Polygenic Risk Scores For Neuroticism Research Articles

Abstract 12440: Depression and Anxiety Accelerate the Rate of Gain of Cardiovascular Risk Factors: Mechanism Leading to Increased Risk of Cardiac Events

Introduction: Depression and anxiety are associated with a greater incidence of major adverse cardiovascular events (MACEs). Hypothesis: We hypothesized that: 1) depression and anxiety accelerate the development of cardiovascular risk factors (CVDRFs), which in turn significantly heightens MACE risk, and 2) a genetic marker of stress sensitivity (polygenic risk score for neuroticism; nPRS) also associates with accelerated gains of CVDRFs. Methods: Subjects enrolled in the Mass General Brigham Biobank were studied. Depression, anxiety, CVDRFs and MACE were defined using ICD codes. Subjects <18 years old, with previous MACE or who developed depression/anxiety after study start date were excluded. CVDRFs were defined as hypertension, hyperlipidemia, and diabetes mellitus. The time between study start date and development of first new CVDRF was measured over 10 years of follow-up. Additionally, nPRS was assessed for subjects who provided genetic data; age of first CVDRF diagnosis was ascertained in this subgroup. Results: Data were obtained for 71,262 subjects (age 49.0 ± 15.6 yrs, 44.7% male). 27,048 (38.0%) subjects gained a new CVDRF (mean time 4.8 ± 2.6 yrs). Depression (β=-0.591; p<0.001) and anxiety (β=-0.567; p<0.001) associated with earlier development of a new CVDRF after adjusting for age, sex, and preexisting CVDRFs ( Fig. 1A). Further, in adjusted analyses, depression and/or anxiety increased the risk of MACE (adjusted odds ratio: 1.353; p<0.001). Mediation analysis shows that 38.9% of the effect of depression and/or anxiety on MACE is explained by the accelerated gains in CVDRFs. Similarly, higher genetic sensitivity to stress (nPRS) associates with an earlier onset of first CVDRF (adjusted β=-0.317; p=0.005, Fig. 1B) . Conclusions: Depression and anxiety accelerate the acquisition of CVDRFs, which in turn significantly explains the heightened risk of MACE. Genetic risk associated with stress sensitivity also accelerates the development of CVDRFs.

Abstract 16298: Higher Genetic Risk for Neuroticism Heightens Cardiovascular Risk Related to Chronic Sleep Deprivation

Introduction: Chronic sleep deprivation associates with an increased risk of Major Adverse Cardiovascular Events (MACE), in part via heightened stress-related neural mechanisms. Similarly, increased polygenic risk score for neuroticism (nPRS), a measure linked to stress-sensitivity, associates with greater activity in stress-related neural pathways. Hypothesis: We hypothesized that higher nPRS increases the MACE risk associated with chronic sleep deprivation. Methods: A total of 9,619 participants (median age 65 years, 46% male) from the Mass General Brigham Biobank were studied. nPRS was assessed. Sleep deprivation was defined as either a short sleep duration (<7 hours/night) or a diagnosis of a sleep disorder (e.g., insomnia, sleep apnea). Sleep duration and disorders, MACE incidence, and cardiovascular risk factors were assessed using health questionnaires and International Classification of Disease codes. Logistic regression models were employed to evaluate the association between sleep deprivation and MACE and the presence of an interaction. Results: During a median (Interquartile range) of 4.9 (4.1-5.9) years of follow-up, 807 (8.3%) individuals experienced MACE. Among individuals with higher nPRS (≥median), sleep deprivation associated with a two-fold increase in MACE risk (odds ratio [OR] [95% confidence interval (CI)]: 2.283 [1.929, 2.703], p<0.001*) compared to individuals with lower nPRS (<median) (OR [95%CI]: 1.632 [1.390, 1.917], p<0.001*; Table 1 ) with a significant interaction observed (p=0.010*). A similar trend was observed in a sensitivity analysis that excluded sleep apnea (p-interaction 0.074). Conclusions: Our findings suggest that a high nPRS doubles the MACE risk associated with sleep deprivation. Further research is warranted to elucidate the underlying mechanisms driving this relationship.

Polygenic risk for neuroticism is associated with less efficient control in more difficult situations

Neuroticism is a heritable trait and a risk factor for mental health due to its relevance to poor control of negative events. To examine the relationship between genetic propensity for neuroticism and control processing, we used the polygenic risk score (PRS) approach and a stop signal task during fMRI. We hypothesized that genetic propensity for neuroticism may moderate control processing as a function of control difficulty. PRSs for neuroticism were computed from a transdiagnostic group of individuals (n=406) who completed the stop signal task. The level of control difficulty was a function of the stop signal asynchrony: shorter asynchrony allows easier stopping whereas longer asynchrony makes stopping difficult. The relationship between PRS for neuroticism and neural activity for controlling responses was examined by the stop signal asynchrony. Although PRS for neuroticism did not relate to the overall inhibitory control, individuals with high PRS for neuroticism showed greater activity in left dorsal prefrontal cortex, middle temporal gyrus, and dorsal posterior cingulate cortex for difficult control. Thus, the genetic propensity for neuroticism affects neural processing in a difficult control context, which may help to explain why individuals with high levels of neuroticism exert poor control of negative events in difficult situations.

Affective wellbeing moderates the association between polygenic risk score for neuroticism and change in neuroticism

IntroductionNeuroticism has societal, mental and physical health relevance, with an etiology involving genetic predisposition, psychological influence, and their interaction.ObjectivesTo understand whether the association between polygenic risk score for neuroticism (PRS-N) and neuroticism is moderated by affective well-being.MethodsData were derived from TwinssCan, a general population twin cohort (age range=15-35 years, 478 monozygotic twins). Self-report questionnaires were used to measure well-being and neuroticism. PRS-N was trained from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB). Multilevel mixed-effects models were used to test baseline and changes in well-being and neuroticism.ResultsBaseline wellbeing and neuroticism were associated (β=-1.35, p<0.001). PRSs-N were associated with baseline neuroticism (lowest p-value: 0.008 in GPC, 0.01 in UKB). In interaction models (PRS x wellbeing), GPC PRS-N (β=0.38, p=0.04) and UKB PRS-N (β=0.81, p<0.001) had significant interactions.PRSs-N were associated with changes in neuroticism (lowest p-value: 0.03 in GPC, 0.3 in UKB). Furthermore, changes in wellbeing and neuroticism were associated (β =-0.66, p<0.001). In interaction models (PRS x change in wellbeing), only UKB PRS-N had a significant interaction (β=0.80, p<0.001).ConclusionsInteraction between polygenic risk, wellbeing and neuroticism, were observed regarding baselines measures and change over time. Depending on the analysis step, the direction of the effect changed.Disclosure of InterestNone Declared

Childhood trajectories of internalising and externalising problems associated with a polygenic risk score for neuroticism in a UK birth cohort study.

Neuroticism represents a personality disposition towards experiencing negative emotions more frequently and intensely. Longitudinal studies suggest that neuroticism increases risk of several psychological problems. Improved understanding of how this trait manifests in early life could help inform preventative strategies in those liable to neuroticism. This study explored how a polygenic risk score for neuroticism (NEU PRS) is expressed from infancy to late childhood across various psychological outcomes using multivariable linear and ordinal regression models. In addition, we employed a three-level mixed-effect model to characterise child internalising and externalising trajectories and estimate how a child PRS associated with both their overall levels and rates of change in 5279 children aged 3-11 in the Avon Longitudinal Study of Parents and Children cohort. We found evidence that the NEU PRS was associated with a more emotionally sensitive temperament in early infancy in addition to higher emotional and behavioural problems and a higher risk of meeting diagnostic criteria for a variety of clinical disorders, particularly anxiety disorders, in childhood. The NEU PRS was associated with overall levels of internalising and externalising trajectories, with a larger magnitude of association on the internalising trajectory. The PRS was also associated with slower rates of reduction of internalising problems across childhood. Our findings using a large, well-characterised birth cohort study suggest that phenotypic manifestations of a PRS for adult neuroticism can be detected as early as in infancy and that this PRS associates with several mental health problems and differences in emotional trajectories across childhood.

Passive and active suicidal ideation in a population-based sample of older adults: Associations with polygenic risk scores of relevance for suicidal behavior.

There are few studies investigating genetic factors related to suicidal ideation or behavior in older adult populations. Our aim was to test associations between passive and active suicidal ideation and polygenic risk scores (PRSs) for suicidality and other traits of relevance for suicidality in old age (i.e. depression, neuroticism, loneliness, Alzheimer's disease, cognitive performance, educational attainment, and several specified vascular diseases) in a population-based sample aged 70 years and older. Participants in the prospective H70 study in Gothenburg, Sweden, took part in a psychiatric examination that included the Paykel questions on active and passive suicidal ideation. Genotyping was performed with the Neurochip (Illumina). After quality control of the genetic data the sample included 3467 participants. PRSs for suicidality and other related traits were calculated based on summary statistics from recent GWASs of relevance. Exclusion of persons with dementia or incomplete data on suicidal ideation yielded 3019 participants, age range 70-101 years. Associations between past year suicidal ideation (any level) and selected PRSs were analysed using general estimation equation (GEE) models, adjusted for sex and age. We observed associations between passive/active suicidal ideation and PRSs for depression (three versions), neuroticism, and general cognitive performance. After excluding individuals with current major depressive disorder (MDD), similar associations were seen with PRS for neuroticism, general cognitive performance and two PRSs for depression. No associations were found between suicidal ideation and PRSs for suicidality, loneliness, Alzheimer's disease, educational attainment, or vascular disease. Our results could indicate which types of genetic susceptibility that are of importance for suicidality in old age, and these findings can help to shed light on potential mechanisms that may be involved in passive and active suicidal ideation in late-life, also in those with no current MDD. However, due to the limited sample size, the results need to be interpreted with caution until replicated in larger samples.

Gene-environment interaction study on the polygenic risk score for neuroticism, childhood adversity, and parental bonding.

The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRSN), in interaction with bullying, parental bonding, and childhood adversity. Data were derived from a general population adolescent and young adult twin cohort. The final sample consisted of 202 monozygotic and 436 dizygotic twins and 319 twin pairs. The Short Eysenck Personality questionnaire was used to measure neuroticism. PRSN was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRSN. Multilevel mixed-effects models were used to analyze the main and interacting associations of PRSN, childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene-environment correlation. PRSN thresholds of .005 and .2 were chosen, based on GPC and UKB datasets, respectively. After correction for confounders, all the individual variables were associated with the expression of neuroticism: both PRSN from GPC and UKB, childhood adversity, maternal bonding, paternal bonding, and bullying in primary school and secondary school. However, the results indicated no evidence for gene-environment interaction in this cohort. These results suggest that genetic vulnerability on the one hand and negative life events (childhood adversity and bullying) and positive life events (optimal parental bonding) on the other represent noninteracting pathways to neuroticism.

Abstract 14748: Genetic and Neurobiological Factors Link Chronic Stress to Earlier Onset Hypertension

Introduction: Chronic stress conditions associate with a greater incidence of hypertension (HTN). Hypothesis: We tested whether genetic risk for or neurobiological features of vulnerability to chronic stress associate with the risk for and timing of HTN. Methods: Data were obtained from Mass General Brigham Biobank participants. HTN was defined as > 2 International Classification of Disease codes at least one week apart. Those with secondary HTN and those diagnosed at age <18 years were excluded. Of this parent dataset, a validated polygenic risk score for neuroticism reflecting stress sensitivity (ssPRS) was assessed in 11,320 participants. Of the same parent dataset, stress-related neural network activity (SNNA), defined as a ratio of amygdalar to regulatory medial prefrontal cortical activity, was measured in 867 individuals who had undergone clinical 18 F-flurodeoxyglucose positron emission tomography imaging. Results: In the genetic subgroup, the median age [interquartile range] of participants was 60 [34-86] years and 56.3% were female. In a Cox regression model, standardized ssPRS predicted incident HTN (hazard ratio [95% confidence interval (CI)]: 1.05 [1.02, 1.08], p<0.001), when adjusted for principal components, age, and sex (Figure 1A). Similarly, standardized SNNA predicted incident HTN (1.44 [1.11, 1.85], p = 0.006) when adjusted for age and sex. The age of onset of HTN was significantly lower in those with high vs. low ssPRS (difference (years) [95% CI]: -1.65 (-2.45, -0.85], p < 0.001) and in those with high vs. low SNNA (-4.67 [-7.68, -1.66], p = 0.002, Figure 1B) in unadjusted models with findings of a similar magnitude and significance in multivariable models. Conclusions: This study identifies genetic and neurobiological factors linking chronic stress to HTN risk and its age of onset. Future studies should evaluate whether therapies targeting this neurobiological pathway may reduce HTN risk.

Genetic sensitivity to stress modifies the relationship between socioeconomic status and major adverse cardiovascular events

Abstract Background Lower socioeconomic status (SES) associates with major adverse cardiovascular events (MACE), in part through stress-related neural pathways that elicit inflammation. However, it is unknown whether genes that heighten stress sensitivity modify the association between lower SES and MACE. Purpose To assess whether genetic predisposition to stress sensitivity would modify the link between low SES and MACE Methods 13,154 participants (median age 60 yrs, 41% male) from the Mass General Brigham Biobank were studied. A polygenic risk score for neuroticism (nPRS) was used as a measure of genetic predisposition to stress sensitivity (GSS). Using home addresses, SES was evaluated as median income and area deprivation index (ADI). Stress-related neural activity (SNA) was assessed (N=978) using validated FDG PET/CT imaging methods. MACE, and cardiovascular disease (CVD) risk factors were evaluated. Mediation analyses were employed. Results Over median (IQR) 4.9 (4.1–5.9) years of follow-up, 1,030 (7.8%) individuals had MACE. Lower SES (as low income, or alternatively as high ADI) associated with incident MACE among individuals with higher GSS (nPRS ≥ median) but not lower GSS (Fig. 1A and 1B). Similarly, lower SES associated with SNA among individuals with higher but not lower GSS (Fig. 1C). SNA mediated the relationship between income and MACE (P<0.05**) among those with higher GSS. Conclusions Genetic predisposition to stress sensitivity appears to heighten CVD risk associated with lower SES. This relationship may result from differential activation of stress-related neural pathways. Funding Acknowledgement Type of funding sources: None.

"The Heidelberg Five" personality dimensions: Genome-wide associations, polygenic risk for neuroticism, and psychopathology 20 years after assessment.

HeiDE is a longitudinal population-based study that started in the 1990s and, at baseline, assessed an array of health-related personality questionnaires in 5133 individuals. Five latent personality dimensions (The Heidelberg Five) were identified and interpreted as Emotional Lability (ELAB), Lack of Behavioral Control (LBCN), Type A Behavior (TYAB), Locus of Control over Disease (LOCC), and Psychoticism (PSYC). At follow-up, 3268 HeiDE participants (post-QC) were genotyped on single nucleotide polymorphism (SNP) arrays. To further characterize The Heidelberg Five, we analyzed genomic underpinnings, their relations to the genetic basis of the Big Five trait Neuroticism, and longitudinal associations with psychiatric symptoms at follow-up. SNP-based heritability was significant for ELAB (34%) and LBCN (29%). A genome-wide association study for each personality dimension was conducted; only the phenotype PSYC yielded a genome-wide significant finding (p < 5 × 10-8 , top SNP rs138223660). Gene-based analyses identified significant findings for ELAB, TYAB, and PSYC. Polygenic risk scores for Neuroticism were only associated with ELAB. Each of The Heidelberg Five was related to depressive symptoms at follow-up. ELAB, LBCN, and PSYC were also associated with lifetime anxiety symptoms. These results highlight the clinical importance of health-related personality traits and identify LBCN as a heritable "executive function" personality trait.

Abstract 16270: Genetic Susceptibility to Stress Associates With Higher Amygdalar Activity and Greater Myocardial Infarction Risk

Introduction and Hypothesis: Chronic psychological stress is strongly linked to cardiovascular disease (CVD) risk. Metabolic activity of the amygdala, a stress-associated brain center, robustly associates with high inflammation and CVD risk. We hypothesized that a validated polygenic risk score for neuroticism (nPRS), a broad trait measure of vulnerability to stress, independently associates with 1) heightened amygdalar activity (AmygA) and 2) increased myocardial infarction (MI) risk Methods: Individuals (N=14349; median age (IQR): 64 (52, 74) yrs, 46%male) were identified from the Partners Biobank where genome wide nPRS and principle components of ancestry (PCI) were calculated. Using validated 18 FDG PET/CT imaging methods, AmygA was measured (N=995) as a target-to-background-ratio in individuals with clinical PET/CT imaging. MI was adjudicated using International Classification of Diseases (ICD) diagnoses. Traditional CVD risk factors * and psychiatric history were obtained using ICD codes and questionnaires. Independent t-tests and linear and logistic regression were employed Results: A total of 1708 (12%) individuals experienced MI. nPRS associated with AmygA (standardized β [95% CI]: 0.07 [0.01, 0.13], p=0.02 Fig A ) after adjustment for age, sex, and 10 PCI. It remained significant after additional adjustment for psychiatric history (p=0.02). AmygA also predicted MI in an adjusted model (OR: 1.50, p=0.006 * ). Importantly, after adjustment for age, sex, and 10 PCI, nPRS significantly associated with MI incidence (standardized OR [95% CI]: 1.12 [1.05, 1.17], p&lt;0.001 Fig B ) and remained significant after additional adjustment for CVD factors (p=0.006*) and psychiatric history (p=0.007) Conclusions: These findings show for the first time that a genetic susceptibility to stress (high nPRS) associates with greater stress-related neurobiological activity, and MI risk. Further, these findings suggest nPRS may serve as a novel risk marker for MI

Shared transethnic genetic basis of panic disorder and psychiatric and related intermediate phenotypes

Panic disorder (PD), a common anxiety disorder, is modestly heritable. The genetic basis of anxiety disorders overlaps with that of other psychiatric disorders and their intermediate phenotypes in individuals of European ancestry. Here, we investigated the transethnic polygenetic features shared between Japanese PD patients and European patients with psychiatric disorders and their intermediate phenotypes by conducting polygenic risk score (PRS) analyses. Large-scale European genome-wide association study (GWAS) datasets (n = 7,556–1,131,881) for ten psychiatric disorders and seven intermediate phenotypes were utilized as discovery samples. PRSs derived from these GWASs were calculated for Japanese target subjects [718 PD patients and 1,717 healthy controls (HCs)]. The effects of these PRSs from European GWASs on the risk of PD in Japanese patients were investigated. The PRSs from European studies of anxiety disorders were marginally higher in Japanese PD patients than in HCs (p = 0.013). Regarding other psychiatric disorders, the PRSs for depression in European patients were significantly higher in Japanese PD patients than in HCs (p = 2.31×10–4), while the PRSs for attention-deficit/hyperactivity disorder in European patients were nominally lower in Japanese PD patients than in HCs (p = 0.024). Regarding health-related, personality-based and cognitive intermediate phenotypes, the PRSs for loneliness (especially isolation) in European individuals were significantly higher in Japanese PD patients than in HCs (p = 9.02×10–4). Furthermore, Japanese PD patients scored nominally higher than HCs in PRSs for neuroticism in European people (p = 3.37×10–3), while Japanese PD patients scored nominally lower than HCs in PRSs for tiredness (p = 0.025), educational attainment (p = 0.035) and cognitive function (p = 9.63×10–3). Our findings suggest that PD shares transethnic genetic etiologies with other psychiatric disorders and related intermediate phenotypes.

Neuroticism as a Predictor of Frailty in Old Age: A Genetically Informative Approach.

Neuroticism is associated with poor health outcomes, but its contribution to the accumulation of health deficits in old age, that is, the frailty index, is largely unknown. We aimed to explore associations between neuroticism and frailty cross-sectionally and longitudinally, and to investigate the contribution of shared genetic influences. Data were derived from the UK Biobank (UKB; n = 274,951), the Australian Over 50's Study (AO50; n = 2849), and the Swedish Twin Registry (Screening Across the Lifespan of Twins Study [SALT], n = 18,960; The Swedish Adoption/Twin Study of Aging [SATSA], n = 1365). Associations between neuroticism and the frailty index were investigated using regression analysis cross-sectionally in UKB, AO50, and SATSA and longitudinally in SALT (25-29 years of follow-up) and SATSA (6 and 23 years of follow-up). The co-twin control method was applied to explore the contribution of underlying shared familial factors (SALT, SATSA, AO50). Genome-wide polygenic risk scores for neuroticism were used in all samples to further assess whether common genetic variants associated with neuroticism predict frailty. High neuroticism was consistently associated with greater frailty cross-sectionally (adjusted β [95% confidence intervals] in UKB = 0.32 [0.32-0.33]; AO50 = 0.35 [0.31-0.39]; SATSA = 0.33 [0.27-0.39]) and longitudinally up to 29 years (SALT = 0.24 [0.22-0.25]; SATSA 6 years = 0.31 [0.24-0.38]; SATSA 23 years = 0.16 [0.07-0.25]). When adjusting for underlying shared genetic and environmental factors, the neuroticism-frailty association remained significant, although decreased. Polygenic risk scores for neuroticism significantly predicted frailty in the two larger samples (meta-analyzed total β = 0.059 [0.055-0.062]). Neuroticism in midlife predicts frailty in late life. Neuroticism may have a causal influence on frailty, whereas both environmental and genetic influences, including neuroticism-associated common genetic variants, contribute to this relationship.

Polygenic risk scores for major depressive disorder and neuroticism as predictors of antidepressant response: Meta-analysis of three treatment cohorts.

There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 760). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10–5 MDD-PRS at 4 weeks, β = -0.019, S.E = 0.008, p = 0.01) and neuroticism (best neuroticism result, p < 0.1 neuroticism-PRS at 8 weeks, β = -0.017, S.E = 0.008, p = 0.03) were associated with less favourable response. We conclude that the PRS approach may offer some promise for treatment stratification in MDD and should now be assessed within larger clinical cohorts.

S182. Evidence That the Polygenic Risk Score for Neuroticism Does Not Moderate the Impact of Childhood Trauma on Neuroticism: A GxE Model

Neuroticism is thought to result from both environmental factors, such as childhood adversities, and individual genetic architecture which consists of many genetic variants of small effect (single nucleotide polymorphisms [SNPs]). We, therefore, aimed to investigate—for the first time—whether the genetic vulnerability (polygenic risk score [PRS] for neuroticism) moderates the impact of childhood adversities (CA) on neuroticism.

Genetic risk for neuroticism predicts emotional health depending on childhood adversity.

Existing evidence for gene × environment interaction (G × E) in neuroticism largely relies on candidate gene studies, although neuroticism is highly polygenic. This study aimed to investigate the long-term associations between polygenic risk scores for neuroticism (PRSN), objective childhood adversity and their interplay on emotional health aspects such as neuroticism itself, depressive symptoms, anxiety symptoms, loneliness and life satisfaction. The sample consisted of reared-apart (TRA) and reared-together (TRT) middle- and old age twins (N = 699; median age at separation = 2). PRSN were created under nine p value cut-off thresholds (pT-s) and the pT with the highest degree of neuroticism variance explained was chosen for subsequent analyses. Linear regressions were used to assess the associations between PRSN, childhood adversity (being reared apart) and emotional health. G × E was further investigated using a discordant twin design. PRSN explained up to 1.7% (pT &lt; 0.01) of phenotypic neuroticism in the total sample. Analyses across two separation groups revealed substantial heterogeneity in the variance explained by PRSN; 4.3% was explained in TRT, but almost no effect was observed in TRA. Similarly, PRSN explained 4% and 1.7% of the variance in depressive symptoms and loneliness, respectively, only in TRT. A significant G × E interaction was identified for depressive symptoms. By taking advantage of a unique sample of adopted twins, we demonstrated the presence of G × E in neuroticism and emotional health using PRSN and childhood adversity. Our results may indicate that genome-wide association studies are detecting genetic main effects associated with neuroticism, but not those susceptible to early environmental influences.

Posttraumatic stress disorder symptom severity is associated with reduced default mode network connectivity in individuals with elevated genetic risk for psychopathology

Accumulating evidence suggests that posttraumatic stress disorder (PTSD) is associated with disrupted default mode network (DMN) connectivity, but findings across studies have not been uniform. Individual differences in relevant genes may account for some of the reported variability in the relationship between DMN connectivity and PTSD. In this study, we investigated this possibility using genome-wide association study (GWAS) derived polygenic risk scores (PRSs) for relevant psychiatric traits. We hypothesized that the association between PTSD and DMN connectivity would be moderated by genetic risk for one or more psychiatric traits such that individuals with elevated polygenic risk for psychopathology and severe PTSD would exhibit disrupted DMN connectivity. Participants were 156 white, non-Hispanic veterans of the wars in Iraq and Afghanistan who were genotyped and underwent resting state functional magnetic resonance imaging and clinical assessment. PRSs for neuroticism, anxiety, major depressive disorder, and cross-disorder risk (based on five psychiatric disorders) were calculated using summary statistics from published large-scale consortia-based GWASs. Cross-disorder polygenic risk influenced the relationship between DMN connectivity and PTSD symptom severity such that individuals at greater genetic risk showed a significant negative association between PTSD symptom severity and connectivity between the posterior cingulate cortex and right middle temporal gyrus. Polygenic risk for neuroticism, anxiety, and major depressive disorder did not influence DMN connectivity directly or through an interaction with PTSD. Findings illustrate the potential power of genome-wide PRSs to advance understanding of the relationship between PTSD and DMN connectivity, a putative neural endophenotype of the disorder.