Biological Determinants of Depression: An epidemiological approach

Understanding the biology behind depression has a long history in research. To date, no unique marker or specific etiological factor was detected. However, we know more about the possible mechanisms that predispose depression or affect clinical presentation and prognosis of depression. In this thesis, we studied various hypotheses to extend our knowledge about biological determinants of depression using an epidemiological approach. The main aims of this thesis were 1) to scrutinize the determinants and the genetic control of different functions of the HPA axis, a well-known neurohormonal correlate of depression, 2) to revisit the vascular depression hypothesis and explored the associations of non-clinical cerebrovascular alterations with depression, and 3) to explore genetic etiology of depression using the genome-wide association approach

Sleep and 24-h activity rhythms in relation to cortisol change after a very low-dose of dexamethasone

The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in sleep. Nevertheless, the association of sleep and its 24-h organization with negative feedback control of the HPA axis has received limited attention in population-based studies. We explored this association in 493 mid

The very low-dose dexamethasone suppression test in the general population: A cross-sectional study

Determinants of the hypothalamic-pituitary-adrenal (HPA) axis functioning are increasingly explored in population-based studies. However, functional tests measuring the negative feedback of the HPA axis cannot easily be implemented into large observational studies. Furthermore, high doses of dexamethasone often completely suppress the HPA axis in healthy persons. This study aimed to detect the effects of the health, lifestyle and sociodemographic factors, psychiatric problems and cognitive functions on the negative feedback of the HPA axis using a very low-dose (0.25 mg) dexamethasone suppression test (DST). We evaluated the associations of several determinants with the saliva cortisol concentrations after dexamethasone intake in a confounder-adjusted model also corrected for baseline saliva cortisol concentrations in the Rotterdam Study, a large population-based study (N = 1822). We found that female sex, low income, lack of exercise, instrumental disability and smoking were all independently associated with stronger suppression of the HPA axis. Even though there were no linear associations between psychiatric measures and cortisol suppression, we found that depressive symptoms and anxiety disorders were more common in persons with non-suppression of cortisol. Conversely, psychotropic medication use was related to enhanced suppression of cortisol after DST. In this large study, we found that female gender, low socioeconomic status and poor health were all related to suppression of the HPA axis. Non-linear associations were detected between the suppression of the HPA axis and common psychiatric disorders in community-dwelling persons

Anxiety disorders and salivary cortisol levels in older adults: A population-based study

Context: The hypothalamic-pituitary-adrenal (HPA) axis is one of the body's main systems that controls response to stress. It acts through the hormone cortisol. While the dysregulation of cortisol has been associated with anxiety disorders, the evidence is inconsistent. Moreover, only a few small studies have assessed this relationship in older adults. Objective: To determine whether in adults aged 65 years and over there is a difference in daily cortisol pattern between those with and without an anxiety disorder. Methods: The study population comprised 1788 older adults from a population-based cohort. The Munich version of the Composite International Diagnostic Interview was used to diagnose anxiety disorders (generalized anxiety disorder, social phobia, specific phobia, agoraphobia and panic disorder). The cortisol awakening response and total cortisol secretion over the day were calculated from cortisol levels in four saliva samples taken over the course of one day (at awakening, 30. min after awakening, at 1700. h, at bedtime). Results: Older adults with an anxiety disorder (n=145, median duration since first symptoms 41 years) had a lower cortisol awakening response (p=0.02) than those without such a disorder (n=1643). This association was most prominent in those with generalized anxiety disorder (p=0.008), but was not associated with the extent of chronicity of anxiety disorders. Conclusion: Older adults from the general population with long-lasting anxiety disorders had a lower cortisol awakening response than those without. This is consistent with the notion that chronic anxiety may result in downregulation of HPA-axis activity. Longitudinal studies are needed to confirm this mechanism

An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

AbstractBackgroundThe genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.MethodsWe analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.ResultsThe SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10–9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10–9).ConclusionsThis large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (P = 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association

Hair Cortisol in Twins : Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

A. Palotie on työryhmän jäsen.Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.Peer reviewe