TY - JOUR A1 - Hibar, Derrek P. A1 - Adams, Hieab H.H. A1 - Jahanshad, Neda A1 - Chauhan, Ganesh A1 - Stein, Jason L A1 - Hofer, Edith A1 - Renteria, Miguel E. A1 - Bis, Joshua C. A1 - Arias-Vasquez, Alejandro A1 - Ikram, M. Kamran A1 - Desrivières, Sylvane A1 - Vernooij, Meike W. A1 - Abramovic, Lucija A1 - Alhusaini, Saud A1 - Amin, Najaf A1 - Andersson, Micael A1 - Arfanakis, Konstantinos A1 - Aribisala, Benjamin S. A1 - Armstrong, Nicola J. A1 - Athanasiu, Lavinia A1 - Axelsson, Tomas A1 - Beecham, Ashley H. A1 - Beiser, Alexa A1 - Bernard, Manon A1 - Blanton, Susan H. A1 - Bohlken, Marc M. A1 - Boks, Marco P. A1 - Bralten, Janita A1 - Brickman, Adam M. A1 - Carmichael, Owen T1 - Novel genetic loci associated with hippocampal volume JF - Nature Communications N2 - The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (r\(_g\)=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. KW - brain KW - hippocampal formation KW - neuropsychiatric disorders KW - Alzheimer’s disease KW - genetic loci KW - hippocampal volume Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-182115 VL - 8 ER - TY - JOUR A1 - Appel, Patricia A1 - Schuler, Michael A1 - Vogel, Heiner A1 - Oezelsel, Amina A1 - Faller, Hermann T1 - Short Questionnaire for Workplace Analysis (KFZA): factorial validation in physicians and nurses working in hospital settings JF - Journal of Occupational Medicine and Toxicology N2 - Background: In recent years, there has been an increasing interest in psychosocial workplace risk assessments in Germany. One of the questionnaires commonly employed for this purpose is the Short Questionnaire for Workplace Analysis (KFZA). Originally, the KFZA was developed and validated for office workers. The aim of the present study was to examine the factorial validity of the KFZA when applied to hospital settings. Therefore, we examined the factorial structure of a questionnaire that contained all the original items plus an extension adding 11 questions specific to hospital workplaces and analyzed both, the original version and the extended version. Methods: We analyzed questionnaire data of a total of 1731 physicians and nurses obtained over a 10-year period. Listwise exclusion of data sets was applied to account for variations in questionnaire versions and yielded 1163 questionnaires (1095 for the extended version) remaining for factor analysis. To examine the factor structure, we conducted a principal component factor analysis. The number of factors was determined using the Kaiser criterion and scree-plot methods. Factor interpretation was based on orthogonal Varimax rotation as well as oblique rotation. Results: The Kaiser criterion revealed a 7-factor solution for the 26 items of the KFZA, accounting for 62.0% of variance. The seven factors were named: “Social Relationships”, “Job Control”, “Opportunities for Participation and Professional Development”, “Quantitative Work Demands”, “Workplace Environment”, “Variability” and “Qualitative Work Demands”. The factor analysis of the 37 items of the extended version yielded a 9-factor solution. The two additional factors were named “Consequences of Strain” and “Emotional Demands”. Cronbach’s α ranged from 0.63 to 0.87 for these scales. Conclusions: Overall, the KFZA turned out to be applicable to hospital workers, and its content-related structure was replicated well with some limitations. However, instead of the 11 factors originally proposed for office workers, a 7-factor solution appeared to be more suitable when employed in hospitals. In particular, the items of the KFZA factor “Completeness of Task” might need adaptation for the use in hospitals. Our study contributes to the assessment of the validity of this popular instrument and should stimulate further psychometric testing. KW - KFZA KW - mental health KW - work-related stress KW - hospital KW - psychosocial workplace risk assessment KW - validation Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157510 VL - 12 IS - 11 ER - TY - JOUR A1 - Vangeel, Elise Beau A1 - Pishva, Ehsan A1 - Hompes, Titia A1 - van den Hove, Daniel A1 - Lambrechts, Diether A1 - Allegaert, Karel A1 - Freson, Kathleen A1 - Izzi, Benedetta A1 - Claes, Stephan T1 - Newborn genome-wide DNA methylation in association with pregnancy anxiety reveals a potential role for \(GABBR1\) JF - Clinical Epigenetics N2 - Background: There is increasing evidence for the role of prenatal stress in shaping offspring DNA methylation and disease susceptibility. In the current study, we aimed to identify genes and pathways associated with pregnancy anxiety using a genome-wide DNA methylation approach. Methods: We selected 22 versus 23 newborns from our Prenatal Early Life Stress (PELS) cohort, exposed to the lowest or highest degree of maternal pregnancy anxiety, respectively. Cord blood genome-wide DNA methylation was assayed using the HumanMethylation450 BeadChip (HM450, n = 45) and candidate gene methylation using EpiTYPER (n = 80). Cortisol levels were measured at 2, 4, and 12 months of age to test infant stress system (re)activity. Results: Data showed ten differentially methylated regions (DMR) when comparing newborns exposed to low versus high pregnancy anxiety scores. We validated a top DMR in the GABA-B receptor subunit 1 gene (GABBR1) revealing the association with pregnancy anxiety particularly in male newborns (most significant CpG Pearson R = 0.517, p = 0.002; average methylation Pearson R = 0.332, p = 0.039). Cord blood GABBR1 methylation was associated with infant cortisol levels in response to a routine vaccination at 4 months old. Conclusions: In conclusion, our results show that pregnancy anxiety is associated with differential DNA methylation patterns in newborns and that our candidate gene GABBR1 is associated with infant hypothalamic-pituitary-adrenal axis response to a stressor. Our findings reveal a potential role for GABBR1 methylation in association with stress and provide grounds for further research. KW - DNA methylation KW - GABBR1 KW - gender differences KW - HPA axis KW - pregnancy anxiety KW - prenatal stress Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173825 VL - 9 ER - TY - JOUR A1 - Buff, Christine A1 - Brinkmann, Leonie A1 - Bruchmann, Maximilian A1 - Becker, Michael P.I. A1 - Tupak, Sara A1 - Herrmann, Martin J. A1 - Straube, Thomas T1 - Activity alterations in the bed nucleus of the stria terminalis and amygdala during threat anticipation in generalized anxiety disorder JF - Social Cognitive and Affective Neuroscience N2 - Sustained anticipatory anxiety is central to Generalized Anxiety Disorder (GAD). During anticipatory anxiety, phasic threat responding appears to be mediated by the amygdala, while sustained threat responding seems related to the bed nucleus of the stria terminalis (BNST). Although sustained anticipatory anxiety in GAD patients was proposed to be associated with BNST activity alterations, firm evidence is lacking. We aimed to explore temporal characteristics of BNST and amygdala activity during threat anticipation in GAD patients. Nineteen GAD patients and nineteen healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) during a temporally unpredictable threat anticipation paradigm. We defined phasic and a systematic variation of sustained response models for blood oxygen level-dependent responses during threat anticipation, to disentangle temporally dissociable involvement of the BNST and the amygdala. GAD patients relative to HC responded with increased phasic amygdala activity to onset of threat anticipation and with elevated sustained BNST activity that was delayed relative to the onset of threat anticipation. Both the amygdala and the BNST displayed altered responses during threat anticipation in GAD patients, albeit with different time courses. The results for the BNST activation hint towards its role in sustained threat responding, and contribute to a deeper understanding of pathological sustained anticipatory anxiety in GAD. KW - medicine KW - anticipatory anxiety KW - anxiety KW - fMRI KW - sustained threat responding KW - phasic threat responding Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173298 VL - 12 IS - 11 ER - TY - JOUR A1 - Grünblatt, Edna A1 - Oneda, Beatrice A1 - Ekici, Arif B. A1 - Ball, Juliane A1 - Geissler, Julia A1 - Uebe, Steffen A1 - Romanos, Marcel A1 - Rauch, Anita A1 - Walitza, Susanne T1 - High resolution chromosomal microarray analysis in paediatric obsessive-compulsive disorder JF - BMC Medical Genomics N2 - Background Obsessive-Compulsive Disorder (OCD) is a common and chronic disorder in which a person has uncontrollable, reoccurring thoughts and behaviours. It is a complex genetic condition and, in case of early onset (EO), the patients manifest a more severe phenotype, and an increased heritability. Large (>500 kb) copy number variations (CNVs) previously associated with autism and schizophrenia have been reported in OCD. Recently, rare CNVs smaller than 500 kb overlapping risk loci for other neurodevelopmental conditions have also been reported in OCD, stressing the importance of examining CNVs of any size range. The aim of this study was to further investigate the role of rare and small CNVs in the aetiology of EO-OCD. Methods We performed high-resolution chromosomal microarray analysis in 121 paediatric OCD patients and in 124 random controls to identify rare CNVs (>50 kb) which might contribute to EO-OCD. Results The frequencies and the size of the observed rare CNVs in the patients did not differ from the controls. However, we observed a significantly higher frequency of rare CNVs affecting brain related genes, especially deletions, in the patients (OR = 1.98, 95% CI 1.02–3.84; OR = 3.61, 95% CI 1.14–11.41, respectively). Similarly, enrichment-analysis of CNVs gene content, performed with three independent methods, confirmed significant clustering of predefined genes involved in synaptic/brain related functional pathways in the patients but not in the controls. In two patients we detected \(de-novo\) CNVs encompassing genes previously associated with different neurodevelopmental disorders \(\textit{NRXN1, ANKS1B, UHRF1BP1}\)). Conclusions Our results further strengthen the role of small rare CNVs, particularly deletions, as susceptibility factors for paediatric OCD. KW - Medicine KW - OCD KW - CNV KW - Enrichment analysis KW - De-novo KW - Early-onset Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172791 VL - 10 IS - 68 ER - TY - JOUR A1 - Schulz, Herbert A1 - Ruppert, Ann-Kathrin A1 - Herms, Stefan A1 - Wolf, Christiane A1 - Mirza-Schreiber, Nazanin A1 - Stegle, Oliver A1 - Czamara, Darina A1 - Forstner, Andreas J. A1 - Sivalingam, Sugirthan A1 - Schoch, Susanne A1 - Moebus, Susanne A1 - Pütz, Benno A1 - Hillmer, Axel A1 - Fricker, Nadine A1 - Vatter, Hartmut A1 - Müller-Myhsok, Bertram A1 - Nöthen, Markus M. A1 - Becker, Albert J. A1 - Hoffmann, Per A1 - Sander, Thomas A1 - Cichon, Sven T1 - Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus JF - Nature Communications N2 - Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the \(cis\)-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify \(cis\)-meQTLs at 14,118 CpG methylation sites and \(cis\)-eQTLs for 302 3′-mRNA transcripts of 288 genes. Hippocampal \(cis\)-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. \(Cis\)-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of \(cis\)-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders. KW - psychiatry KW - epigenetics in the nervous system KW - epigenomics KW - gene expression KW - neurological disorders Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173168 VL - 8 ER - TY - JOUR A1 - Katzorke, Andrea A1 - Zeller, Julia B. M. A1 - Müller, Laura D. A1 - Lauer, Martin A1 - Polak, Thomas A1 - Reif, Andreas A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Reduced activity in the right inferior frontal gyrus in elderly APOE-E4 carriers during a verbal fluency task JF - Frontiers in Human Neuroscience N2 - Apolipoprotein-E4 (APOE-E4) is a major genetic risk factor for developing Alzheimer’s disease (AD). The verbal fluency task (VFT), especially the subtask category fluency, has shown to provide a good discrimination between cognitively normal controls and subjects with AD. Interestingly, APOE-E4 seems to have no effect on the behavioral performance during a VFT in healthy elderly. Thus, the purpose of the present study was to reveal possible compensation mechanisms by investigating the effect of APOE-E4 on the hemodynamic response in non-demented elderly during a VFT by using functional near-infrared spectroscopy (fNIRS). We compared performance and hemodynamic response of high risk APOE-E4/E4, -E3/E4 carriers with neutral APOE-E3/E3 non-demented subjects (N = 288; 70–77 years). No difference in performance was found. APOE-E4/E4, -E3/E4 carriers had a decreased hemodynamic response in the right inferior frontal junction (IFJ) with a corresponding higher response in the left middle frontal gyrus (MFG) during category fluency. Performance was correlated with the hemodynamic response in the MFG. We assume a compensation of decreased IFJ brain activation by utilizing the MFG during category fluency and thus resulting in no behavioral differences between APOE-groups during the performance of a VFT. KW - psychiatry KW - near-infrared spectroscopy KW - verbal fluency task KW - apolipoprotein-E4 KW - Alzheimer's disease KW - elderly Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171892 VL - 11 ER - TY - JOUR A1 - Kingslake, Jonathan A1 - Dias, Rebecca A1 - Dawson, Gerard R. A1 - Simon, Judit A1 - Goodwin, Guy M. A1 - Harmer, Catherine J. A1 - Morriss, Richard A1 - Brown, Susan A1 - Guo, Boliang A1 - Dourish, Colin T. A1 - Ruhé, Henricus G. A1 - Lever, Anne G. A1 - Veltman, Dick J. A1 - van Schaik, Anneke A1 - Deckert, Jürgen A1 - Reif, Andreas A1 - Stäblein, Michael A1 - Menke, Andreas A1 - Gorwood, Philip A1 - Voegeli, Géraldine A1 - Perez, Victor A1 - Browning, Michael T1 - The effects of using the PReDicT Test to guide the antidepressant treatment of depressed patients: study protocol for a randomised controlled trial JF - Trials N2 - Background Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4–6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen. Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual. Methods/design The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient’s antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50% or greater decrease in baseline scores of depressionmeasured using the Quick Inventory of Depressive Symptoms – Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed. Discussion This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients. Trial registration ClinicalTrials.gov, ID: NCT02790970. Registered on 30 March 2016. KW - psychiatry KW - depression KW - prediction KW - treatment KW - antidepressant KW - primary care Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173012 VL - 18 ER - TY - JOUR A1 - Grünewald, Benedikt A1 - Lange, Maren D A1 - Werner, Christian A1 - O'Leary, Aet A1 - Weishaupt, Andreas A1 - Popp, Sandy A1 - Pearce, David A A1 - Wiendl, Heinz A1 - Reif, Andreas A1 - Pape, Hans C A1 - Toyka, Klaus V A1 - Sommer, Claudia A1 - Geis, Christian T1 - Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis JF - eLife N2 - Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3\(^{Δex1-6}\)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition. KW - CLN3 KW - mutation KW - mouse model KW - synaptic transmission KW - amygdala KW - hippocampus Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170004 VL - 6 IS - e28685 ER - TY - JOUR A1 - Waider, J A1 - Popp, S A1 - Lange, MD A1 - Kern, R A1 - Kolter, JF A1 - Kobler, J A1 - Donner, NC A1 - Lowe, KR A1 - Malzbender, JH A1 - Brazell, CJ A1 - Arnold, MR A1 - Aboagye, B A1 - Schmitt-Böhrer, A A1 - Lowry, CA A1 - Pape, HC A1 - Lesch, KP T1 - Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice JF - Translational Psychiatry N2 - Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutive Tph2 inactivation and consequential lack of 5-HT synthesis in Tph2 null mutant mice (Tph2\(^{-/-}\)) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed in Tph2 heterozygous mice (Tph\(^{+/-}\)) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based on Slc6a4 mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala. KW - anxiety KW - stress KW - serotonin KW - genetics KW - mice Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170239 VL - 7 IS - e1246 ER -