DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment.

Epigenetic alterations are regarded as a potential mechanism mediating the effects of environmental risk factors on vulnerability for a range of mental health problems. Recent studies have addressed the question whether DNA methylation patterns predict the outcome of psychological interventions and whether treatment effects might be associated with changes of DNA methylation. We assessed phobic fear symptoms, treatment-relevant traits and treatment response in 308 adults free of psychotropic medication - highly fearful of either spiders, blood-injury-injections, dental-treatments or heights - all subjected to highly standardized exposure-based one-session fear treatment. DNA methylation level of the promotor region of the serotonin transporter gene (SLC6A4) was assessed in either saliva samples (spider and dental treatment fear cohorts) or oral mucosa (BII, heights) to check whether possible effects are independent of the surrogate tissue examined. Moreover, in order to examine possible DNA methylation by genotype effects, patients were assessed for genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR). DNA methylation levels were neither associated with pre-treatment fear levels, treatment relevant traits or treatment outcome data even when allelic variation of the 5HTTLPR was considered. Overall DNA methylation levels were higher in saliva samples compared to buccal samples. In saliva samples there was a small pre- to post-treatment increase in DNA methylation, which, however, was also not associated with the investigated phenotypes. We conclude that DNA methylation of SLC6A4 is no suitable biomarker for response efficacy to highly standardized one-session exposure-based fear treatments.

Risk and protective factors of mental health in children in residential care: A nationwide study from Luxembourg.

BACKGROUND: Children who grow up in residential care are at high risk for mental health problems. Existing studies have focused on negative mental health indicators and risk factors. There has been less emphasis on identifying protective factors, particularly those associated with positive mental health outcomes. OBJECTIVE: This study explores positive and negative dimensions of mental health and their links to risk and protective factors in children who have experienced early adversity and trauma and have been placed in residential care. PARTICIPANTS AND SETTINGS: Children aged 11 to 18 (N = 264) were recruited from residential care homes in Luxembourg, a small, high-income European country. METHODS: The children completed self-report questionnaires on mental health, perceived stress, school pressure, and participation. Residential care workers provided information on demographic factors, developmental and care history, and pre-care experiences of early adversity and trauma. RESULTS: Confirmatory factor analysis indicated that subjective well-being, internalising problems, and externalising problems are separate yet interconnected components of mental health. Multiple Indicators Multiple Causes models showed that individual, contextual, and psychosocial predictors contribute differentially to positive and negative mental health outcomes. CONCLUSIONS: Using a national sample of children in residential care in Luxembourg, this research indicates that subjective well-being, internalising problems, and externalising problems are distinct but related aspects of mental health. 'Child participation' and 'school pressure' displayed strong links with positive mental health outcomes and may serve as a potential path for improving public health interventions for children in care.

The role of stress in the biological embedding of experience.

Exposure to early adversity is one of the most important and pervasive risk factors for the development of nearly all major mental disorders across the lifespan. In the search for the mediating mechanisms and processes that underlie long-term stability of these effects, changes to stress-associated hormonal and cellular signalling have emerged as prime candidates. This review summarises evidence showing that experience of early adversity in the form of childhood abuse or neglect and exposure to severe institutional deprivation influences multiple interconnected bio-behavioural, physiological and cellular processes. This paper focusses on dysregulations of hormonal stress regulation, altered DNA methylation pattern, changes to transcriptomic profiles in the context of stress-immune interplay, and mitochondrial biology. Consistent findings that have emerged include a relative cortisol hypoactivity and hyporeactivity in response to challenge, increased activity of pro-inflammatory genes, and altered mitochondrial function. The majority of investigations have focussed on single outcomes, but there is a clear rationale of conceiving the implicated physiological processes as interconnected parts of a wider stress-associated regulatory network, which in turn is connected to behaviour and mental disorders. This calls for integrated and longitudinal investigations to come to a more comprehensive understanding of the role of stress in the biological embedding of experience. The review concludes with considerations of how stress research can contribute to translational efforts through characterising subtypes of mental disorders which arise as a function of early adversity, and have distinct features of behavioral and biological stress processing.

The DNA methylation landscape of the human oxytocin receptor gene (OXTR): data-driven clusters and their relation to gene expression and childhood adversity.

The oxytocin receptor gene (OXTR) is of interest when investigating the effects of early adversity on DNA methylation. However, there is heterogeneity regarding the selection of the most promising CpG sites to target for analyses. The goal of this study was to determine functionally relevant clusters of CpG sites within the OXTR CpG island in 113 mother-infant dyads, with 58 of the mothers reporting childhood maltreatment (CM). OXTR DNA methylation was analyzed in peripheral/umbilical blood mononuclear cells. Different complexity reduction approaches were used to reduce the 188 CpG sites into clusters of co-methylated sites. Furthermore, associations between OXTR DNA methylation (cluster- and site-specific level) and OXTR gene expression and CM were investigated in mothers. Results showed that, first, CpG sections differed strongly regarding their statistical utility for research of individual differences in DNA methylation. Second, cluster analyses and Partial Least Squares (PLS) suggested two clusters consisting of intron1/exon2 and the protein-coding region of exon3, respectively, as most strongly associated with outcome measures. Third, cross-validated PLS regression explained 7% of variance in CM, with low cross-validated variance explained for the prediction of gene expression. Fourth, substantial mother-child correspondence was observed in correlation patterns within the identified clusters, but only modest correspondence outside these clusters. This study makes an important contribution to the mapping of the DNA methylation landscape of the OXTR CpG island by highlighting clusters of CpG sites that show desirable statistical properties and predictive value. We provide a Companion Web Application to facilitate the choice of CpG sites.

No association between war-related trauma or PTSD symptom severity and epigenome-wide DNA methylation in Burundian refugees.

Background: War-related trauma is associated with varying posttraumatic stress disorder (PTSD) prevalence rates in refugees. In PTSD development, differential DNA methylation (DNAm) levels associated with trauma exposure might be involved in risk versus resilience processes. Studies investigating DNAm profiles related to trauma exposure and PTSD among refugees remain sparse.Objective: The present epigenome-wide association study investigated associations between war-related trauma, PTSD, and altered DNAm patterns in Burundian refugee families with 110 children and their 207 female and male caregivers.Method: War-related trauma load and PTSD symptom severity were assessed in structured clinical interviews with standardised instruments. Epigenome-wide DNAm levels were quantified from buccal epithelia using the Illumina EPIC beadchip.Results: Controlling for biological confounders, no significant epigenome-wide DNAm alterations associated with trauma exposure or PTSD were identified in children or caregivers (FDRs > .05). Co-methylated positions derived as modules from weighted gene correlation network analyses were not significantly associated with either war-related trauma experience in children or caregivers or with PTSD.Conclusions: These results do not provide evidence for altered DNAm patterns associated with exposure to war-related trauma or PTSD.

The study examines an understudied population in epigenome-wide association studies.Burundian refugees' war-trauma, PTSD, and DNA methylation were studied.Epigenome-wide DNA methylation was not significantly associated with war-trauma or PTSD in the conflict-affected sample.

MicroRNA-Related Polymorphism and Their Association with Fibromyalgia.

MicroRNAs are tissue-specific expressed short RNAs that serve post-transcriptional gene regulation. A specific microRNA can bind to mRNAs of different genes and thereby suppress their protein production. In the context of the complex phenotype of fibromyalgia, we used the Axiom miRNA Target Site Genotyping Array to search genome-wide for DNA variations in microRNA genes, their regulatory regions, and in the 3'UTR of protein-coding genes. To identify disease-relevant DNA polymorphisms, a cohort of 176 female fibromyalgia patients was studied in comparison to a cohort of 162 healthy women. The association between 48,329 markers and fibromyalgia was investigated using logistic regression adjusted for population stratification. Results show that 29 markers had p-values < 1 × 10-3, and the strongest association was observed for rs758459 (p-value of 0.0001), located in the Neurogenin 1 gene which is targeted by hsa-miR-130a-3p. Furthermore, variant rs2295963 is predicted to affect binding of hsa-miR-1-3p. Both microRNAs were previously reported to be differentially expressed in fibromyalgia patients. Despite its limited statistical power, this study reports two microRNA-related polymorphisms which may play a functional role in the pathogenesis of fibromyalgia. For a better understanding of the disease pattern, further functional analyses on the biological significance of microRNAs and microRNA-related polymorphisms are required.

Treatment-associated mRNA co-expression changes in monocytes of patients with posttraumatic stress disorder.

PTSD is a prevalent mental disorder that results from exposure to extreme and stressful life events and comes at high costs for both the individual and society. Therapeutic treatment presents the best way to deal with PTSD-the mechanisms underlying change after treatment, however, remain poorly understood. While stress and immune associated gene expression changes have been associated with PTSD development, studies investigating treatment effects at the molecular level so far tended to focus on DNA methylation. Here we use gene-network analysis on whole-transcriptome RNA-Seq data isolated from CD14+ monocytes of female PTSD patients (N = 51) to study pre-treatment signatures of therapy response and therapy-related changes at the level of gene expression. Patients who exhibited significant symptom improvement after therapy showed higher baseline expression in two modules involved in inflammatory processes (including notable examples IL1R2 and FKBP5) and blood coagulation. After therapy, expression of an inflammatory module was increased, and expression of a wound healing module was decreased. This supports findings reporting an association between PTSD and dysregulations of the inflammatory and the hemostatic system and mark both as potentially treatment sensitive.

Structural architecture and brain network efficiency link polygenic scores to intelligence.

Intelligence is highly heritable. Genome-wide association studies (GWAS) have shown that thousands of alleles contribute to variation in intelligence with small effect sizes. Polygenic scores (PGS), which combine these effects into one genetic summary measure, are increasingly used to investigate polygenic effects in independent samples. Whereas PGS explain a considerable amount of variance in intelligence, it is largely unknown how brain structure and function mediate this relationship. Here, we show that individuals with higher PGS for educational attainment and intelligence had higher scores on cognitive tests, larger surface area, and more efficient fiber connectivity derived by graph theory. Fiber network efficiency as well as the surface of brain areas partly located in parieto-frontal regions were found to mediate the relationship between PGS and cognitive performance. These findings are a crucial step forward in decoding the neurogenetic underpinnings of intelligence, as they identify specific regional networks that link polygenic predisposition to intelligence.

A matter of habit? Stressful life events and cognitive flexibility in 15-month-olds.

Exposure to chronic stress is associated with habitual learning in adults. We studied the origins of this association by examining the link between stressful life events and infant cognitive flexibility. The final sample consisted of N = 72 fifteen-month-old infants and their mothers. Mothers completed a survey on pre- and postnatal negative life events. To assess chronic stress physiologically, infant and maternal hair cortisol concentrations were determined for cortisol accumulation during the past 3 months. Each infant participated in two cognitive tasks in the laboratory. An instrumental learning task tested infants' ability to disengage from a habituated action when this action became ineffective (Seehagen et al., 2015). An age-adequate version of the A-not-B task tested infants' ability to find a toy at location B after repeatedly finding it at location A. Correlations between cortisol concentrations and postnatal negative life events (number, perceived impact) did not yield significance. Infant and maternal hair cortisol concentrations were not correlated. Infants' ability to shift to a new action in either task, controlled for acute stress, correlated neither with pre- and postnatal negative life events nor with cortisol concentrations. Taken together, these results indicate that the potential link between long-term stress exposure and cognitive flexibility might not be present in samples with low levels of psychosocial stress.

Proteome analysis of monocytes implicates altered mitochondrial biology in adults reporting adverse childhood experiences.

The experience of adversity in childhood has been associated with poor health outcomes in adulthood. In search of the biological mechanisms underlying these effects, research so far focused on alterations of DNA methylation or shifts in transcriptomic profiles. The level of protein, however, has been largely neglected. We utilized mass spectrometry to investigate the proteome of CD14+ monocytes in healthy adults reporting childhood adversity and a control group before and after psychosocial stress exposure. Particular proteins involved in (i) immune processes, such as neutrophil-related proteins, (ii) protein metabolism, or (iii) proteins related to mitochondrial biology, such as those involved in energy production processes, were upregulated in participants reporting exposure to adversity in childhood. This functional triad was further corroborated by protein interaction- and co-expression analyses, was independent of stress exposure, i.e. observed at both pre- and post-stress time points, and became evident especially in females. In line with the mitochondrial allostatic load model, our findings provide evidence for the long-term effects of childhood adversity on mitochondrial biology.

No evidence for intervention-associated DNA methylation changes in monocytes of patients with posttraumatic stress disorder.

DNA methylation patterns can be responsive to environmental influences. This observation has sparked interest in the potential for psychological interventions to influence epigenetic processes. Recent studies have observed correlations between DNA methylation changes and therapy outcome. However, most did not control for changes in cell composition. This study had two aims: first, we sought to replicate therapy-associated changes in DNA methylation of commonly assessed candidate genes in isolated monocytes from 60 female patients with post-traumatic stress disorder (PTSD). Our second, exploratory goal was to identify novel genomic regions with substantial pre-to-post intervention DNA methylation changes by performing whole-genome bisulfite sequencing (WGBS) in two patients with PTSD. Equivalence testing and Bayesian analyses provided evidence against physiologically meaningful intervention-associated DNA methylation changes in monocytes of PTSD patients in commonly investigated target genes (NR3C1, FKBP5, SLC6A4, OXTR). Furthermore, WGBS yielded only a limited set of candidate regions with suggestive evidence of differential DNA methylation pre- to post-therapy. These differential DNA methylation patterns did not prove replicable when investigated in the entire cohort. We conclude that there is no evidence for major, recurrent intervention-associated DNA methylation changes in the investigated genes in monocytes of patients with PTSD.

Study protocol for a multi-center RCT testing a group-based parenting intervention tailored to mothers with borderline personality disorder against a waiting control group (ProChild*-SP1).

BACKGROUND/AIMS: Borderline personality disorder (BPD) is a severe mental disorder characterized by an unstable sense of self, intense and rapidly changing affect, as well as impulsive and self-destructive behaviors. Interpersonal relationships of individuals with BPD are characterized by marked instability, a lack of dependability, and quick changes between love and hate. For children of individuals with BPD, this can lead to permanent stress and attachment insecurity and an increased risk of adverse physical and mental health development. To reduce dysfunctional parenting and improve positive parenting, and in turn, to promote healthy child development, a group intervention for mothers with BPD was developed. This study aims to evaluate this first disorder-specific parenting intervention for BPD in a randomized controlled trial. METHOD: In a parallel-group, two-arm, randomized controlled trial, an initial N = 178 mothers diagnosed with BPD and their children aged 6 months to 6 years are assigned to either the parenting intervention or a waiting control group. If taking place, participants of both groups continue their regular treatment for BPD diagnosis (e.g., individual therapy, medication). The primary outcomes are changes in parenting from baseline (day 0) to post intervention (week 12) and follow-up (6 months after group intervention; month 9). The waiting control group can attend the group intervention at the end of all assessments. Participants allocated to the intervention group are expected to show improvement in their parenting and a reduction in child abuse potential. Maternal emotion regulation and mental distress are analyzed as secondary outcomes. DISCUSSION: Mothers with BPD may need tailored help when reporting difficulties raising their children. The first disorder-specific parenting intervention has been developed to close this gap. ProChild is part of a large government-supported consortium, which aims to investigate different aspects of abuse and maltreatment in childhood and adolescence. TRIAL REGISTRATION: ClinicalTrials.gov NCT04169048 . Registered on Nov 19, 2019.

Urbanicity, behavior problems and HPA axis regulation in preschoolers.

Growing up in cities is associated with increased risk for developing mental health problems. Stress exposure and altered stress regulation have been proposed as mechanisms linking urbanicity and psychopathology, with most research conducted in adult populations. Here, we focus on early childhood, and investigate urbanicity, behavior problems and the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, a central circuit of the stress system, in a sample of N = 399 preschoolers aged 45 months. Urbanicity was coded dichotomously distinguishing between residences with more or less than 100,000 inhabitants. Behavior problems were measured using the Child Behavior Checklist (CBCL) 1½ - 5. Cortisol stress reactivity was assessed using an age-appropriated game-like stress task, and cortisol in the first morning urine was measured to assess nocturnal HPA axis activity. Urbanicity was not associated with behavior problems, urinary cortisol or the cortisol stress response. Neither urinary cortisol nor salivary cortisol response after stress exposure were identified as mediators of the relationship between urbanicity and behavior problems. The findings suggest no strong association of urbanicity with behavior problems and HPA axis regulation in preschool age. To our knowledge, this is the youngest sample to date studying the relationship between urbanicity and behavior problems as well as HPA axis regulation. Future research should examine at which age associations can first be identified and which mechanisms contribute to these relationships.

Prenatal exposure to endocrine disrupting chemicals is associated with altered DNA methylation in cord blood.

Prenatal exposure to endocrine disrupting chemicals can interfere with development, and has been associated with social-cognitive functioning and adverse health outcomes later in life. Exposure-associated changes of DNA methylation (DNAm) patterns have been suggested as a possible mediator of this relationship. This study investigated whether prenatal low-dose exposure to polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) is associated with altered DNAm patterns across the genome in a Western urban-industrial population. In 142 mother-infant pairs from the Duisburg Birth Cohort Study, PCBs and PCDD/Fs levels were quantified from maternal blood during late pregnancy and associated with DNAm levels in cord blood using the Illumina EPIC beadchip. The epigenome-wide association studies (EWAS) identified 32 significantly differentially methylated positions (DMPs) and eight differentially methylated regions (DMRs) associated with six congeners of PCB and PCDD in females or males (FDRs < 0.05). DMPs and DMRs mapped to genes involved in neurodevelopment, gene regulation, and immune functioning. Weighted gene correlation network analysis (WGCNA) showed 31 co-methylated modules (FDRs < 0.05) associated with one congener of PCDF levels in females. Results of both analytical strategies indicate that prenatal exposure to PCBs and PCDD/Fs is associated with altered DNAm of genes involved in neurodevelopment, gene expression and immune functioning. DNAm and gene expression levels of several of these genes were previously associated with EDC exposure in rodent models. Follow-up studies will clarify whether these epigenetic changes might contribute to the origin for adverse mental and health outcomes.

Polygenic scores for handedness and their association with asymmetries in brain structure.

Handedness is the most widely investigated motor preference in humans. The genetics of handedness and especially the link between genetic variation, brain structure, and right-left preference have not been investigated in detail. Recently, several well-powered genome-wide association studies (GWAS) on handedness have been published, significantly advancing the understanding of the genetic determinants of left and right-handedness. In the present study, we estimated polygenic scores (PGS) of handedness-based on the GWAS by de Kovel and Francks (Sci Rep 9: 5986, 2019) in an independent validation cohort (n = 296). PGS reflect the sum effect of trait-associated alleles across many genetic loci. For the first time, we could show that these GWAS-based PGS are significantly associated with individual handedness lateralization quotients in an independent validation cohort. Additionally, we investigated whether handedness-derived polygenic scores are associated with asymmetries in gray matter macrostructure across the whole brain determined using magnetic resonance imaging. None of these associations reached significance after correction for multiple comparisons. Our results implicate that PGS obtained from large-scale handedness GWAS are significantly associated with individual handedness in smaller validation samples with more detailed phenotypic assessment.

Polygenic Scores for Cognitive Abilities and Their Association with Different Aspects of General Intelligence-A Deep Phenotyping Approach.

Intelligence is a highly polygenic trait and genome-wide association studies (GWAS) have identified thousands of DNA variants contributing with small effects. Polygenic scores (PGS) can aggregate those effects for trait prediction in independent samples. As large-scale light-phenotyping GWAS operationalized intelligence as performance in rather superficial tests, the question arises which intelligence facets are actually captured. We used deep-phenotyping to investigate the molecular determinants of individual differences in cognitive ability. We, therefore, studied the association between PGS of intelligence (IQ-PGS), cognitive performance (CP-PGS), and educational attainment (EA-PGS) with a wide range of intelligence facets in a sample of 557 healthy adults. IQ-PGS, CP-PGS, and EA-PGS had the highest incremental R2s for general (2.71%; 4.27%; 2.06%), verbal (3.30%; 4.64%; 1.61%), and numerical intelligence (3.06%; 3.24%; 1.26%) and the weakest for non-verbal intelligence (0.89%; 1.47%; 0.70%) and memory (0.80%; 1.06%; 0.67%). These results indicate that PGS derived from light-phenotyping GWAS do not reflect different facets of intelligence equally well, and thus should not be interpreted as genetic indicators of intelligence per se. The findings refine our understanding of how PGS are related to other traits or life outcomes.

Genes in treatment: Polygenic risk scores for different psychopathologies, neuroticism, educational attainment and IQ and the outcome of two different exposure-based fear treatments.

OBJECTIVES: Evidence for a genetic influence on psychological treatment outcome so far has been inconsistent, likely due to the focus on candidate genes and the heterogeneity of the disorders treated. Using polygenic risk scores (PRS) in homogenous patient samples may increase the chance of detecting genetic influences. METHODS: A sample of 342 phobic patients treated either for clinically relevant dental fear (n = 189) or other (mixed) phobic fears (n = 153) underwent highly standardised exposure-based CBT. A brief five-session format was used to treat dental fear, whereas longer multi-session treatments were used with the mixed-fear cohort. PRS were calculated based on large genetic studies of Neuroticism, Educational Attainment (EA), Intelligence, and four psychopathology domains. We compared PRS of post-treatment and follow-up remitters and non-remitters and regressed PRS on fear reduction percentages. RESULTS: In the dental fear cohort, EA PRS were associated with treatment outcomes, i.e. drop-out, short- and long-term remission state, fear reduction, and attendance of subsequent dental appointments. In the mixed fear treatment cohort, no gene effects were observable. CONCLUSIONS: Results indicate the importance of EA-related traits for outcomes following brief, but not long, standardised exposure-based CBT. Such use of PRS may help inform selection and tailoring of treatments.

The brain under stress-A systematic review and activation likelihood estimation meta-analysis of changes in BOLD signal associated with acute stress exposure.

Psychosocial stress is an omnipresent phenomenon whose neural correlates in humans are still poorly understood. Several paradigms have been developed to induce acute stress in fMRI settings, but it is unclear whether there is a global brain activation pattern related to psychosocial stress. To integrate the different neuronal activation patterns, we conducted an activation likelihood estimation analysis on 31 studies totaling 1279 participants. Studies used the ScanSTRESS, Montreal Imaging Stress Test, aversive viewing paradigm (AVP), Social-Evaluative Threat or Cyberball. The analysis revealed bilateral activation clusters comprising the claustrum, insula and inferior frontal gyrus. This indicates that exposure to psychosocial stress leads to activations in brain areas involved in affective processing and the endocrine stress response. Furthermore, in a systematic review, Cyberball and AVP presented themselves as outliers due to increased activation in motor areas and lack of induction of stress related activity changes, respectively. As different paradigms emphasize different dimensions of psychosocial stress such as social evaluation or performance pressure, future research is needed to identify differences between the paradigms.

Event-related functional MRI of awake behaving pigeons at 7T.

Animal-fMRI is a powerful method to understand neural mechanisms of cognition, but it remains a major challenge to scan actively participating small animals under low-stress conditions. Here, we present an event-related functional MRI platform in awake pigeons using single-shot RARE fMRI to investigate the neural fundaments for visually-guided decision making. We established a head-fixated Go/NoGo paradigm, which the animals quickly learned under low-stress conditions. The animals were motivated by water reward and behavior was assessed by logging mandibulations during the fMRI experiment with close to zero motion artifacts over hundreds of repeats. To achieve optimal results, we characterized the species-specific hemodynamic response function. As a proof-of-principle, we run a color discrimination task and discovered differential neural networks for Go-, NoGo-, and response execution-phases. Our findings open the door to visualize the neural fundaments of perceptual and cognitive functions in birds-a vertebrate class of which some clades are cognitively on par with primates.

Highs and lows: Genetic susceptibility to daily events.

Why people differ in their susceptibility to external events is essential to our understanding of personality, human development, and mental disorders. Genes explain a substantial portion of these differences. Specifically, genes influencing the serotonin system are hypothesized to be differential susceptibility factors, determining a person's reactivity to both positive and negative environments. We tested whether genetic variation in the serotonin transporter (5-HTTLPR) is a differential susceptibility factor for daily events. Participants (N = 326, 77% female, mean age = 25, range = 17-36) completed smartphone questionnaires four times a day over four to five days, measuring stressors, uplifts, positive and negative affect. Affect was predicted from environment valence in the previous hour on a within-person level using three-level autoregressive linear mixed models. The 5-HTTLPR fulfilled all criteria of a differential susceptibility factor: Positive affect in carriers of the short allele (S) was less reactive to both uplifts and stressors, compared to homozygous carriers of the long allele (L/L). This pattern might reflect relative affective inflexibility in S-allele carriers. Our study provides insight into the serotonin system's general role in susceptibility and highlights the need to assess the whole spectrum of naturalistic experiences.