Common and specific determinants of 9-year depression and anxiety course-trajectories: a machine-learning investigation in the Netherlands Study of Depression and Anxiety (NESDA)

Background: Given the strong relationship between depression and anxiety, there is an urge to investigate their shared and specific long-term course determinants. The current study aimed to identify and compare the main determinants of the 9-year trajectories of combined and pure depression and anxiety symptom severity. Methods: Respondents with a 6-month depression and/or anxiety diagnosis (n=1,701) provided baseline data on 152 sociodemographic, clinical and biological variables. Depression and anxiety symptom severity assessed at baseline, 2-, 4-, 6- and 9-year follow-up, were used to identify data-driven course-trajectory subgroups for general psychological distress, pure depression, and pure anxiety severity scores. For each outcome (classprobability), a Superlearner (SL) algorithm identified an optimally weighted (minimum mean squared error) combination of machine-learning prediction algorithms. For each outcome, the top determinants in the SL were identified by determining variable-importance and correlations between each SL-predicted and observed outcome (rho pred) were calculated. Results: Low to high prediction correlations (rho pred: 0.41-0.91, median=0.73) were found. In the SL, important determinants of psychological distress were age, young age of onset, respiratory rate, participation disability, somatic disease, low income, minor depressive disorder and mastery score. For course of pure depression and anxiety symptom severity, similar determinants were found. Specific determinants of pure depression included several types of healthcare-use, and of pure-anxiety course included somatic arousal and psychological distress. Limitations: Limited sample size for machine learning. Conclusions: The determinants of depression- and anxiety-severity course are mostly shared. Domain-specific exceptions are healthcare use for depression and somatic arousal and distress for anxiety-severity course.Stress-related psychiatric disorders across the life spa

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

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs.Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.Molecular Epidemiolog

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

The genetics of the mood disorder spectrum:genome-wide association analyses of over 185,000 cases and 439,000 controls

Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. Methods To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell-types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum

Predicting the naturalistic course of depression from a wide range of clinical, psychological, and biological data: a machine learning approach

Contains fulltext : 208597.pdf (publisher's version ) (Open Access)Many variables have been linked to different course trajectories of depression. These findings, however, are based on group comparisons with unknown translational value. This study evaluated the prognostic value of a wide range of clinical, psychological, and biological characteristics for predicting the course of depression and aimed to identify the best set of predictors. Eight hundred four unipolar depressed patients (major depressive disorder or dysthymia) patients were assessed on a set involving 81 demographic, clinical, psychological, and biological measures and were clinically followed-up for 2 years. Subjects were grouped according to (i) the presence of a depression diagnosis at 2-year follow-up (yes n = 397, no n = 407), and (ii) three disease course trajectory groups (rapid remission, n = 356, gradual improvement n = 273, and chronic n = 175) identified by a latent class growth analysis. A penalized logistic regression, followed by tight control over type I error, was used to predict depression course and to evaluate the prognostic value of individual variables. Based on the inventory of depressive symptomatology (IDS), we could predict a rapid remission course of depression with an AUROC of 0.69 and 62% accuracy, and the presence of an MDD diagnosis at follow-up with an AUROC of 0.66 and 66% accuracy. Other clinical, psychological, or biological variables did not significantly improve the prediction. Among the large set of variables considered, only the IDS provided predictive value for course prediction on an individual level, although this analysis represents only one possible methodological approach. However, accuracy of course prediction was moderate at best and further improvement is required for these findings to be clinically useful

[Behavioural standard or coercive measure? Some considerations regarding the special issue on ROM]

BACKGROUND: The cost of mental health care has possibly risen more than costs in other sectors of health care in the Netherlands. In an attempt to control the rising costs, new policies have been implemented that include the introduction of selective financial penalties for those in need of mental health care as well as the start of performance-based mental health care reimbursement. In order to achieve the latter goal, a nation-wide large-scale data collection was introduced based on clinical routine outcome monitoring (ROM) data, with a view to using these data for benchmarking. AIM: Closer inspection of the benchmarking efforts in terms of scientific validity. METHOD: Qualitative review and analysis. RESULTS: Analysis shows that the type of ROM data that is collected in the Netherlands is valid for tracking the outcomes of individual patients, but unsuitable for performance comparisons between institutions for reasons of case-mix, instrument-mix, bias and lack of sensitivity. CONCLUSION: Attempts to introduce benchmarking based on rom will probably have a negative impact on the practice of mental health care in the Netherlands. More input from mental health professionals and scientists is required in order to identify more rational and efficient ways of spending scarce resources

[Behavioural standard or coercive measure? Some considerations regarding the special issue on ROM]

BACKGROUND: The cost of mental health care has possibly risen more than costs in other sectors of health care in the Netherlands. In an attempt to control the rising costs, new policies have been implemented that include the introduction of selective financial penalties for those in need of mental health care as well as the start of performance-based mental health care reimbursement. In order to achieve the latter goal, a nation-wide large-scale data collection was introduced based on clinical routine outcome monitoring (ROM) data, with a view to using these data for benchmarking. AIM: Closer inspection of the benchmarking efforts in terms of scientific validity. METHOD: Qualitative review and analysis. RESULTS: Analysis shows that the type of ROM data that is collected in the Netherlands is valid for tracking the outcomes of individual patients, but unsuitable for performance comparisons between institutions for reasons of case-mix, instrument-mix, bias and lack of sensitivity. CONCLUSION: Attempts to introduce benchmarking based on rom will probably have a negative impact on the practice of mental health care in the Netherlands. More input from mental health professionals and scientists is required in order to identify more rational and efficient ways of spending scarce resources

Does Childhood Trauma Moderate Polygenic Risk for Depression? A Meta-analysis of 5765 Subjects From the Psychiatric Genomics Consortium

Background: The heterogeneity of genetic effects on major depressive disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRSs) and CT, albeit in opposing directions. This study aims to meta-analyze MDD-PRS × CT interaction results across these two and other cohorts, while applying more accurate PRSs based on a larger discovery sample. Methods: Data were combined from 3024 MDD cases and 2741 control subjects from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD-PRS were based on a discovery sample of ∼110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 control subjects, a more detailed five-domain measure additionally included emotional abuse, physical neglect, and emotional neglect. Results: MDD was associated with the MDD-PRS (odds ratio [OR] = 1.24, p = 3.6 × 10−5, R2 = 1.18%) and with CT (OR = 2.63, p = 3.5 × 10−18 and OR = 2.62, p = 1.4 ×10−5 for the two- and five-domain measures, respectively). No interaction was found between MDD-PRS and the two-domain and five-domain CT measure (OR = 1.00, p =.89 and OR = 1.05, p =.66). Conclusions: No meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT