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.

Exploring the genetics of lithium response in bipolar disorders.

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

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.

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.

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.

Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10- 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3ß. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.

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.

Generation of three induced pluripotent stem cell lines carrying different variants of the BDNF (Val66Met) polymorphism.

Brain-derived neurotrophic factor (BDNF) has been implicated in a multitude of neurodevelopmental processes including neuronal differentiation, axonal outgrowth, synaptic plasticity, or survival. One human-specific single nucleotide polymorphism (rs6265) in the BDNF gene causes a substitution of valine (Val) to methionine (Met) at codon 66 in the pro domain of the protein (Val66Met). This substitution is associated to reduced hippocampal volumes, poor performance on hippocampal-dependent memory tasks, and some mental disorders such as schizophrenia, depression or Alzheimer's disease. Here we generated three iPSC lines from healthy donors, either homozygous (Val/Val and Met/Met) or heterozygous (Val/Met) for the polymorphism.

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 interplay of family history of depression and early trauma: associations with lifetime and current depression in the German national cohort (NAKO).

Introduction: Family history of depression and childhood maltreatment are established risk factors for depression. However, how these factors are interrelated and jointly influence depression risk is not well understood. The present study investigated (i) if childhood maltreatment is associated with a family history of depression (ii) if family history and childhood maltreatment are associated with increased lifetime and current depression, and whether both factors interact beyond their main effects, and (iii) if family history affects lifetime and current depression via childhood maltreatment. Methods: Analyses were based on a subgroup of the first 100,000 participants of the German National Cohort (NAKO), with complete information (58,703 participants, mean age = 51.2 years, 53% female). Parental family history of depression was assessed via self-report, childhood maltreatment with the Childhood Trauma Screener (CTS), lifetime depression with self-reported physician's diagnosis and the Mini-International Neuropsychiatric Interview (MINI), and current depressive symptoms with the depression scale of the Patient Health Questionnaire (PHQ-9). Generalized linear models were used to test main and interaction effects. Mediation was tested using causal mediation analyses. Results: Higher frequencies of the childhood maltreatment measures were found in subjects reporting a positive family history of depression. Family history and childhood maltreatment were independently associated with increased depression. No statistical interactions of family history and childhood maltreatment were found for the lifetime depression measures. For current depressive symptoms (PHQ-9 sum score), an interaction was found, with stronger associations of childhood maltreatment and depression in subjects with a positive family history. Childhood maltreatment was estimated to mediate 7%-12% of the effect of family history on depression, with higher mediated proportions in subjects whose parents had a depression onset below 40 years. Abuse showed stronger associations with family history and depression, and higher mediated proportions of family history effects on depression than neglect. Discussion: The present study confirms the association of childhood maltreatment and family history with depression in a large population-based cohort. While analyses provide little evidence for the joint effects of both risk factors on depression beyond their individual effects, results are consistent with family history affecting depression via childhood maltreatment to a small extent.

Depression and bipolar disorder subtypes differ in their genetic correlations with biological rhythms.

Major Depression and Bipolar Disorder Type I (BIP-I) and Type II (BIP-II), are characterized by depressed, manic, and hypomanic episodes in which specific changes of physical activity, circadian rhythm, and sleep are observed. It is known that genetic factors contribute to variation in mood disorders and biological rhythms, but unclear to what extent there is an overlap between their underlying genetics. In the present study, data from genome-wide association studies were used to examine the genetic relationship between mood disorders and biological rhythms. We tested the genetic correlation of depression, BIP-I, and BIP-II with physical activity (overall physical activity, moderate activity, sedentary behaviour), circadian rhythm (relative amplitude), and sleep features (sleep duration, daytime sleepiness). Genetic correlations of depression, BIP-I, and BIP-II with biological rhythms were compared to discover commonalities and differences. A gene-based analysis tested for associations of single genes and common circadian genes with mood disorders. Depression was negatively correlated with overall physical activity and positively with sedentary behaviour, while BIP-I showed associations in the opposite direction. Depression and BIP-II had negative correlations with relative amplitude. All mood disorders were positively correlated with daytime sleepiness. Overall, we observed both genetic commonalities and differences across mood disorders in their relationships with biological rhythms: depression and BIP-I differed the most, while BIP-II was in an intermediate position. Gene-based analysis suggested potential targets for further investigation. The present results suggest shared genetic underpinnings for the clinically observed associations between mood disorders and biological rhythms. Research considering possible joint mechanisms may offer avenues for improving disease detection and treatment.

The association between genetic variability in the NPS/NPSR1 system and chronic stress responses: A gene-environment-(quasi-) experiment.

The neuropeptide S (NPS) and its receptor (NPSR1) have been implicated in stress regulation and stress-related disorders. The present study aimed at investigating the association between overall genetic variability in the NPS/NPSR1 system and psychological and cortisol stress regulation in everyday life. Our study was conceptualized as a gene-environment-(quasi-) experiment, a design that facilitates the detection of true GxE interactions. As environmental variable, we used the preparation for the first state examination for law students. In the prospective and longitudinal LawSTRESS project, students were examined at six sampling points over a 13-months period. While students who prepared for the exam and experienced long-lasting and significant stress, formed the stress group, law students experiencing usual study-related workload were assigned to the control group. As phenotypes we assessed changes over time in the cortisol awakening response (CAR; n = 176), perceived stress levels (n = 401), and anxiety symptoms (n = 397). The CAR was assessed at each sampling point immediately upon awakening and 30 as well as 45 min later. Perceived stress levels in daily life were measured by repeated ambulatory assessments and anxiety symptoms were repeatedly assessed with the anxiety subscale of the Hospital Anxiety and Depression Scale. With gene-set analyses we examined the joint association of 936 NPS/NPSR1 single nucleotide polymorphisms with the phenotypes to overcome well known limitations of candidate gene studies. As previously reported, we found a blunted CAR during the exam as well as significant increases in perceived stress levels and anxiety symptoms until the exam in the stress group, compared to the control group. The gene-set analysis did not confirm associations between genetic variability in the NPS/NPSR1 system and changes in perceived stress levels and anxiety symptoms. Regarding the CAR, we found a significant GxE interaction for the area under the curve with respect to the ground (p = .050) and a trend towards a significant effect for the area under the curve with respect to the increase (p = .054). When the analysis was restricted to the SG, associations for both CAR parameters were significant (ps < .050). This finding suggests that the association between genetic variability in the NPS/NPSR1 system and the CAR becomes visible under the environmental condition 'chronic stress exposure'. We conclude that the present study complements findings from animal models and that it provides novel evidence for a modulatory influence of the NPS/NPSR1 system on cortisol regulation in humans.

Association of polygenic risk for schizophrenia with fast sleep spindle density depends on pro-cognitive variants.

Cognitive impairment is a common feature in schizophrenia and the strongest prognostic factor for long-term outcome. Identifying a trait associated with the genetic background for cognitive outcome in schizophrenia may aid in a deeper understanding of clinical disease subtypes. Fast sleep spindles may represent such a biomarker as they are strongly genetically determined, associated with cognitive functioning and impaired in schizophrenia and unaffected relatives. We measured fast sleep spindle density in 150 healthy adults and investigated its association with a genome-wide polygenic score for schizophrenia (SCZ-PGS). The association between SCZ-PGS and fast spindle density was further characterized by stratifying it to the genetic background of intelligence. SCZ-PGS was positively associated with fast spindle density. This association mainly depended on pro-cognitive genetic variants. Our results strengthen the evidence for a genetic background of spindle abnormalities in schizophrenia. Spindle density might represent an easily accessible marker for a favourable cognitive outcome which should be further investigated in clinical samples.

Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum.

Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. Differential gene expression was observed in the dorsal (FDR < 0.05), but not the ventral striatum of AUD cases. In the VS, DE genes at FDR < 0.25 were overrepresented in a recent GWAS of problematic alcohol use. The ARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune- and inflammation-related processes in AUD.

Epigenetic Signatures of Smoking in Five Brain Regions.

(1) Background: Epigenome-wide association studies (EWAS) in peripheral blood have repeatedly found associations between tobacco smoking and aberrant DNA methylation (DNAm), but little is known about DNAm signatures of smoking in the human brain, which may contribute to the pathophysiology of addictive behavior observed in chronic smokers. (2) Methods: We investigated the similarity of DNAm signatures in matched blood and postmortem brain samples (n = 10). In addition, we performed EWASs in five brain regions belonging to the neurocircuitry of addiction: anterior cingulate cortex (ACC), Brodmann Area 9, caudate nucleus, putamen, and ventral striatum (n = 38-72). (3) Results: cg15925993 within the LOC339975 gene was epigenome-wide significant in the ACC. Of 16 identified differentially methylated regions, two (PRSS50 and LINC00612/A2M-AS1) overlapped between multiple brain regions. Functional enrichment was detected for biological processes related to neuronal development, inflammatory signaling and immune cell migration. Additionally, our results indicate the association of the well-known AHRR CpG site cg05575921 with smoking in the brain. (4) Conclusion: The present study provides further evidence of the strong relationship between aberrant DNAm and smoking.

Borderline personality disorder and the big five: molecular genetic analyses indicate shared genetic architecture with neuroticism and openness.

Both environmental (e.g. interpersonal traumatization during childhood and adolescence) and genetic factors may contribute to the development of Borderline Personality Disorder (BPD). Twin studies assessing borderline personality symptoms/features in the general population indicate that genetic factors underlying these symptoms/features are shared in part with the personality traits of the Five Factor Model (FFM) of personality-the "Big Five". In the present study, the genetic overlap of BPD with the Big Five -Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism- was assessed. Linkage disequilibrium score regression was used to calculate genetic correlations between a genome-wide association study (GWAS) in central European populations on BPD (N = 2543) and GWAS on the Big Five (N = 76,551-122,886, Neuroticism N = 390,278). Polygenic scores (PGS) were calculated to test the association of the genetic disposition for the personality traits with BPD case-control status. Significant positive genetic correlations of BPD were found with Neuroticism (rg = 0.34, p = 6.3*10-5) and Openness (rg = 0.24, p = 0.036), but not with the other personality traits (all | rg | <0.14, all p > 0.30). A cluster and item-level analysis showed positive genetic correlations of BPD with the Neuroticism clusters "Depressed Affect" and "Worry", and with a broad range of Neuroticism items (N = 348,219-376,352). PGS analyses confirmed the genetic correlations, and found an independent contribution of the personality traits to BPD risk. The observed associations indicate a partially shared genetic background of BPD and the personality traits Neuroticism and Openness. Larger GWAS of BPD and the "Big Five" are needed to further explore the role of personality traits in the etiology of BPD.

Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms.

BACKGROUND: Previous genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions. METHODS: We conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants. RESULTS: Variants at the CTRC (p = 1.22 × 10-21) and SPINK1 (p = 6.59 × 10-47) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220. CONCLUSIONS: A shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression.