Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP.

Antidepressants demonstrate modest response rates in the treatment of major depressive disorder (MDD). Despite previous genome-wide association studies (GWAS) of antidepressant treatment response, the underlying genetic factors are unknown. Using prescription data in a population and family-based cohort (Generation Scotland: Scottish Family Health Study; GS:SFHS), we sought to define a measure of (a) antidepressant treatment resistance and (b) stages of antidepressant resistance by inferring antidepressant switching as non-response to treatment. GWAS were conducted separately for antidepressant treatment resistance in GS:SFHS and the Genome-based Therapeutic Drugs for Depression (GENDEP) study and then meta-analysed (meta-analysis n = 4213, cases = 358). For stages of antidepressant resistance, a GWAS on GS:SFHS only was performed (n = 3452). Additionally, we conducted gene-set enrichment, polygenic risk scoring (PRS) and genetic correlation analysis. We did not identify any significant loci, genes or gene sets associated with antidepressant treatment resistance or stages of resistance. Significant positive genetic correlations of antidepressant treatment resistance and stages of resistance with neuroticism, psychological distress, schizotypy and mood disorder traits were identified. These findings suggest that larger sample sizes are needed to identify the genetic architecture of antidepressant treatment response, and that population-based observational studies may provide a tractable approach to achieving the necessary statistical power.

Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland.

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 × 10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 × 10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 × 10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 × 10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 × 10-6). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 × 10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.

A validation of the diathesis-stress model for depression in Generation Scotland.

Depression has well-established influences from genetic and environmental risk factors. This has led to the diathesis-stress theory, which assumes a multiplicative gene-by-environment interaction (GxE) effect on risk. Recently, Colodro-Conde et al. empirically tested this theory, using the polygenic risk score for major depressive disorder (PRS, genes) and stressful life events (SLE, environment) effects on depressive symptoms, identifying significant GxE effects with an additive contribution to liability. We have tested the diathesis-stress theory on an independent sample of 4919 individuals. We identified nominally significant positive GxE effects in the full cohort (R2 = 0.08%, p = 0.049) and in women (R2 = 0.19%, p = 0.017), but not in men (R2 = 0.15%, p = 0.07). GxE effects were nominally significant, but only in women, when SLE were split into those in which the respondent plays an active or passive role (R2 = 0.15%, p = 0.038; R2 = 0.16%, p = 0.033, respectively). High PRS increased the risk of depression in participants reporting high numbers of SLE (p = 2.86 × 10-4). However, in those participants who reported no recent SLE, a higher PRS appeared to increase the risk of depressive symptoms in men (ß = 0.082, p = 0.016) but had a protective effect in women (ß = -0.061, p = 0.037). This difference was nominally significant (p = 0.017). Our study reinforces the evidence of additional risk in the aetiology of depression due to GxE effects. However, larger sample sizes are required to robustly validate these findings.

Genetic and environmental contributions to psychological resilience and coping.

Background: Twin studies indicate that genetic and environmental factors contribute to both psychological resilience and coping style, but estimates of their relative molecular and shared environmental contributions are limited. The degree of overlap in the genetic architectures of these traits is also unclear. Methods: Using data from a large population- and family-based cohort Generation Scotland (N = 8,734), we estimated the genetic and shared environmental variance components for resilience, task-, emotion-, and avoidance-oriented coping style in a linear mixed model (LMM). Bivariate LMM analyses were used to estimate the genetic correlations between these traits. Resilience and coping style were measured using the Brief Resilience Scale and Coping Inventory for Stressful Situations, respectively. Results: The greatest proportion of the phenotypic variance in resilience remained unexplained, although significant contributions from common genetic variants and family-shared environment were found. Both task- and avoidance-oriented coping had significant contributions from common genetic variants, sibling- and couple-shared environments, variance in emotion-oriented coping was attributable to common genetic variants, family- and couple-shared environments. The estimated correlation between resilience and emotion-oriented coping was high for both common-variant-associated genetic effects (r G = -0.79, se = 0.19), and for the additional genetic effects from the pedigree (r K = -0.94, se = 0.30). Genetic correlations between resilience and task- and avoidance-oriented coping did not meet statistical significance. Conclusions: Both genetics and shared environmental effects were major contributing factors to coping style, whilst the variance in resilience remains largely unexplained. Strong genetic overlap between resilience and emotion-oriented coping suggests a relationship whereby genetic factors that increase negative emotionality also lead to decreased resilience. We suggest that genome-wide family-based studies of resilience and coping may help to elucidate tractable methodologies to identify genetic architectures and modifiable environmental risk factors to protect against psychiatric illness, although further work with larger sample sizes is needed.

Genetic and environmental determinants of stressful life events and their overlap with depression and neuroticism.

Background: Stressful life events (SLEs) and neuroticism are risk factors for major depressive disorder (MDD). However, SLEs and neuroticism are heritable and genetic risk for SLEs is correlated with risk for MDD. We sought to investigate the genetic and environmental contributions to SLEs in a family-based sample, and quantify genetic overlap with MDD and neuroticism. Methods: A subset of Generation Scotland: the Scottish Family Health Study (GS), consisting of 9618 individuals with information on MDD, past 6 month SLEs, neuroticism and genome-wide genotype data was used in the present study. We estimated the heritability of SLEs using GCTA software. The environmental contribution to SLEs was assessed by modelling familial, couple and sibling components. Using polygenic risk scores (PRS) and LD score regression (LDSC) we analysed the genetic overlap between MDD, neuroticism and SLEs. Results: Past 6-month life events were positively correlated with lifetime MDD status (ß=0.21, r 2=1.1%, p=2.5 x 10 -25) and neuroticism (ß =0.13, r 2=1.9%, p=1.04 x 10 -37) at the phenotypic level.  Common SNPs explained 8% of the phenotypic variance in personal life events (those directly affecting the individual) (S.E.=0.03, p= 9 x 10 -4). A significant effect of couple environment was detected accounting for 13% (S.E.=0.03, p=0.016) of the phenotypic variation in SLEs. PRS analyses found that reporting more SLEs was associated with a higher polygenic risk for MDD (ß =0.05, r 2=0.3%, p=3 x 10 -5), but not a higher polygenic risk for neuroticism. LDSC showed a significant genetic correlation between SLEs and both MDD (r G=0.33, S.E.=0.08 ) and neuroticism (r G=0.15, S.E.=0.07). Conclusions: These findings suggest that SLEs should not be regarded solely as environmental risk factors for MDD as they are partially heritable and this heritability is shared with risk for MDD and neuroticism. Further work is needed to determine the causal direction and source of these associations.

Affective enhancement of working memory is maintained in depression.

We currently know little about how performance on assessments of working memory capacity (WMC) that are designed to mirror the concurrent task demands of daily life are impacted by the presence of affective information, nor how those effects may be modulated by depression-a syndrome where sufferers report global difficulties with executive processing. Across 3 experiments, we investigated WMC for sets of neutral words in the context of processing either neutral or affective (depressogenic) sentences, which had to be judged on semantic accuracy (Experiments 1 and 2) or self-reference (Experiment 3). Overall, WMC was significantly better in the context of depressogenic compared with neutral sentences. However, there was no support for this effect being modulated by symptoms of depression (Experiment 1) or the presence of recurrent major depressive disorder (MDD; Experiments 2 and 3). Implications of these findings for cognitive theories of the role of WM in depression are discussed in the context of a growing body of research showing no support for a differential impact of depressogenic compared with neutral information on WM accuracy. (PsycINFO Database Record

Self-reported medication use validated through record linkage to national prescribing data.

OBJECTIVES: Researchers need to be confident about the reliability of epidemiologic studies that quantify medication use through self-report. Some evidence suggests that psychiatric medications are systemically under-reported. Modern record linkage enables validation of self-report with national prescribing data as gold standard. Here, we investigated the validity of medication self-report for multiple medication types. STUDY DESIGN AND SETTING: Participants in the Generation Scotland population-based cohort (N = 10,244) recruited 2009-2011 self-reported regular usage of several commonly prescribed medication classes. This was matched against Scottish NHS prescriptions data using 3- and 6-month fixed time windows. Potential predictors of discordant self-report, including general intelligence and psychological distress, were studied via multivariable logistic regression. RESULTS: Antidepressants self-report showed very good agreement (κ = 0.85, [95% confidence interval (CI) 0.84-0.87]), comparable to antihypertensives (κ = 0.90 [CI 0.89-0.91]). Self-report of mood stabilizers showed moderate-poor agreement (κ = 0.42 [CI 0.33-0.50]). Relevant past medical history was the strongest predictor of self-report sensitivity, whereas general intelligence was not predictive. CONCLUSION: In this large population-based study, we found self-report validity varied among medication classes, with no simple relationship between psychiatric medication and under-reporting. History of indicated illness predicted more accurate self-report, for both psychiatric and nonpsychiatric medications. Although other patient-level factors influenced self-report for some medications, none predicted greater accuracy across all medications studied.

Moral Chivalry: Gender and Harm Sensitivity Predict Costly Altruism.

Moral perceptions of harm and fairness are instrumental in guiding how an individual navigates moral challenges. Classic research documents that the gender of a target can affect how people deploy these perceptions of harm and fairness. Across multiple studies, we explore the effect of an individual's moral orientations (their considerations of harm and justice) and a target's gender on altruistic behavior. Results reveal that a target's gender can bias one's readiness to engage in harmful actions and that a decider's considerations of harm-but not fairness concerns-modulate costly altruism. Together, these data illustrate that moral choices are conditional on the social nature of the moral dyad: Even under the same moral constraints, a target's gender and a decider's gender can shift an individual's choice to be more or less altruistic, suggesting that gender bias and harm considerations play a significant role in moral cognition.

What we say and what we do: the relationship between real and hypothetical moral choices.

Moral ideals are strongly ingrained within society and individuals alike, but actual moral choices are profoundly influenced by tangible rewards and consequences. Across two studies we show that real moral decisions can dramatically contradict moral choices made in hypothetical scenarios (Study 1). However, by systematically enhancing the contextual information available to subjects when addressing a hypothetical moral problem-thereby reducing the opportunity for mental simulation-we were able to incrementally bring subjects' responses in line with their moral behaviour in real situations (Study 2). These results imply that previous work relying mainly on decontextualized hypothetical scenarios may not accurately reflect moral decisions in everyday life. The findings also shed light on contextual factors that can alter how moral decisions are made, such as the salience of a personal gain.