Andrea Schulz

Moderation of Adult Depression by a Polymorphism in the FKBP5 Gene and Childhood Physical Abuse in the General Population

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.

Childhood maltreatment, the corticotropin-releasing hormone receptor gene and adult depression in the general population†‡

Dysregulations of the hypothalamic‐pituitary‐adrenal (HPA) axis have been implicated in the pathogenesis of depressive disorders and the corticotropin‐releasing hormone (CRH) was found to modulate emotional memory consolidation. Recently, two studies have reported an interaction between childhood abuse and the TAT–haplotype of the CRH‐Receptor Gene (CRHR1) connecting childhood adversities and genetic susceptibility to adult depression. We tested the hypothesis of an interaction of childhood maltreatment with single nucleotide polymorphisms (SNPs) and haplotypes of the CRHR1 gene not previously investigated. Caucasian subjects (n = 1,638) from the German general population (Study of Health in Pomerania, SHIP) were analyzed. As in the previous studies, childhood abuse and neglect were assessed with the Childhood Trauma Questionnaire (CTQ) and depression with the Beck Depression Inventory (BDI‐2). The CRHR1‐SNPs were genotyped on the Affymetrix Genome‐Wide Human SNP Array 6.0 platform. We identified an interaction between the TAT–haplotype and childhood physical neglect. The interaction with physical neglect showed significant (P < 0.05) results in 23 of the 28 SNPs, with rs17689882 (P = 0.0013) reaching “gene‐wide” significance. Although we did not replicate the specific interaction of abuse and the TAT–haplotype of the CRHR1 gene we confirmed the relevance of an interplay between variants within the CRHR1 gene and childhood adversities in the modulation of depression in adults. The largest effect was found for rs17689882, a SNP previously not analyzed. Relevant sample differences between this and prior studies like lower BDI‐2 scores, less childhood maltreatment and higher psychosocial functioning may account for the differences in gene–environment interaction findings.

Genetic epistasis between the brain-derived neurotrophic factor Val66Met polymorphism and the 5-HTT promoter polymorphism moderates the susceptibility to depressive disorders after childhood abuse.

BACKGROUND Based on biological interactions between the serotonergic system and the brain-derived neurotrophic factor (BDNF), BDNF is a plausible candidate for a gene-gene-environment interaction moderating the interaction between the s/l- promoter polymorphism of the serotonin transporter (5-HTTLPR) and childhood abuse. We tested the hypothesis of a three-way interaction with respect to depressive symptoms. METHODS 2035 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and the Childhood Trauma Questionnaire. All subjects were genotyped for the BDNF Val66Met (rs6265) and the s/l 5-HTTLPR polymorphisms. RESULTS Tobit regression analyses revealed a three-way-interaction between the three genotypes of 5-HTTLPR and the BDNF genotypes and overall childhood abuse for the BDI-II score (p=0.02). Emotional abuse carried the main effect of the interaction (p=0.008). The s/s genotype of the 5-HTTLPR exerted its negative impact on mental health after childhood abuse only in the presence of the BDNF Val/Val genotype but not in the presence of the BDNF Met allele. In contrast, the l allele of the 5-HTTLPR also emerged as a genetic risk factor for depression in carriers of one or two Met alleles. CONCLUSIONS Our results point to a gene-gene-environment interaction that relevantly impacts on the role of the s/s genotype of the 5-HTTLPR in childhood abuse: Depending on the BDNF background (Val/Val versus Met allele) the s/s genotype showed either protective or risk properties with regard to depressive symptoms.

Moderation of adult depression by the serotonin transporter promoter variant (5‐HTTLPR), childhood abuse and adult traumatic events in a general population sample

The impact of the promoter polymorphisms of the serotonin transporter (5‐HTTLPR) on mood has been studied by two‐way interaction models comprising one environmental factor and genotype variants. However, childhood abuse is assumed to be associated with different psychobiological long‐term effects than adult traumatic events. Both types of trauma may interact on an individual basis throughout the lifespan moderating the impact of the 5‐HTTLPR s allele on depressive disorders. Therefore, the hypothesis of a three‐way interaction among the 5‐HTTLPR, childhood abuse and adult traumatic experience was tested. Caucasian subjects (1,974) from the general population in Germany (Study of Health in Pomerania (SHIP)) were analyzed. Depressive symptoms were measured with the Beck Depression Inventory (BDI‐II). Childhood abuse was assessed with the Childhood Trauma Questionnaire. Adult traumatic events were derived from the SCID interview (DSM‐IV) on posttraumatic stress disorder (PTSD). Global three‐way interactions among the 5‐HTTLPR, adult traumatic experiences and childhood abuse (P = 0.0007) were found. Carriers of the ss or sl genotypes who had been exposed to childhood abuse and to more than two adult traumatic events had higher mean BDI‐II scores (16.0 [95% CI 8.4–23.6]) compared to those carrying the ll genotype (7.6 [4.5–10.7]). These results were supported using a second, more severe definition of childhood abuse (P = 0.02). No two‐way interactions were observed (P > 0.05). Childhood abuse and adult traumatic events may act synergistically in interaction with the s allele of the 5‐HTTLPR to increase the risk for depressive symptoms independently from the lifetime diagnosis of PTSD.

Linear, nonlinear or categorical: how to treat complex associations in regression analyses? Polynomial transformations and fractional polynomials

Nonlinear approaches to assess exposure-outcome relations are still fairly uncommon in public health research. The predominant reliance on linear associations and categorized continuous predictors is surprising, given the availability of powerful alternatives with sophisticated and user friendly software implementations. This simplicity threatens one of the major aims in regression analyses: to obtain an unbiased mean estimate of the dependent variable conditional on the predictor variables. In the first part of this non-technical series, we will briefly discuss problems of linear models and categorized continuous predictor variables. Polynomial and fractional polynomial approaches will be introduced, as well as information on selected statistical procedures in main software packages (Table 1). In the second part, splines and non-parametric approaches will be illustrated (Schmidt et al. 2012). Linear modeling and categorization: the common approaches

Update on the 2005 paper: moderation of mental and physical distress by polymorphisms in the 5-HT transporter gene by interacting with social stressors and chronic disease burden

Update on the 2005 paper: moderation of mental and physical distress by polymorphisms in the 5-HT transporter gene by interacting with social stressors and chronic disease burden

The impact of childhood trauma on depression: does resilience matter? Population-based results from the Study of Health in Pomerania

OBJECTIVE Data suggests that traumatic experiences at early age contribute to the onset of major depressive disorder (MDD) in later life. This study aims at investigating the influence of dispositional resilience on this relationship. METHODS Two thousand and forty-six subjects aged 29-89 (SD=13.9) from a community based sample who were free of MDD during the last 12 months prior to data collection were diagnosed for Lifetime diagnosis of MDD by the Munich-Composite International Diagnostic Interview (M-CIDI) according to DSM-IV criteria. Childhood maltreatment (CM) and resilience were assessed with the Childhood Trauma Questionnaire (CTQ) and the Resilience-Scale (RS-25). RESULTS Both CM (OR=1.03, 95% CI [1.02, 1.04], P<.000) and resilience (OR=0.98, 95% CI [0.98, 0.99], P<.000) were associated with MDD later in life. The detrimental effects of low resilience on MDD were not only especially prominent in subjects with a history of CM (OR=3.18, 95% CI [1.84, 5.50], P<.000), but also effective in subjects without CM (OR=2.62, 95% CI [1.41, 4.88], P=.002). CONCLUSIONS The findings support the clinical assumption that resilient subjects may be partly protected against the detrimental long-term effects of child abuse and neglect.

Die Lebenszeitprävalenz psychischer Störungen in Vorpommern

OBJECTIVE This work addresses the life-time-prevalence of mental disorders in the adult general population in a German region (Vorpommern). We address effects of attrition on prevalence estimates. METHODS Analyses are based on a general population cohort study (29 - 89 years, Study of Health in Pomerania, N = 2400), using the M-CIDI to obtain life-time diagnoses of mental disorders according to ICD-10. Statistical weights were used to assess the effects of selective non-response on prevalence estimates related to baseline physical and psychological morbidity and sociodemographic variables, measured 10 years before. RESULTS In total 44.6 % of the male and 55.2 % of the female participants fulfilled criteria for at least one ICD mental disorder including specific phobias and tobacco dependence. Physical but not psychological baseline morbidity showed relevant associations to participation in the psychological examination ten years later. Weighted and unweighted prevalence estimates for mental disorders were very similar. CONCLUSION Our results illustrate the high burden due to mental disorders. Most prevalence estimates seem robust to prior mental comorbidities.

Psychometric functioning, socio‐demographic variability of childhood maltreatment in the general population and its effects of depression

Maltreatment of children is a major public‐health and social‐welfare problem but socio‐demographic variability has received little attention. This work addresses such variability in a general population cohort and associations with depression. Analyses were based on the cross‐sectional SHIP‐LEGEND examination among 2265 adults (29–89 years). Childhood maltreatment was multi‐dimensionally assessed with the German 28‐item Childhood Trauma Questionnaire (CTQ): emotional neglect; emotional abuse; physical neglect; physical abuse; sexual abuse. Non‐linear associations between CTQ responses and age were assessed with fractional polynomials and cubic splines. Scale properties were analysed with confirmatory factor analyses and item response models. Associations between childhood maltreatment domains and depression [Beck Depression Inventory‐II (BDI‐II)] were assessed. The majority (58.9%) reported events indicative of at least mild levels of childhood maltreatment. CTQ subscales showed characteristically different non‐linear associations to age across the five studied domains, indicating methodological issues like recall bias and the influence of seminal events. Psychometric scale properties were acceptable to good for all subscales except for physical neglect. Associations to depression measures varied systematically across socio‐demographic strata. We conclude that socio‐demographic variability is a major issue when studying self‐reported childhood maltreatment in a community sample. This needs to be taken into account for the study of associations to psychiatric key outcomes. Copyright

The phenomenology of the first panic attack in clinical and community-based samples

The purpose of the study was to contrast first panic attacks (PAs) of patients with panic disorder (PD) with vs. without agoraphobia and to explore differences between first PAs leading to the development of PD and those that remain isolated. Data were drawn from a community survey (N=2259 including 88 isolated PAs and 75 PD cases). An additional sample of 234 PD patients was recruited in a clinical setting. A standardized interview assessed the symptoms of the first PA, context of its occurrence and subsequent coping attempts. Persons who developed PD reported more severe first PAs, more medical service utilization and exposure-limiting coping attempts than those with isolated PAs. The context of the first PA did not differ between PD and isolated PAs. PD with agoraphobia was specifically associated with greater symptom severity and occurrence of first attacks in public. Future research should validate these findings using a longitudinal approach.