Hans J. Grabe

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.

Serotonin transporter gene (SLC6A4) promoter polymorphisms and the susceptibility to posttraumatic stress disorder in the general population.

OBJECTIVE There has been debate whether polymorphisms within the serotonin transporter-linked polymorphic region (5-HTTLPR) moderate susceptibility to posttraumatic stress disorder (PTSD). The authors investigated 5-HTTLPR genotypes and their interaction with the number of traumatic events in the prediction of PTSD in a general population sample. METHOD Analyses were based on data from 3,045 subjects who participated in the Study of Health in Pomerania. All participants were assessed with the PTSD module of the Structured Clinical Interview for DSM-IV. The short (S)/long (L) polymorphism of 5-HTTLPR (rs4795541) and the A-G polymorphism (rs25531) were genotyped. RESULTS Among the participants, 1,663 had been exposed to at least one traumatic event, and 67 (4.0%) developed PTSD. Among those who had experienced less than three traumatic events, the lifetime prevalence of PTSD was 2.6%, 3.5%, and 4.3% for those with zero, one, and two L(A) alleles, respectively, but the lifetime prevalence was 0%, 7.3%, and 19.6%, respectively, among those with three or more traumatic experiences. This finding suggests that there is an additive excess risk for frequent trauma in the L(A)/L(A) genotype, which was confirmed by the relative excess risk due to interaction (RERI). In allelic analysis, RERI was 3.3. Thus, the odds ratio for PTSD in L(A) allele carriers exposed to three or more traumas was 3.3 times higher as a result of the interaction between PTSD and the L(A) allele. CONCLUSIONS An additive gene-environment interaction with the high expression L(A) allele of 5-HTTLPR and frequent trauma in PTSD was found. The attributable proportion indicated that more than 60% of all L(A) allele carriers who were exposed to three or more traumas developed PTSD as a result of an interaction between genotype and exposure.

A Genome-Wide Association Study of Depressive Symptoms

BACKGROUND Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. RESULTS The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258). CONCLUSIONS The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

Minimization of childhood maltreatment is common and consequential: results from a large, multinational sample using the childhood trauma questionnaire

Childhood maltreatment has diverse, lifelong impact on morbidity and mortality. The Childhood Trauma Questionnaire (CTQ) is one of the most commonly used scales to assess and quantify these experiences and their impact. Curiously, despite very widespread use of the CTQ, scores on its Minimization-Denial (MD) subscale—originally designed to assess a positive response bias—are rarely reported. Hence, little is known about this measure. If response biases are either common or consequential, current practices of ignoring the MD scale deserve revision. Therewith, we designed a study to investigate 3 aspects of minimization, as defined by the CTQ’s MD scale: 1) its prevalence; 2) its latent structure; and finally 3) whether minimization moderates the CTQ’s discriminative validity in terms of distinguishing between psychiatric patients and community volunteers. Archival, item-level CTQ data from 24 multinational samples were combined for a total of 19,652 participants. Analyses indicated: 1) minimization is common; 2) minimization functions as a continuous construct; and 3) high MD scores attenuate the ability of the CTQ to distinguish between psychiatric patients and community volunteers. Overall, results suggest that a minimizing response bias—as detected by the MD subscale—has a small but significant moderating effect on the CTQ’s discriminative validity. Results also may suggest that some prior analyses of maltreatment rates or the effects of early maltreatment that have used the CTQ may have underestimated its incidence and impact. We caution researchers and clinicians about the widespread practice of using the CTQ without the MD or collecting MD data but failing to assess and control for its effects on outcomes or dependent variables.

Depressive and Anxiety Symptoms as Risk Factors for Temporomandibular Joint Pain: A Prospective Cohort Study in the General Population

UNLABELLED Previous studies have associated depression and temporomandibular joint disorders (TMDs). The temporality, however, remains to be clarified. Most patient studies have selected subjects from treatment facilities, whereas in epidemiological studies a clinical examination has not been performed. In this study the 5-year follow-up data of the population-based Study of Health in Pomerania (SHIP) were analyzed. To estimate the effect of symptoms of depression and those of anxiety on the risk of TMD pain, the Composite International Diagnostic-Screener (CID-S) and a clinical functional examination with palpation of the temporomandibular joint and the masticatory muscles were used. After exclusion of subjects having joint pain at baseline, a sample of 3,006 Caucasian participants with a mean age of 49 years resulted. Of those, 122 participants had signs of TMD joint pain upon palpation. Subjects with symptoms of depression had an increased risk of TMD joint pain upon palpation (rate ratio: 2.1; 95% confidence interval: 1.5-3.0; P < .001). Anxiety symptoms were associated with joint and with muscle pain. The diagnosis, prevention, and therapy of TMD pain should also consider symptoms of depression and those of anxiety, and appropriate therapies if necessary. PERSPECTIVE Depressive and anxiety symptoms should be considered as risk factors for TMD pain. Depressive symptoms are specific for joint pain whereas anxiety symptoms are specific for muscle pain, findings that deserve detailed examination. These findings may support decision-making in treating TMD.

Current Smoking and Reduced Gray Matter Volume—a Voxel-Based Morphometry Study

Nicotine modulates prefrontal processing when tested with functional imaging. Previous studies on changes in regional brain volumes in small samples, reporting different life-time exposure to nicotine, identified reduced volume in smokers in prefrontal areas but reported controversial results for other areas. We investigated the association of cigarette smoking and regional gray and white matter volume by using voxel-based morphometry (VBM) for T1-weighted high-resolution magnetic resonance imaging in 315 current-smokers and 659 never-smokers from the representative Study of Health in Pomerania (SHIP). Our study showed that in current-smokers smoking is significantly associated with gray matter volume loss in the prefrontal cortex, the anterior cingulate cortex, the insula, and the olfactory gyrus. White matter volumes were not relevantly reduced in current-smokers. In current-smokers, we found associations of gray matter loss and smoking exposure (pack-years) in the prefrontal cortex, the anterior and middle cingulate cortex, and the superior temporal and angular gyrus, which however did not stand corrections for multiple testing. We confirmed associations between smoking and gray matter differences in the prefrontal cortex, the anterior cingulate cortex and the insula in the general population of Pomerania (Germany). For the first time, we identified differences in brain volumes in the olfactory gyrus. Other cerebral regions did not show significant differences when correcting for multiple comparisons within the whole brain. The regions of structural deficits might be involved in addictive behavior and withdrawal symptoms, whereas further investigations have to show if the observed atrophies were caused by smoking itself or are preexisting differences between smoking and non-smoking individuals.

Association of Childhood Neglect with Adult Dissociation in Schizophrenic Inpatients

Background: Dissociation is often related to previous trauma and also occurs frequently in schizophrenia. Dissociation and psychosis may reflect a posttraumatic syndrome in some patients with schizophrenia. Sampling and Methods: In total, 80 patients diagnosed with schizophrenia were investigated by means of the Childhood Trauma Questionnaire (CTQ), the Dissociative Experience Scale and the Symptom Check List 90-R. CTQ subscales and groups reporting high and low dissociation were compared using MANOVA. Results: Childhood traumatic experiences were frequent [mean CTQ total score = 45.4 ± 17.5 (SD)]. Physical neglect was clearly associated with high dissociation, whereas abuse was not. Furthermore, there was a significant association of physical neglect with psychopathological distress not fully accounted for by dissociation. Conclusions: Dissociation may be specifically linked to childhood physical neglect in patients diagnosed with schizophrenia. Dissociation alone may not explain the effects of childhood maltreatment on adult psychopathology in schizophrenia; however, conclusions from the present study are limited due to its cross-sectional design.

Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Background Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. Methods Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer’s disease, and coronary artery disease. Results We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11–1.21, p = 5.2 × 10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. Conclusions We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.

Menopause and determinants of quality of life in women at midlife and beyond: the study of health in pomerania (SHIP).

Objective: Determinants of quality of life (QoL) in pre- and postmenopausal women including nonhormonal modulators of QoL in adult women are not well understood; there is an ongoing controversy about the impact of menopause on health-related QoL. We investigated the extent to which diverse mental and physical symptoms are associated with (a) menopausal status; (b) sociodemographic, psychosocial, and lifestyle factors; and (c) menopausal hormone therapy (MHT) in adult women after the German reunification in a region of the former German Democratic Republic. Design: The Study of Health in Pomerania is a cross-sectional, population-based survey. Computer-based structured interviews and self-administered questionnaires were used to capture QoL (Zerssen Symptom List) and sociodemographic parameters, psychosocial, and lifestyle indicators (age, socioeconomic status, abuse, social support, nutrition, body mass index, self-rated health, chronic diseases, and use of MHT) in 1,119 pre- and postmenopausal women with an intact uterus. Results: Analyses suggest that menopausal status was not associated with QoL. MHT was associated with physical, mental, and gastrointestinal symptoms. Age was a significant predictor for cardiopulmonary symptoms and sensory impairment. The relationship between age and both physical and mental complaints was inverse as was the relationship between age and both mood and gastrointestinal symptoms. Age, socioeconomic status, physical and sexual abuse, perceived social support, nutrition, body mass index, self-rated health, chronic diseases, and MHT modulated QoL. Conclusions: Our findings do not support the hypothesis that QoL is reduced after menopause. Differences between pre- and postmenopausal women can be explained by sociodemographic, psychosocial, and lifestyle factors.

Age- and Sex-Specific Reference Intervals Across Life Span for Insulin-Like Growth Factor Binding Protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 Ratio Measured by New Automated Chemiluminescence Assays

CONTEXT Measurement of IGF-binding protein-3 (IGFBP-3) can aid the diagnosis of GH-related diseases. Furthermore, epidemiological studies suggest that IGFBP-3 and the molar IGF-I to IGFBP-3 ratio are associated with clinical end points like cancer or cardiovascular disease. However, their clinical use is limited by the lack of validated reference intervals. OBJECTIVE The objective of the study was the establishment of age- and sex-specific reference intervals for IGFBP-3 and the molar IGF-I to IGFBP-3 ratio by newly developed automated immunoassays. SETTING This was a multicenter study with samples from 11 cohorts from the United States, Canada, and Europe. PARTICIPANTS A total of 14 970 healthy subjects covering all ages from birth to senescence participated in the study. MAIN OUTCOME MEASURES Concentrations of IGFBP-3 and the IGF-I to IGFBP-3 ratio as determined by the IDS iSYS IGF-I and IGFBP-3 assays were measured. RESULTS Both the concentration of IGFBP-3 and the IGF-I to IGFBP-3 ratio are mainly determined by age. IGFBP-3 concentrations increase until the age of 22 years, with a plateau being visible between 15 and 25 years. Determined by the high peripubertal peak in IGF-I, the peak in the IGF-I to IGFBP-3 ratio occurs already around the age of 15 years, with a slightly earlier and higher peak in females. Beyond the age of 60 years, IGFBP-3 concentrations remain higher in females, whereas IGF-I as well as the IGF-I to IGFBP-3 ratio remains significantly higher in males. CONCLUSIONS We present an extensive set of assay-specific age- and sex-adjusted normative data for concentrations of IGFBP-3 and the molar IGF-I to IGFBP-3 ratio and demonstrate distinct sex specific differences across the life span.