Dataset Information

Moderation of adult depression by a polymorphism in the FKBP5 gene and childhood physical abuse in the general population.

ABSTRACT: Childhood maltreatment and depressive disorders have both been associated with a dysregulation of the hypothalamic-pituitary-adrenal axis. The FKBP5 gene codes for a co-chaperone regulating the glucocorticoid-receptor sensitivity. Previous evidence suggests that subjects carrying the TT genotype of the FKBP5 gene single-nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to adverse effects of experimental stress. We therefore tested the hypothesis of an interaction of childhood abuse with rs1360780 in predicting adult depression. In all, 2157 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and Childhood Trauma Questionnaire. The DSM-IV diagnosis of major depressive disorder (MDD) was assessed by interview. Genotypes of rs1360780 were taken from the Affymetrix Human SNP Array 6.0. Significant interaction (p=0.006) of physical abuse with the TT genotype of rs1360780 was found increasing the BDI-II score to 17.4 (95% confidence interval (CI)=12.0-22.9) compared with 10.0 (8.2-11.7) in exposed CC/CT carriers. Likewise, the adjusted odds ratio for MDD in exposed TT carriers was 8.2 (95% CI=1.9-35.0) compared with 1.3 (0.8-2.3) in exposed subjects with CC/CT genotypes. Relative excess risk due to interaction (RERI) analyses confirmed a significant additive interaction effect (RERI=6.8; 95% CI=0.64-33.7; p<0.05). In explorative analyses, the most severe degree of sexual and emotional abuse also yielded significant interaction effects (p<0.05). This study revealed interactions between physical abuse and rs1360780 of the FKBP5 gene, confirming its role in the individual susceptibility to depression. Given the large effect sizes, rs1360780 could be included into prediction models for depression in individuals exposed to childhood abuse.

SUBMITTER: Appel K

PROVIDER: S-EPMC3158316 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Moderation of adult depression by a polymorphism in the FKBP5 gene and childhood physical abuse in the general population.

Appel Katja K Schwahn Christian C Mahler Jessie J Schulz Andrea A Spitzer Carsten C Fenske Kristin K Stender Jan J Barnow Sven S John Ulrich U Teumer Alexander A Biffar Reiner R Nauck Matthias M Völzke Henry H Freyberger Harald J HJ Grabe Hans J HJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20110608 10

Childhood maltreatment and depressive disorders have both been associated with a dysregulation of the hypothalamic-pituitary-adrenal axis. The FKBP5 gene codes for a co-chaperone regulating the glucocorticoid-receptor sensitivity. Previous evidence suggests that subjects carrying the TT genotype of the FKBP5 gene single-nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to adverse effects of experimental stress. We therefore tested the hypothesis of an interaction of childh ...[more]

PMID: 21654733

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Project description:The endocannabinoid system has been implicated in stress adaptation and the regulation of mood in rodent studies, but few human association studies have examined these links and replications are limited.To examine whether a synonymous polymorphism, rs1049353, in exon 4 of the gene encoding the human endocannabinoid receptor (CNR1) moderates the effect of self-reported childhood physical abuse on lifetime anhedonia and depression and to replicate this interaction in an independent sample.Genetic association study in 1041 young US women with replication in an independent Australian sample of 1428 heroin-dependent individuals as cases and 506 participants as neighborhood controls.Self-reported anhedonia and depression (with anhedonia).In both samples, individuals who experienced childhood physical abuse were considerably more likely to report lifetime anhedonia. However, in those with 1 or more copies of the minor allele of rs1049353, this pathogenic effect of childhood physical abuse was attenuated. Thus, in participants reporting childhood physical abuse, although 57.1% of those homozygous for the major allele reported anhedonia, only 28.6% of those who were carriers of the minor allele reported it (P=.01). The rs1049353 polymorphism also buffered the effects of childhood physical abuse on major depressive disorder; however, this influence was largely attributable to anhedonic depression. These effects were also noted in an independent sample, in which minor allele carriers were at decreased risk for anhedonia even when exposed to physical abuse.Consistent with preclinical findings, a synonymous CNR1 polymorphism, rs1049353, is linked to the effects of stress attributable to childhood physical abuse on anhedonia and anhedonic depression. This polymorphism reportedly resides in the neighborhood of an exon splice enhancer; hence, future studies should carefully examine its effect on expression and conformational variation in CNR1, particularly in relation to stress adaptation.

Project description:ContextGenetic 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.ObjectiveTo 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.DesignAssociation study examining gene x environment interactions between genetic polymorphisms at the CRHR1 locus and measures of child abuse on adult depressive symptoms.SettingGeneral medical clinics of a large, public, urban hospital and Emory University, Atlanta, Georgia.ParticipantsThe 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 measuresBeck Depression Inventory scores and history of major depressive disorder by the Structured Clinical Interview for DSM-IV Axis I Disorders.ResultsFifteen 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).ConclusionsThese 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.

Project description:Abstract Background: We have previously shown elevated cortisol levels during the day and a blunted cortisol awakening response (CAR) at the onset of psychosis. Although stressful events and childhood abuse have been suggested to possibly play a role in these abnormalities, the evidence behind this link remains inconsistent, and it has been suggested that these could be partly due to genetic predisposition. The aim of this study was to test interaction between history of childhood abuse and rs1360780 FKBP5 genotype on cortisol levels during the day and cortisol awakening response. Methods: Eighty-two first-episode psychosis patients and 53 controls were enrolled in the study. Saliva samples were collected at multiple time points during the day to measure diurnal cortisol levels and cortisol awakening response (CAR); DNA was extracted from blood or saliva samples and evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. Information about presence of absence childhood physical or sexual abuse was collected using the Childhood Experience of Care and Abuse questionnaire. Univariate analyses were performed to test the effects of the interaction between presence of childhood abuse and FKBP5 genotype on cortisol measurements. Results: We found a significant interaction between history of childhood abuse and FKBP5 genotype on the CAR in first episode psychosis (F = 1.132, P = .01) but not in controls (P = .3). In particular patients with T allele (CT or TT) and history of childhood abuse had higher CAR than those with the same allele but without childhood abuse, while patients with CC genotype and history of childhood abuse had lower CAR than those with the same genotype but without childhood abuse. We also found a trend for interaction between history of childhood abuse and FKBP5 genotype on the cortisol levels during the day (F = 3.604, P = .06) in first episode psychosis but in controls (P = .3). In particular patients with T allele (CT or TT) and history of childhood abuse had higher diurnal cortisol levels than those with the same allele but without childhood abuse, while patients with CC genotype and history of childhood abuse had lower diurnal cortisol levels than those with the same genotype but without childhood abuse. Conclusion: Our findings suggest a role of interaction between childhood abuse and FKBP5 genotype in determining HPA axis abnormalities observed at the onset of psychosis.

Project description:ContextIn 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.ObjectiveTo 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 participantsA 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 measuresSeverity 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.ResultsLevel 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.ConclusionsFour 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.

Dataset Information

Moderation of adult depression by a polymorphism in the FKBP5 gene and childhood physical abuse in the general population.

Publications

Moderation of adult depression by a polymorphism in the FKBP5 gene and childhood physical abuse in the general population.

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