these alleles. For European Americans, however, the pattern was reversed such that the positivity bias was stronger, albeit non-significantly, among the carriers than among the non-carriers. Of note, the culture × DRD4 interaction effect was absent for desirability ratings of experiencing the same set of emotions. Implications for cultural acquisition processes are discussed.

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Abstract: Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson’s Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

A DRD2/ANNK1-COMT interaction, consisting of functional variants, confers risk of post-traumatic stress disorder in traumatized Chinese

Abstract: Objective: Post-traumatic stress disorder (PTSD) is a trauma- and stress-related psychiatric syndrome that occurs after exposure to extraordinary stressors. The neurotransmitter dopamine (DA) plays important roles in neurobiological processes like reward and stress, and a link between PTSD and the dopaminergic system has been reported. Thus, the investigation of an association between PTSD and gene–gene interaction (epistasis) within dopaminergic genes could uncover the genetic basis of dopamine-related PTSD symptomatology and contribute to precision medicine. Methods: We genotyped seven single nucleotide polymorphisms (SNPs) of three dopaminergic genes DRD2/ANNK1 (rs1800497 and rs1801028), COMT (rs6269, rs4633, rs4818 and rs4680) and DBH (rs1611115), in a Chinese predominantly adult cohort that had been exposed to an earthquake (156 PTSD cases and 978 controls). Results: Statistical genetics analysis identified a DRD2/ANNK1–COMT interaction (rs1800497×rs6269), which is associated with PTSD diagnosis (Pinteraction = 0.0008055 and Pcorrected = 0.0169155). Single-variant and haplotype-based subset analyses showed that rs1800497 modulates the association directions of both the rs6269 G allele and the rs6269-rs4633-rs4818-rs4680 haplotype G-C-G-G. The interaction (rs1800497×rs6269) was replicated in a Chinese young female cohort (32 cases and 581 controls, Pinteraction = 0.01329). Conclusions: Rs1800497 is related to the DA receptor D2 density and rs6269-rs4633-rs4818-rs4680 haplotypes affect the catechol O-methyltransferase level and enzyme activity. Thus, the interaction was inferred to be at protein–protein and DA activity level. The genotype combinations of the two SNPs indicate a potential origin of DA homeostasis abnormalities in PTSD development.

Effects of Trauma in Adulthood and Adolescence on Fear Extinction and Extinction Retention: Advancing Animal Models of Posttraumatic Stress Disorder

Abstract: Evidence for and against adolescent vulnerability to posttraumatic stress disorder (PTSD) is mounting, but this evidence is largely qualitative, retrospective, or complicated by variation in prior stress exposure and trauma context. Here, we examine the effects of development on trauma vulnerability using adult and adolescent (early and mid adolescence) rats and two types of trauma: an established animal model of PTSD, single prolonged stress (SPS), and a novel composite model - single prolonged stress-predation version (SPSp). We demonstrate for the first time that early and mid adolescent rats are capable of fear and safety learning, as well as the retention of safety learning. Our results also demonstrate that both types of trauma attenuated the retention of safety learning (fear extinction), a hallmark of PTSD-like phenotype after trauma in adulthood, but not after early or mid adolescence trauma, suggesting that adolescence might convey resilience to SPS and SPSp traumas. Across all three life stages, the effects of SPS exposure and a novel predation trauma model, SPSp, had similar effects on behavior suggesting that trauma type did not affect the likelihood of developing PTSD-like symptoms, and that the predation-based trauma model may have convergent validity with SPS, a prominent model of behavioral, physiological, and neurological PTSD symptomatology.

Gestational and Postnatal Cortisol Profiles of Women With Posttraumatic Stress Disorder and the Dissociative Subtype

Abstract: Objective To test the hypothesis that women with posttraumatic stress disorder (PTSD) have greater salivary cortisol levels across the diurnal curve and throughout gestation, birth, and the postpartum period than women who do not have PTSD. Design Prospective, longitudinal, biobehavioral cohort study. Setting Prenatal clinics at academic health centers in the Midwest region of the United States. Participants Women expecting their first infants who fit with one of four cohorts: a nonexposed control group, a trauma-exposed control group, a group with PTSD, and a group with the dissociative subtype of PTSD. Methods In the first half of pregnancy, 395 women provided three salivary cortisol specimens on a single day for diurnal data. A subsample of 111 women provided three salivary cortisol specimens per day, 12 times, from early pregnancy to 6 weeks postpartum for longitudinal data. Trauma history, PTSD, and dissociative symptoms were measured via standardized telephone diagnostic interviews with the use of validated epidemiologic measures. Generalized estimating equations were used to determine group differences. Results Generalized estimating equations showed that women with the dissociative subtype of PTSD had the highest and flattest gestational cortisol level curves. The difference was greatest in early pregnancy, when participants in the dissociative subtype group had cortisol levels 8 times greater in the afternoon and 10 times greater at bedtime than those in the nonexposed control group. Conclusion Women with the dissociative subtype of PTSD, a complex form associated with a history of childhood maltreatment, may have toxic levels of cortisol that contribute to intergenerational patterns of adverse health outcomes.

Gene by Culture Effects on Emotional Processing of Social Cues among East Asians and European Americans.

Abstract: While Western cultures are more focused on individualization and self-expression, East Asian cultures promote interrelatedness. Largely unknown is how gene by culture interactions influence the degree to which individuals acquire culture, and the neurocircuitry underlying how social cues are processed. We sought to examine the interaction between DRD4 polymorphism and culture in the neural processing of social emotional cues. 19 Asian-born East Asian (AA) and 20 European American (EA) participants performed a shifted attention emotion appraisal functional magnetic resonance imaging (fMRI) task, which probes implicit emotional processing and regulation in response to social emotional cues. Half of the participants in each group were DRD4 2- or 7-repeat allele (2R/7R) carriers. AA participants showed larger left and right amygdala, and left hippocampal activation during implicit processing of fearful faces. There was a gene by culture interaction in the left insula during implicit processing of facial cues, while activation in EA DRD4 2R/7R carriers was larger than EA non-carriers and AA carriers. Our findings suggest that emotional facial cues are more salient to AA participants and elicit a larger amygdala reaction. Gene by culture interaction finding in insula suggests that DRD4 2R/7R carriers in each culture are more prone to adopting their cultural norm.

Brain Structural Abnormalities in Posttraumatic Stress Disorder and Relations with Sleeping Problems

Abstract: Increasing number of neuroimaging studies examine brain structure in posttraumatic stress disorder (PTSD) patients. Limited studies begin to examine the relationship of brain structure and sleep problems in PTSD patients. The current review summarizes the existing findings on structural brain differences between the PTSD patients and control subjects without PTSD, with emphasis on studies related to sleep problems in PTSD patients. The findings of structural differences in hippocampus, prefrontal cortex, anterior cingulate cortex, insular cortex, and corpus callosum of PTSD patients have been reported in multiple studies, but changes in other brain regions are yet to be reliably replicated. Limited studies on pediatric PTSD suggest different picture of structural abnormalities as compared to adult patients. The longitudinal studies suggest that structural properties of prefrontal cortex in trauma-exposed individuals dynamically change over time, and these dynamic brain changes may associate with progression of PTSD symptoms. Finally, limited studies suggest that structural changes in hippocampus and prefrontal brain regions may be associated with the severity of sleep problems in trauma-exposed individuals, but further investigation on this issue is clearly needed.