Multimodal workflows optimally predict response to repetitive transcranial magnetic stimulation in patients with schizophrenia: a multisite machine learning analysis.

The response variability to repetitive transcranial magnetic stimulation (rTMS) challenges the effective use of this treatment option in patients with schizophrenia. This variability may be deciphered by leveraging predictive information in structural MRI, clinical, sociodemographic, and genetic data using artificial intelligence. We developed and cross-validated rTMS response prediction models in patients with schizophrenia drawn from the multisite RESIS trial. The models incorporated pre-treatment sMRI, clinical, sociodemographic, and polygenic risk score (PRS) data. Patients were randomly assigned to receive active (N = 45) or sham (N = 47) rTMS treatment. The prediction target was individual response, defined as ≥20% reduction in pre-treatment negative symptom sum scores of the Positive and Negative Syndrome Scale. Our multimodal sequential prediction workflow achieved a balanced accuracy (BAC) of 94% (non-responders: 92%, responders: 95%) in the active-treated group and 50% in the sham-treated group. The clinical, clinical + PRS, and sMRI-based classifiers yielded BACs of 65%, 76%, and 80%, respectively. Apparent sadness, inability to feel, educational attainment PRS, and unemployment were most predictive of non-response in the clinical + PRS model, while grey matter density reductions in the default mode, limbic networks, and the cerebellum were most predictive in the sMRI model. Our sequential modelling approach provided superior predictive performance while minimising the diagnostic burden in the clinical setting. Predictive patterns suggest that rTMS responders may have higher levels of brain grey matter in the default mode and salience networks which increases their likelihood of profiting from plasticity-inducing brain stimulation methods, such as rTMS. The future clinical implementation of our models requires findings to be replicated at the international scale using stratified clinical trial designs.

Multimodal Associations of FKBP5 Methylation with Emotion-Regulatory Brain Circuits.

BACKGROUND: Understanding the biological processes underlying individual differences in emotion regulation and stress responsivity is a key challenge for translational neuroscience. The gene FKBP5 is a core regulator in molecular stress signaling that is implicated in the development of psychiatric disorders. Yet it remains unclear how FKBP5 DNA methylation (DNAm) in peripheral blood relates to individual differences in measures of neural structure and function, and their relevance to daily-life stress responsivity. METHODS: Here, we characterize multimodal correlates of FKBP5 DNAm by combining epigenetic data with neuroimaging and Ambulatory Assessment in a sample of 395 healthy individuals. RESULTS: First, we show that FKBP5 demethylation as a psychiatric risk factor relates to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex (vmPFC), a brain area that is involved in emotion regulation and mental health risk and resilience. This effect of epigenetic upregulation of FKBP5 on neuronal structure is more pronounced where FKBP5 is epigenetically downregulated at baseline. Leveraging 208 functional MRI scans during a well-established emotion processing task we find that FKBP5 DNAm in peripheral blood is associated with functional difference of prefrontal-limbic circuits modulating affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life. CONCLUSIONS: Overall, we demonstrate how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits.

Biological aging markers in blood and brain tissue indicate age acceleration in alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is associated with increased mortality and morbidity risk. A reason for this could be accelerated biological aging, which is strongly influenced by disease processes such as inflammation. As recent studies of AUD show changes in DNA methylation and gene expression in neuroinflammation-related pathways in the brain, biological aging represents a potentially important construct for understanding the adverse effects of substance use disorders. Epigenetic clocks have shown accelerated aging in blood samples from individuals with AUD. However, no systematic evaluation of biological age measures in AUD across different tissues and brain regions has been undertaken. METHODS: As markers of biological aging (BioAge markers), we assessed Levine's and Horvath's epigenetic clocks, DNA methylation telomere length (DNAmTL), telomere length (TL), and mitochondrial DNA copy number (mtDNAcn) in postmortem brain samples from Brodmann Area 9 (BA9), caudate nucleus, and ventral striatum (N = 63-94), and in whole blood samples (N = 179) of individuals with and without AUD. To evaluate the association between AUD status and BioAge markers, we performed linear regression analyses while adjusting for covariates. RESULTS: The majority of BioAge markers were significantly associated with chronological age in all samples. Levine's epigenetic clock and DNAmTL were indicative of accelerated biological aging in AUD in BA9 and whole blood samples, while Horvath's showed the opposite effect in BA9. No significant association of AUD with TL and mtDNAcn was detected. Measured TL and DNAmTL showed only small correlations in blood and none in brain. CONCLUSIONS: The present study is the first to simultaneously investigate epigenetic clocks, telomere length, and mtDNAcn in postmortem brain and whole blood samples in individuals with AUD. We found evidence for accelerated biological aging in AUD in blood and brain, as measured by Levine's epigenetic clock, and DNAmTL. Additional studies of different tissues from the same individuals are needed to draw valid conclusions about the congruence of biological aging in blood and brain.

Speech Features as Predictors of Momentary Depression Severity in Patients With Depressive Disorder Undergoing Sleep Deprivation Therapy: Ambulatory Assessment Pilot Study.

BACKGROUND: The use of mobile devices to continuously monitor objectively extracted parameters of depressive symptomatology is seen as an important step in the understanding and prevention of upcoming depressive episodes. Speech features such as pitch variability, speech pauses, and speech rate are promising indicators, but empirical evidence is limited, given the variability of study designs. OBJECTIVE: Previous research studies have found different speech patterns when comparing single speech recordings between patients and healthy controls, but only a few studies have used repeated assessments to compare depressive and nondepressive episodes within the same patient. To our knowledge, no study has used a series of measurements within patients with depression (eg, intensive longitudinal data) to model the dynamic ebb and flow of subjectively reported depression and concomitant speech samples. However, such data are indispensable for detecting and ultimately preventing upcoming episodes. METHODS: In this study, we captured voice samples and momentary affect ratings over the course of 3 weeks in a sample of patients (N=30) with an acute depressive episode receiving stationary care. Patients underwent sleep deprivation therapy, a chronotherapeutic intervention that can rapidly improve depression symptomatology. We hypothesized that within-person variability in depressive and affective momentary states would be reflected in the following 3 speech features: pitch variability, speech pauses, and speech rate. We parametrized them using the extended Geneva Minimalistic Acoustic Parameter Set (eGeMAPS) from open-source Speech and Music Interpretation by Large-Space Extraction (openSMILE; audEERING GmbH) and extracted them from a transcript. We analyzed the speech features along with self-reported momentary affect ratings, using multilevel linear regression analysis. We analyzed an average of 32 (SD 19.83) assessments per patient. RESULTS: Analyses revealed that pitch variability, speech pauses, and speech rate were associated with depression severity, positive affect, valence, and energetic arousal; furthermore, speech pauses and speech rate were associated with negative affect, and speech pauses were additionally associated with calmness. Specifically, pitch variability was negatively associated with improved momentary states (ie, lower pitch variability was linked to lower depression severity as well as higher positive affect, valence, and energetic arousal). Speech pauses were negatively associated with improved momentary states, whereas speech rate was positively associated with improved momentary states. CONCLUSIONS: Pitch variability, speech pauses, and speech rate are promising features for the development of clinical prediction technologies to improve patient care as well as timely diagnosis and monitoring of treatment response. Our research is a step forward on the path to developing an automated depression monitoring system, facilitating individually tailored treatments and increased patient empowerment.

Childhood Trauma and Somatic and Mental Illness in Adulthood.

BACKGROUND: Childhood trauma is associated with somatic and mental illness in adulthood. The strength of the association varies as a function of age, sex, and type of trauma. Pertinent studies to date have mainly focused on individual diseases. In this study, we investigate the association between childhood trauma and a multiplicity of somatic and mental illnesses in adulthood. METHODS: Data from 156 807 NAKO Health Study participants were analyzed by means of logistic regressions, with adjustment for age, sex, years of education, and study site. The Childhood Trauma Screener differentiated between no/minor (n = 115 891) and moderate/severe childhood trauma (n = 40 916). The outcome variables were medical diagnoses of five somatic and two mental health conditions as stated in the clinical history. RESULTS: Persons with childhood trauma were more likely to bear a diagnosis of all of the studied conditions: cancer (odds ratio [OR] = 1.10; 95% confidence interval: [1.05; 1.15]), myocardial infarction (OR = 1.13 [1.03; 1.24]), diabetes (OR = 1.16, [1.10; 1.23]), stroke (OR = 1.35 [1.23; 1.48]), chronic obstructive pulmonary disease (OR = 1.45 [1.38; 1.52]), depression (OR = 2.36 [2.29; 2.43]), and anxiety disorders (OR = 2.08 [2.00; 2.17]). All of these associations were stronger in younger persons, regardless of the nature of childhood trauma. Differences between the sexes were observed only for some of these associations. CONCLUSION: Childhood trauma was associated with a higher probability of developing mental as well as somatic illness in adulthood. As childhood trauma is an element of individual history that the victim has little to no control over, and because the illnesses that can arise in adulthood in association with it are a heavy burden on the affected persons and on society, there is a need for research on these associations and for the development of preventive measures.

Impulsivity, decision-making, and risk behavior in bipolar disorder and major depression from bipolar multiplex families.

OBJECTIVES: Bipolar disorder (BD) and major depressive disorder (MDD) are characterized by specific alterations of mood. In both disorders, alterations in cognitive domains such as impulsivity, decision-making, and risk-taking have been reported. Identification of similarities and differences of these domains in BD and MDD could give further insight into their etiology. The present study assessed impulsivity, decision-making, and risk-taking behavior in BD and MDD patients from bipolar multiplex families. METHODS: Eighty-two participants (BD type I, n = 25; MDD, n = 26; healthy relatives (HR), n = 17; and healthy controls (HC), n = 14) underwent diagnostic interviews and selected tests of a cognitive battery assessing neurocognitive performance across multiple subdomains including impulsivity (response inhibition and delay aversion), decision-making, and risk behavior. Generalized estimating equations (GEEs) were used to analyze whether the groups differed in the respective cognitive domains. RESULTS: Participants with BD and MDD showed higher impulsivity levels compared to HC; this difference was more pronounced in BD participants. BD participants also showed lower inhibitory control than MDD participants. Overall, suboptimal decision-making was associated with both mood disorders (BD and MDD). In risk-taking behavior, no significant impairment was found in any group. LIMITATIONS: As sample size was limited, it is possible that differences between BD and MDD may have escaped detection due to lack of statistical power. CONCLUSIONS: Our findings show that alterations of cognitive domains-while present in both disorders-are differently associated with BD and MDD. This underscores the importance of assessing such domains in addition to mere diagnosis of mood disorders.

Evidence for a shared genetic contribution to loneliness and borderline personality disorder.

Loneliness, influenced by genetic and environmental factors such as childhood maltreatment, is one aspect of interpersonal dysfunction in Borderline Personality Disorder (BPD). Numerous studies link loneliness and BPD and twin studies indicate a genetic contribution to this association. The aim of our study was to investigate whether genetic predisposition for loneliness and BPD risk overlap and whether genetic risk for loneliness contributes to higher loneliness reported by BPD patients, using genome-wide genotype data. We assessed the genetic correlation of genome-wide association studies (GWAS) of loneliness and BPD using linkage disequilibrium score regression and tested whether a polygenic score for loneliness (loneliness-PGS) was associated with case-control status in two independent genotyped samples of BPD patients and healthy controls (HC; Witt2017-sample: 998 BPD, 1545 HC; KFO-sample: 187 BPD, 261 HC). In the KFO-sample, we examined associations of loneliness-PGS with reported loneliness, and whether the loneliness-PGS influenced the association between childhood maltreatment and loneliness. We found a genetic correlation between the GWAS of loneliness and BPD in the Witt2017-sample (rg = 0.23, p = 0.015), a positive association of loneliness-PGS with BPD case-control status (Witt2017-sample: NkR² = 2.3%, p = 2.7*10-12; KFO-sample: NkR² = 6.6%, p = 4.4*10-6), and a positive association between loneliness-PGS and loneliness across patient and control groups in the KFO-sample (ß = 0.186, p = 0.002). The loneliness-PGS did not moderate the association between childhood maltreatment and loneliness in BPD. Our study is the first to use genome-wide genotype data to show that the genetic factors underlying variation in loneliness in the general population and the risk for BPD overlap. The loneliness-PGS was associated with reported loneliness. Further research is needed to investigate which genetic mechanisms and pathways are involved in this association and whether a genetic predisposition for loneliness contributes to BPD risk.

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.

Association of polygenic scores for depression and neuroticism with perceived stress in daily life during a long-lasting stress period.

Genetic factors contribute significantly to interindividual differences in the susceptibility to stress-related disorders. As stress can also be conceptualized as environmental exposure, controlled gene-environment interaction (GxE) studies with an in-depth phenotyping may help to unravel mechanisms underlying the interplay between genetic factors and stress. In a prospective-longitudinal quasi-experimental study, we investigated whether polygenic scores (PGS) for depression (DEP-PGS) and neuroticism (NEU-PGS), respectively, were associated with responses to chronic stress in daily life. We examined law students (n = 432) over 13 months. Participants in the stress group experienced a long-lasting stress phase, namely the preparation for the first state examination for law students. The control group consisted of law students without particular stress exposure. In the present manuscript, we analyzed perceived stress levels assessed at high frequency and in an ecologically valid manner by ambulatory assessments as well as depression symptoms and two parameters of the cortisol awakening response. The latter was only assessed in a subsample (n = 196). No associations between the DEP-PGS and stress-related variables were found. However, for the NEU-PGS we found a significant GxE effect. Only in individuals experiencing academic stress a higher PGS for neuroticism predicted stronger increases of perceived stress levels until the exam. At baseline, a higher NEU-PGS was associated with higher perceived stress levels in both groups. Despite the small sample size, we provide preliminary evidence that the genetic disposition for neuroticism is associated with stress level increases in daily life during a long-lasting stress period.

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.

Psychological, endocrine and polygenic predictors of emotional well-being during the COVID-19 pandemic in a longitudinal birth cohort.

The COVID-19 pandemic severely affected the lives of families and the well-being of both parents and their children. Various factors, including prenatal stress, dysregulated stress response systems, and genetics may have influenced how the stress caused by the pandemic impacted the well-being of different family members. The present work investigated if emotional well-being during the COVID-19 pandemic could be predicted by developmental stress-related and genetic factors. Emotional well-being of 7-10 year-old children (n = 263) and mothers (n = 241) (participants in a longitudinal German birth cohort (POSEIDON)) was assessed during the COVID-19 pandemic using the CRISIS questionnaire at two time periods (July 2020-October 2020; November 2020-February 2021). Associations of the children's and mothers' well-being with maternal perceived stress, of the children's well-being with their salivary and morning urine cortisol at 45 months, and polygenic risk scores (PRSs) for depression, schizophrenia, loneliness were investigated. Lower emotional well-being was observed in both children and mothers during compared to before the pandemic, with the children's but not the mothers' emotional well-being improving over the course of the pandemic. A positive association between the child and maternal emotional well-being was found. Prenatally assessed maternal perceived stress was associated with a lower well-being in children, but not in mothers. Cortisol measures and PRSs were not significantly associated with the children's emotional well-being. The present study confirms that emotional well-being of children and mothers are linked, and were negatively affected by the COVID-19 pandemic, with differences in development over time.

The Impact of Childhood Traumatization on Diabetes Mellitus Type 2 Risk in World War II Refugees and Their Offspring.

OBJECTIVE: Type 2 diabetes mellitus (T2D) is a chronic disease that is influenced by different factors. The extent to which degree adverse childhood events (ACEs) can modify the potential to development of T2D is still not explored and therefore represents one of the central questions of the childhood escape-late life outcome (DRKS00012419) study. In addition, transgenerational effects were considered in the analyses. METHODS: The study analyzed the association of self-reported traumatic experiences and T2D disease of refugees from East Prussia, who were displaced from their former homeland at the end of the World War II. In addition, an independent sample consisting of participants of first-generation offspring of refugees was analyzed. RESULTS: Of the 242 refugees, all aged between 73 and 93 years, 17.36% reported T2D disease, whereas among the offspring ( n = 272), aged between 47 and 73 years, it was 5.5%, meaning reduced T2D prevalence for both generations compared with the German population of comparable age. In the refugee generation, emotional neglect showed a negative association with development of T2D in later life. In women, separation from close caregivers in childhood showed a negative association with later T2D. In contrast, experiencing emotional abuse in childhood showed a positive association with later T2D. The offspring generation showed no associations of adverse childhood events and reported T2D diagnoses in later life. CONCLUSIONS: Our results demonstrate that individual trauma in childhood is responded to with different mechanisms that can lead to both increased and decreased reported T2D diagnoses in adulthood and thus should by no means be considered in a generalized manner.

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.

DNA methylation in cocaine use disorder-An epigenome-wide approach in the human prefrontal cortex.

Background: Cocaine use disorder (CUD) is characterized by a loss of control over cocaine intake and is associated with structural, functional, and molecular alterations in the human brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes observed in CUD. Most evidence of cocaine-associated epigenetic changes comes from animal studies while only a few studies have been performed using human tissue. Methods: We investigated epigenome-wide DNA methylation (DNAm) signatures of CUD in human post-mortem brain tissue of Brodmann area 9 (BA9). A total of N = 42 BA9 brain samples were obtained from N = 21 individuals with CUD and N = 21 individuals without a CUD diagnosis. We performed an epigenome-wide association study (EWAS) and analyzed CUD-associated differentially methylated regions (DMRs). To assess the functional role of CUD-associated differential methylation, we performed Gene Ontology (GO) enrichment analyses and characterized co-methylation networks using a weighted correlation network analysis. We further investigated epigenetic age in CUD using epigenetic clocks for the assessment of biological age. Results: While no cytosine-phosphate-guanine (CpG) site was associated with CUD at epigenome-wide significance in BA9, we detected a total of 20 CUD-associated DMRs. After annotation of DMRs to genes, we identified Neuropeptide FF Receptor 2 (NPFFR2) and Kalirin RhoGEF Kinase (KALRN) for which a previous role in the behavioral response to cocaine in rodents is known. Three of the four identified CUD-associated co-methylation modules were functionally related to neurotransmission and neuroplasticity. Protein-protein interaction (PPI) networks derived from module hub genes revealed several addiction-related genes as highly connected nodes such as Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit (JUN). In BA9, we observed a trend toward epigenetic age acceleration (EAA) in individuals with CUD remaining stable even after adjustment for covariates. Conclusion: Results from our study highlight that CUD is associated with epigenome-wide differences in DNAm levels in BA9 particularly related to synaptic signaling and neuroplasticity. This supports findings from previous studies that report on the strong impact of cocaine on neurocircuits in the human prefrontal cortex (PFC). Further studies are needed to follow up on the role of epigenetic alterations in CUD focusing on the integration of epigenetic signatures with transcriptomic and proteomic data.

Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation.

Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.

Genetic contributions to transdiagnostic symptom dimensions in patients with major depressive disorder, bipolar disorder, and schizophrenia spectrum disorders.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorders (SZ) exhibit considerable phenotypic and genetic overlap. However, the contribution of genetic factors to their shared psychopathological symptom dimensions remains unclear. The present exploratory study investigated genetic contributions to the symptom dimensions "Depression", "Negative syndrome", "Positive formal thought disorder", "Paranoid-hallucinatory syndrome", and "Increased appetite" in a transdiagnostic subset of the German FOR2107 cohort (n = 1042 patients with MDD, BD, or SZ). As replication cohort, a subset of the German/Austrian PsyCourse study (n = 816 patients with MDD, BD, or SZ) was employed. First, the relationship between symptom dimensions and common variants associated with MDD, BD, and SZ was investigated via polygenic risk score (PRS) association analyses, with disorder-specific PRS as predictors and symptom dimensions as outcomes. In the FOR2107 study sample, PRS for BD and SZ were positively associated with "Positive formal thought disorder", the PRS for SZ was positively associated with "Paranoid-hallucinatory syndrome", and the PRS for BD was negatively associated with "Depression". The effects of PRS for SZ were replicated in PsyCourse. No significant associations were observed for the MDD PRS. Second, genome-wide association studies (GWAS) were performed for the five symptom dimensions. No genome-wide significant associations and no replicable suggestive associations (p < 1e-6 in the GWAS) were identified. In summary, our results suggest that, similar to diagnostic categories, transdiagnostic psychiatric symptom dimensions are attributable to polygenic contributions with small effect sizes. Further studies in larger thoroughly phenotyped psychiatric cohorts are required to elucidate the genetic factors that shape psychopathological symptom dimensions.

Generalised anxiety and panic symptoms in the German National Cohort (NAKO).

OBJECTIVES: Anxiety disorders (AD) are common in the general population, leading to high emotional distress and disability. The German National Cohort (NAKO) is a population-based mega-cohort study, examining participants in 16 German regions. The present study includes data of the first 101,667 participants and investigates the frequency and severity of generalised anxiety symptoms and panic attacks (PA). METHODS: The Generalised Anxiety Disorder Symptoms Scale (GAD-7) and the first part of the Patient Health Questionnaire Panic Disorder (PHQ-PD) were filled out by NAKO participants (93,002). We examined the correlation of GAD-7 and PHQ-PD with demographic variables, stress (PHQ-Stress), depression (PHQ-9) and childhood trauma (CTS). RESULTS: The total proportion of prior lifetime diagnoses of AD in the NAKO cohort reached 7.8%. Panic attacks were reported by 6.0% and possible/probable current GAD symptoms in 5.2% of the examined participants. Higher anxiety severity was associated with female sex, lower education level, German as a foreign language and younger age as well as high perceived stress and depression. CONCLUSIONS: Clinically relevant GAD symptoms as well as panic attacks are frequent in the NAKO and are associated with sociodemographic factors, and high anxiety symptoms are accompanied by pronounced stress and depression levels.

Lifetime and current depression in the German National Cohort (NAKO).

OBJECTIVES: The present study introduces the assessment of depression and depressive symptoms in the German National Cohort (NAKO), a population-based mega cohort. Distribution of core measures, and associations with sociodemographic factors are examined. METHODS: The current analysis includes data from the first 101,667 participants (NAKO data freeze 100,000). Depression and depressive symptoms were assessed using a modified version of the depression section of the Mini-International Neuropsychiatric Interview (MINI), self-reported physician's diagnosis of depression, and the depression scale of the Patient Health Questionnaire (PHQ-9). RESULTS: A lifetime physician's diagnosis of depression was reported by 15.0% of participants. Of those, 47.6% reported having received treatment for depression within the last 12 months. Of the subset of 26,342 participants undergoing the full depression section of the modified MINI, 15.9% were classified by the MINI with a lifetime depressive episode. Based on the PHQ-9, 5.8% of the participants were classified as currently having a major or other depression by the diagnostic algorithm, and 7.8% according to the dimensional assessment (score ≥ 10). Increased frequency of depression measures and higher depression scores were observed in women and participants with lower education level or a family history of depression. CONCLUSIONS: The observed distributions of all depression measures and their associations with sociodemographic variables are consistent with the literature on depression. The NAKO represents a valuable epidemiologic resource to investigate depression, and the range of measures for lifetime and current depression allows users to select the most suitable instrument for their specific research question.

The assessment of cognitive function in the German National Cohort (NAKO) - Associations of demographics and psychiatric symptoms with cognitive test performance.

OBJECTIVES: To describe the cognitive test battery of the German National Cohort (NAKO), a population-based mega cohort of 205,000 randomly selected participants, and to examine associations with demographic variables and selected psychiatric and neurological conditions. METHODS: Initial data from 96,401 participants providing data on the cognitive performance measured by a brief cognitive test battery (12-word list recall task, semantic fluency, Stroop test, digit span backwards) was examined. Test results were summarised in cognitive domain scores using exploratory and confirmatory factor analyses. Associations with sociodemographic and psychiatric factors were analysed using linear regression and generalised additive models. RESULTS: Cognitive test results were best represented by two domain scores reflecting memory and executive functions. Lower cognitive functions were associated with increasing age and male sex. Higher education and absence of childhood trauma were associated with better cognitive function. Moderate to severe levels of anxiety and depression, and a history of stroke, were related to lower cognitive function with a stronger effect on executive function as compared to memory. Some associations with cognition differed by German language proficiency. CONCLUSIONS: The NAKO cognitive test battery and the derived cognitive domain scores for memory and executive function are sensitive measures of cognition.

General cognitive ability assessment in the German National Cohort (NAKO) - The block-adaptive number series task.

Objectives. Evaluate the block-adaptive number series task of reasoning, as a time-efficient proxy of general cognitive ability in the Level-2 sample of the German National Cohort (NAKO), a population-based mega cohort.Methods. The number series task consisted of two blocks of three items each, administered as part of the touchscreen-based assessment. Based on performance on the first three items, a second block of appropriate difficulty was automatically administered. Scoring of performance was based on the Rasch model. Relations of performance scores to age, sex, education, study centre, language proficiency, and scores on other cognitive tasks were examined.Results. Except for one very difficult item, the data of the remaining 14 items showed sufficient fit to the Rasch model (Infit: 0.89-1.04; Outfit: 0.80-1.08). The resulting performance scores (N = 21,056) had a distribution that was truncated at very high levels of ability. The reliability of the performance estimates was satisfactory. Relations to age, sex, education, and the executive function factor of the other cognitive tasks in the NAKO supported the validity.Conclusions. The number series task provides a valid proxy of general cognitive ability for the Level-2 sample of the NAKO, based on a highly time-efficient assessment procedure.