Charles F. Gillespie

Association of FKBP5 Polymorphisms and Childhood Abuse With Risk of Posttraumatic Stress Disorder Symptoms in Adults

CONTEXT In addition to trauma exposure, other factors contribute to risk for development of posttraumatic stress disorder (PTSD) in adulthood. Both genetic and environmental factors are contributory, with child abuse providing significant risk liability. OBJECTIVE To increase understanding of genetic and environmental risk factors as well as their interaction in the development of PTSD by gene x environment interactions of child abuse, level of non-child abuse trauma exposure, and genetic polymorphisms at the stress-related gene FKBP5. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study examining genetic and psychological risk factors in 900 nonpsychiatric clinic patients (762 included for all genotype studies) with significant levels of childhood abuse as well as non-child abuse trauma using a verbally presented survey combined with single-nucleotide polymorphism (SNP) genotyping. Participants were primarily urban, low-income, black (>95%) men and women seeking care in the general medical care and obstetrics-gynecology clinics of an urban public hospital in Atlanta, Georgia, between 2005 and 2007. MAIN OUTCOME MEASURES Severity of adult PTSD symptomatology, measured with the modified PTSD Symptom Scale, non-child abuse (primarily adult) trauma exposure and child abuse measured using the traumatic events inventory and 8 SNPs spanning the FKBP5 locus. RESULTS Level of child abuse and non-child abuse trauma each separately predicted level of adult PTSD symptomatology (mean [SD], PTSD Symptom Scale for no child abuse, 8.03 [10.48] vs > or =2 types of abuse, 20.93 [14.32]; and for no non-child abuse trauma, 3.58 [6.27] vs > or =4 types, 16.74 [12.90]; P < .001). Although FKBP5 SNPs did not directly predict PTSD symptom outcome or interact with level of non-child abuse trauma to predict PTSD symptom severity, 4 SNPs in the FKBP5 locus significantly interacted (rs9296158, rs3800373, rs1360780, and rs9470080; minimum P = .0004) with the severity of child abuse to predict level of adult PTSD symptoms after correcting for multiple testing. This gene x environment interaction remained significant when controlling for depression severity scores, age, sex, levels of non-child abuse trauma exposure, and genetic ancestry. This genetic interaction was also paralleled by FKBP5 genotype-dependent and PTSD-dependent effects on glucocorticoid receptor sensitivity, measured by the dexamethasone suppression test. CONCLUSIONS Four SNPs of the FKBP5 gene interacted with severity of child abuse as a predictor of adult PTSD symptoms. There were no main effects of the SNPs on PTSD symptoms and no significant genetic interactions with level of non-child abuse trauma as predictor of adult PTSD symptoms, suggesting a potential gene-childhood environment interaction for adult PTSD.

Influence of child abuse on adult depression: Moderation by the corticotropin-releasing hormone receptor gene

CONTEXT Genetic inheritance and developmental life stress both contribute to major depressive disorder in adults. Child abuse and trauma alter the endogenous stress response, principally corticotropin-releasing hormone and its downstream effectors, suggesting that a gene x environment interaction at this locus may be important in depression. OBJECTIVE To examine whether the effects of child abuse on adult depressive symptoms are moderated by genetic polymorphisms within the corticotropin-releasing hormone type 1 receptor (CRHR1) gene. DESIGN Association study examining gene x environment interactions between genetic polymorphisms at the CRHR1 locus and measures of child abuse on adult depressive symptoms. SETTING General medical clinics of a large, public, urban hospital and Emory University, Atlanta, Georgia. PARTICIPANTS The primary participant population was 97.4% African American, of low socioeconomic status, and with high rates of lifetime trauma (n = 422). A supportive independent sample (n = 199) was distinct both ethnically (87.7% Caucasian) and socioeconomically (less impoverished). MAIN OUTCOME MEASURES Beck Depression Inventory scores and history of major depressive disorder by the Structured Clinical Interview for DSM-IV Axis I Disorders. RESULTS Fifteen single-nucleotide polymorphisms spanning 57 kilobases of the CRHR1 gene were examined. We found significant gene x environment interactions with multiple individual single-nucleotide polymorphisms (eg, rs110402, P = .008) as well as with a common haplotype spanning intron 1 (P < .001). Specific CRHR1 polymorphisms appeared to moderate the effect of child abuse on the risk for adult depressive symptoms. These protective effects were supported with similar findings in a second independent sample (n = 199). CONCLUSIONS These data support the corticotropin-releasing hormone hypothesis of depression and suggest that a gene x environment interaction is important for the expression of depressive symptoms in adults with CRHR1 risk or protective alleles who have a history of child abuse.

Trauma exposure and stress-related disorders in inner city primary care patients

OBJECTIVE This study was undertaken to increase understanding of environmental risk factors for posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) within an urban, impoverished, population. METHOD This study examined the demographic characteristics, patterns of trauma exposure, prevalence of PTSD and MDD, and predictors of posttraumatic stress and depressive symptomatology using a verbally presented survey and structured clinical interviews administered to low-income, primarily African-American (>93%) women and men seeking care in the primary care and obstetrics-gynecology clinics of an urban public hospital. RESULTS Of the sample, 87.8% (n=1256) reported some form of significant trauma in their lifetime. Accidents were the most common form of trauma exposure followed by interpersonal violence and sexual assault. Childhood level of trauma and adult level of trauma separately, and in combination, predicted level of adult PTSD and depressive symptomatology. The lifetime prevalence of PTSD was 46.2% and the lifetime prevalence of MDD was 36.7%. CONCLUSIONS These data document high levels of childhood and adult trauma exposure, principally interpersonal violence, in a large sample of an inner-city primary care population. Within this group of subjects, PTSD and depression are highly prevalent conditions.

Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder.

DNA methylation may mediate persistent changes in gene function following chronic stress. To examine this hypothesis, we evaluated African American subjects matched by age and sex, and stratified into four groups by post‐traumatic stress disorder (PTSD) diagnosis and history of child abuse. Total Life Stress (TLS) was also assessed in all subjects. We evaluated DNA extracted from peripheral blood using the HumanMethylation27 BeadChip and analyzed both global and site‐specific methylation. Methylation levels were examined for association with PTSD, child abuse history, and TLS using a linear mixed model adjusted for age, sex, and chip effects. Global methylation was increased in subjects with PTSD. CpG sites in five genes (TPR, CLEC9A, APC5, ANXA2, and TLR8) were differentially methylated in subjects with PTSD. Additionally, a CpG site in NPFFR2 was associated with TLS after adjustment for multiple testing. Notably, many of these genes have been previously associated with inflammation. Given these results and reports of immune dysregulation associated with trauma history, we compared plasma cytokine levels in these subjects and found IL4, IL2, and TNFα levels associated with PTSD, child abuse, and TLS. Together, these results suggest that psychosocial stress may alter global and gene‐specific DNA methylation patterns potentially associated with peripheral immune dysregulation. Our results suggest the need for further research on the role of DNA methylation in stress‐related illnesses.

The neurobiological toll of child abuse and neglect

Exposure to interpersonal violence or abuse affects the physical and emotional well-being of affected individuals. In particular, exposure to trauma during development increases the risk of psychiatric and other medical disorders beyond the risks associated with adult violence exposure. Alterations in the hypothalamic-pituitary-adrenal (HPA) axis, a major mediating pathway of the stress response, contribute to the long-standing effects of early life trauma. Although early life trauma elevates the risk of psychiatric and medical disease, not all exposed individuals demonstrate altered HPA axis physiology, suggesting that genetic variation influences the consequences of trauma exposure. In addition, the effects of abuse may extend beyond the immediate victim into subsequent generations as a consequence of epigenetic effects transmitted directly to offspring and/or behavioral changes in affected individuals. Recognition of the biological consequences and transgenerational impact of violence and abuse has critical importance for both disease research and public health policy.

Polymorphisms in CRHR1 and the serotonin transporter loci: gene x gene x environment interactions on depressive symptoms.

Gene × environment (G × E) interactions mediating depressive symptoms have been separately identified in the stress‐sensitive serotonergic (5‐HTTLPR) and corticotropin‐releasing hormone (CRHR1) systems. Our objective was to examine whether the effects of child abuse are moderated by gene × gene (G × G) interactions between CRHR1 and 5‐HTTLPR polymorphisms. We used an association study examining G × G × E interactions of CRHR1 and 5‐HTTLPR polymorphisms and measures of child abuse on adult depressive symptomatology. The participant population (N = 1,392) was African‐American, of low socioeconomic status (60% with <

Gender differences in 542 Chinese inpatients with schizophrenia

1,000/month family income), and with high rates of childhood and lifetime trauma. Depressive symptoms were measured with Beck Depression Inventory (BDI) and history of Major Depression by Structure Clinical Interview based on DSM‐IV (SCID). We first replicated an interaction of child abuse and 5‐HTTLPR on lifetime SCID diagnosis of major depression in a subsample (N = 236) of the study population—the largest African‐American 5‐HTTLPR cohort reported to date. We then extended our previously reported interaction with both a CRHR1 SNP (rs110402) and TCA haplotype interacting with child abuse to predict current symptoms (N = 1,059; P = 0.0089). We found that the 5‐HTTLPR S allele interacted with CRHR1 haplotypes and child abuse to predict current depressive symptoms (N = 856, P = 0.016). These data suggest that G × E interactions predictive of depressive symptoms may be differentially sensitive to levels of childhood trauma, and the effects of child abuse are moderated by genetic variation at both the CRHR1 and 5‐HTTLPR loci and by their G × G interaction.

Differential Genetic and Epigenetic Regulation of catechol-O-methyltransferase is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder

OBJECTIVE To investigate gender differences in the onset and other clinical features of Han Chinese inpatients with schizophrenia. METHODS Five-hundred-and-forty-two Han Chinese inpatients with DSM-IV schizophrenia were assessed with the Positive and Negative Symptoms Scale (PANSS), the Brief Psychiatric Rating Scale (BPRS), the Global Assessment of Function scale (GAF) and locally-developed standardized data collection forms. Comparisons were made between male and female patients. RESULTS This is the largest study of gender differences in schizophrenia to be conducted in a Chinese population. In our sample, we found that schizophrenia onset occurred at a significantly earlier age in male patients compared to female patients and that late-onset schizophrenia (as defined by onset> or =45 years) was significantly more common in female patients. The paranoid subtype of schizophrenia was less common in male patients, males received higher daily doses of antipsychotics and demonstrated a different pattern of antipsychotic usage, being less likely to be treated with SGAs. Further, cigarette smoking was more common in male patients and male patients were more likely to be single or never married. By contrast, female patients showed a different pattern of ongoing symptoms and severity, being more likely to have persistent positive symptoms, more severe positive and affective symptoms, and a greater number of suicide attempts whereas male patients were more likely to show severe deterioration over time. CONCLUSIONS There are notable gender differences in the age at onset, treatment and a range of other clinical features in Han Chinese patients with schizophrenia. Such differences were largely consistent with those reported in Western studies. These gender differences need to be considered in the assessment and management of Chinese patients with schizophrenia.

Posttraumatic stress disorder is a risk factor for metabolic syndrome in an impoverished urban population

The catechol-O-methyltransferase (COMT) enzyme is critical for the catabolic regulation of synaptic dopamine, resulting in altered cortical functioning. The COMT Val158Met polymorphism has been implicated in human mental illness, with Met/Met homozygotes associated with increased susceptibility to posttraumatic stress disorder (PTSD). Our primary objective was to examine the intermediate phenotype of fear inhibition in PTSD stratified by COMT genotype (Met/Met, Val/Met, and Val/Val) and differential gene regulation via methylation status at CpG sites in the COMT promoter region. More specifically, we examined the potential interaction of COMT genotype and PTSD diagnosis on fear-potentiated startle during fear conditioning and extinction and COMT DNA methylation levels (as determined using genomic DNA isolated from whole blood). Participants were recruited from medical and gynecological clinics of an urban hospital in Atlanta, GA, USA. We found that individuals with the Met/Met genotype demonstrated higher fear-potentiated startle to the CS− (safety signal) and during extinction of the CS+ (danger signal) compared to Val/Met and Val/Val genotypes. The PTSD+ Met/Met genotype group had the greatest impairment in fear inhibition to the CS− (p = 0.006), compared to Val carriers. In addition, the Met/Met genotype was associated with DNA methylation at four CpG sites, two of which were associated with impaired fear inhibition to the safety signal. These results suggest that multiple differential mechanisms for regulating COMT function – at the level of protein structure via the Val158Met genotype and at the level of gene regulation via differential methylation – are associated with impaired fear inhibition in PTSD.

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond.

OBJECTIVE Metabolic syndrome is associated with elevated risk for cardiovascular disease and diabetes and has increased prevalence in low-income African Americans, which constitutes a significant health disparity. The mechanisms responsible for this disparity remain unclear; the current study investigated the relationship between posttraumatic stress disorder (PTSD) and metabolic syndrome. METHOD We assessed childhood and adult trauma history, major depressive disorder, PTSD and the components of metabolic syndrome in an urban population. We recruited 245 low-socioeconomic-status, primarily African American subjects from general medical clinics in an inner-city hospital. RESULTS Trauma exposure was extremely prevalent, with 90.6% of subjects reporting at least one significant trauma and 18.8% of subjects meeting criteria for current PTSD. Metabolic syndrome was also prevalent in this population (33.2%), with significantly higher rates among patients with current PTSD (47.8%, P<.05). After controlling for demographics, smoking history, antipsychotic use, depression and exercise, current PTSD remained the only significant predictor of metabolic syndrome (P=.006). CONCLUSIONS PTSD is associated with increased rates of metabolic syndrome within a traumatized, impoverished urban population. Further studies should investigate if PTSD treatment may reduce the rates of metabolic syndrome, improve overall health outcomes and decrease health care disparities in minority populations.