Associations of Leisure-Time and Occupational Physical Activity and Cardiorespiratory Fitness With Incident and Recurrent Major Depressive Disorder, Depressive Symptoms, and Incident Anxiety in a General Population.

OBJECTIVE: Physical activity and cardiorespiratory fitness may help prevent depression and anxiety. Previous studies have been limited by error-prone measurements. We examined whether self-reported physical activity domains and peak exercise capacity (peakVO2) are associated with incident and recurrent major depressive disorder (MDD), depressive symptoms, and anxiety disorders. METHODS: This was a prospective population-based study of 1,080 adult men and women (25-83 years) with a median follow-up of 4.5 years and measures of physical activity during leisure time, sports, and work (Baecke questionnaire); a measure of depressive symptoms (Beck Depression Inventory II); symptom-limited cycle ergometer testing (peakVO2, oxygen uptake at anaerobic threshold [VO2@AT], maximum power output at peak exertion); and a structured psychiatric interview (Munich Composite International Diagnostic Interview). Baseline data were collected between 2002 and 2006, and follow-up data, between 2007 and 2010. RESULTS: After adjustment for age, sex, education, smoking, alcohol consumption, and waist circumference, the relative risks for incident MDD per standard deviation (SD) increase in leisure-time physical activity, physical activity during sport, physical activity at work, peakVO2, VO2@AT, and maximum power output were 1.002 (95% confidence interval, 0.90 to 1.12), 1.02 (0.90 to 1.15), 0.94 (0.80 to 1.10), 0.71 (0.52 to 0.98), 0.83 (0.66 to 1.04), and 0.71 (0.52 to 0.96), respectively. PeakVO2, VO2@AT, and maximum power output were associated with recurrent MDD, depressive symptoms, and anxiety. PeakVO2 was more strongly related to the co-occurrence of MDD and anxiety (adjusted odds ratio [OR] = 0.45 [0.24 to 0.84]) than depression or anxiety alone (OR = 0.71 [0.53 to 0.94]). CONCLUSIONS: Greater cardiorespiratory fitness but not domain-specific physical activity was associated with a lower incidence of MDD and clinical anxiety.

Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium.

Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.

Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder.

IMPORTANCE: Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63,000 participants (including MDD cases). OBJECTIVES: To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD. DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014. MAIN OUTCOMES AND MEASURES: Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts. RESULTS: A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12 < P < .05) and MDD (4.02 × 10-9 < P < .05) in the 2 other cohorts. CONCLUSIONS AND RELEVANCE: This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.

Diagnosed thyroid disorders are associated with depression and anxiety.

PURPOSE: Associations between thyroid diseases and depression have been described since the 1960s but there is a lack of population-based studies investigating associations of thyroid diseases with depression and anxiety defined by gold-standard methods. Thus, the aim was to investigate the association of diagnosed thyroid disorders, serum thyroid-stimulating hormone (TSH) levels, and anti-thyroid-peroxidase antibodies (TPO-abs) with depression and anxiety. METHODS: We used data from 2142 individuals, who participated in the first follow-up of the Study of Health in Pomerania (SHIP-1) and in the Life-Events and Gene-Environment Interaction in Depression (LEGEND). DSM-VI diagnoses of major depression disorder and anxiety were defined using the Munich-Composite International Diagnostic Interview; the Beck depression inventory (BDI-II) was used for the assessment of current depressive symptoms. Thyroid diseases were assessed by interviews and by biomarkers and were associated with depression and anxiety using Poisson regression adjusted for age, sex, marital status, educational level, smoking status, BMI, and the log-transformed time between SHIP-1 and LEGEND. RESULTS: Untreated diagnosed hypothyroidism was positively associated with the BDI-II-score and with anxiety, while untreated diagnosed hyperthyroidism was significantly related to MDD during the last 12 months. Serum TSH levels and TPO-Abs were not significantly associated with depression and anxiety. In sub-analyses, distinct interactions were found between childhood maltreatment and thyroid disorders in modifying the association on depression and anxiety disorders. CONCLUSIONS: Our results substantiate evidence that diagnosed untreated hypothyroidism is associated with depression and anxiety, and that diagnosed untreated hyperthyroidism is associated with depression.

Neuroticism developmental courses--implications for depression, anxiety and everyday emotional experience; a prospective study from adolescence to young adulthood.

BACKGROUND: Neuroticism is frequently discussed as a risk factor for psychopathology. According to the maturity principle, neuroticism decreases over the course of life, but not uniformly across individuals. However, the implications of differences in personality maturation on mental health have not been well studied so far. Hence, we hypothesized that different forms of neuroticism development from adolescence to young adulthood are associated with differences in depression, anxiety and everyday emotional experience at the age of 25. METHODS: A sample of 266 adolescents from the general population was examined three times over ten years (age at T0: 15, T1: 20 and T2: 25) using questionnaires, interviews and ecological momentary assessment (EMA). At all measurement points, neuroticism was assessed with the NEO inventory. At T2, diagnoses of major depression and anxiety disorders were captured with a structured clinical interview (M-CIDI). Phone-based EMA was used to assess emotional experience and affective instability over a two-week period at T2. RESULTS: The best fitting model was a latent class growth analysis with two groups of neuroticism development. Most individuals (n = 205) showed moderate values whereas 61 participants were clustered into a group with elevated neuroticism levels. In both groups neuroticism significantly changed during the ten year period with a peak at the age of 20. Individuals with a higher absolute level were at 14-fold increased risk for depression and 7-fold risk for anxiety disorders at the age of 25. In EMA, increased negative affect and arousal as well as decreased positive emotions were found in this high group. CONCLUSIONS: Other than expected, personality did not mature in our sample. However, there was a significant change of neuroticism values from adolescence to young adulthood. Further, over 20% of our participants showed a neuroticism development which was associated with adverse outcomes such as negatively toned emotional experience and a heightened risk to suffer from depressive and anxiety disorders in young adulthood. These high-risk persons need to be identified early to provide interventions supporting continuous personality maturation.

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.

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.

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data.

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

Borderline personality disorder in four different age groups: a cross-sectional study of community residents in Germany.

Studies examining the natural course of borderline personality disorder (BPD) over the life span have yielded declining prevalence rates in older age groups. However, there is evidence that different BPD symptoms have different longitudinal patterns, with impulsivity decreasing with advancing age and negative affect remaining stable into late adulthood. However, since all studies dealt with treated, clinical samples of BPD patients, it is not yet known whether this represents the natural course of BPD symptoms or just mirrors difference in treatability of these symptoms. The authors addressed this issue by investigating a nonclinical population and compared prevalence of BPD, impulsivity, and depressivity in various age groups from adolescence to late adulthood (N = 2,488); all individuals were assessed by standardized clinical interviews. Syndromal and subsyndromal BPD rates sharply decreased between adolescents and young adults and remained stable thereafter. Whereas the same course was found for impulsivity, depressivity increased between young, middle-aged, and older adults. The present results support the hypothesis that age-related decreases in BPD diagnosis might be attributable to declining levels of impulsivity, whereas the persistence of a subsyndromal BPD might be attributable to an enduring negative affect.

Personality-related factors as predictors of help-seeking for depression: a population-based study applying the Behavioral Model of Health Services Use.

BACKGROUND: Although the prevalence of mental disorders and the demand for mental health services are increasing, little is known about the impact of personality-related factors on help-seeking among depressive individuals. We, therefore, investigated the relationship between the "Big Five" personality traits, resilience, alexithymia, childhood neglect or abuse, and help-seeking among depressive individuals. METHODS: We used data from 354 persons with a diagnosis of major depression from the population-based cohort study of health in Pomerania within the theoretical framework of the Andersen Behavioral Model of Health Services Use. RESULTS: Using stepwise regression techniques, we found that older age, higher education, more perceived social support, presence of childhood abuse, higher levels of conscientiousness, lower levels of resilience, and more severe depression were associated with help-seeking for depression. In contrast, gender, extraversion, openness, agreeableness, neuroticism, and alexithymia did not significantly predict help-seeking. In addition, no evidence for gender-specific effects was observed. CONCLUSION: Personality-related predisposing factors are important predictors of help-seeking. The influence of resilience on help-seeking among depressed individuals merits further exploration.

Identification of common variants associated with human hippocampal and intracranial volumes.

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).

[A brief instrument for the assessment of childhood abuse and neglect: the childhood trauma screener (CTS)]. / Ein Screeninginstrument für Missbrauch und Vernachlässigung in der Kindheit: der Childhood Trauma Screener (CTS).

OBJECTIVE: There is a lack of a psychometrically sound screening questionnaire that assesses important dimensions of traumatic experiences during childhood and adolescence in a time-efficient way. Based on the German version of the "Childhood Trauma Questionnaire" (CTQ, 28 items) we developed a five-item self-report childhood trauma screener (CTS) that covers sexual, emotional and physical abuse and emotional and physical neglect. METHOD: The data set of the SHIP-LEGEND study (n = 1668) was used to extract five items of the CTQ that optimally covered the five dimensions and showed a high correlation with the total score. In two validation samples (clinical sample [n = 211] and subjects from the BiDirect study [n = 288]) the psychometric properties of the CTS were evaluated. RESULTS: The correlations between the five CTS Items and the corresponding dimensions from the CTQ were r = 0.55 to 0.87 (p < 0.0001) within the clinical sample. Furthermore, we found high correlations (r = 0.88; p < 0.0001) with the total CTQ score. The internal consistency was 0.757 (Cronbachs α). CONCLUSION: The CTS is a reliable, valid and economic screener for the retrospective assessment of adverse childhood experiences especially in large epidemiological studies.

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.

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 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. © 2010 Wiley-Liss, Inc.