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Projects: Genetic Epidemiology in Psychiatry

CA17130: Enhancing Psychiatric Genetic Counselling, Testing, and Training in Europe (EnGagE). 09/2018-09/2022.

The Action Enhancing Psychiatric Genetic Counselling, Testing, and Training in Europe (EnGagE) aims to strengthen pan-European research into the newly emerging disciplines of Psychiatric Genetic Counselling (PsyGC) and Psychiatric Genetic Testing (PsyGT); and to develop a framework to facilitate the implementation of both disciplines into routine clinical care. Psychiatric disorders are common, with estimated life-time risks of around 1-3 % for schizophrenia, bipolar disorder, and major depressive disorder. The last decade has witnessed major advances in psychiatric genetics. Currently, no form of valid, high certainty diagnostic PsyGT is available in routine clinical practice. However, in view of recent genetic findings (particularly the identification of pathogenic copy number variants that are associated with high risks for schizophrenia), major efforts to establish such testing are now underway. The publication of the major advances in psychiatric genetics have received wide media coverage and awareness among patients and their family members of the role of genetics in psychiatric disorders is growing. An increased demand for high-quality information on psychiatric genetics likely provided in the form of PsyGC, is anticipated. EnGagE is a knowledge-sharing and expertise-enhancing network comprising preclinical and clinical researchers from the fields of neuroscience, psychiatric genetics, psychosocial research, and ethics; clinicians from the fields of psychiatry, psychology, and medical genetics; genetic counsellors, and scientists from diagnostic genetic testing laboratories from Europe and beyond. EnGagE will establish a framework for PsyGC and PsyGT; develop standardised guidelines, practice recommendations and research protocols; share scientific knowledge and data and provide standardized training in PsyGC and PsyGT.

Schmahl C. Ruprecht-Karls-Universität Heidelberg GRK 2350/1: Graduertenkolleg "Der Einfluss von Traumatisierung im Kindes- und Jugendalter auf psychosoziale und somatische Erkrankungen über die Lebensspanne". 04/2018-09/2022.

Das geplante Graduiertenkolleg (GRK) untersucht die neurobiologischen, somatischen und psychosozialen Folgen von traumatischen Kindheitserfahrungen (bis 18 Jahre; adverse childhood experiences, ACE). Eingebunden in die zentralen Forschungsschwerpunkte des Zentralinstituts für Seelische Gesundheit und beider Medizinischen Fakultäten der Universität Heidelberg, profitiert das GRK inhaltlich von bestehenden Forschungsverbünden zum Thema ACE und existierenden Kohorten sowie strukturell von langjähriger Erfahrung mit Graduiertenprogrammen. ACE wie z.B. sexueller und körperlicher Missbrauch oder Vernachlässigung stellen massive Stressoren dar, die auf vulnerable Phasen der somato-psychischen Entwicklung treffen und damit sowohl kurz- als auch langfristig erhebliche Auswirkungen auf die psychische und körperliche Gesundheit haben. Weder die kausalen Zusammenhänge noch vermittelnde Mechanismen dieser Schädigungen sind ausreichend verstanden. Dies liegt zum einen an der großen Varianz bezüglich Art, Zeitpunkt, und Intensität der Traumatisierung sowie an einer Vielzahl möglicher protektiver Faktoren. Auf der anderen Seite manifestieren sich die Folgen von ACE in sehr diversen psychosozialen und somatischen Problemen wie etwa dysfunktionaler Stressreaktivität oder Emotionalität, zwischenmenschlichen Problemen, Depression, Sucht, chronischen Schmerzen oder inflammatorischen und metabolischen Erkrankungen. Die zentralen Ziele des GRK sind: (1) den Einfluss von Art, Zeitpunkt und Intensität von ACE sowie protektiver Faktoren auf die Entstehung von psycho-somatischen Folgeerkrankungen zu untersuchen; (2) das Verständnis psychosozialer, neurobiologischer und epigenetischer Mechanismen von ACE-assoziierten psychischen und physischen Erkrankungen zu verbessern; (3) neue psychosoziale und pharmakologische Behandlungsansätze und Public Health Programme für die Folgen von ACE zu entwickeln. Das geplante GRK wird Doktoranden der Fächer Medizin, Psychologie, Biologie und verwandter Naturwissenschaften sorgfältig auswählen und ausbilden. Neben der direkten wissenschaftlichen Betreuung in den beteiligten Arbeitsgruppen wird ein strukturiertes Betreuungs- und Qualifizierungskonzept – basierend auf der langjährigen Erfahrung in ähnlichen Programmen (SFB 636, KFO 256, weiteren Graduiertenschulen der Universität Heidelberg) – die bestehenden institutionellen Voraussetzungen für die Ausbildung international führender WissenschaftlerInnen optimieren. Das umfassende Lehrprogramm besteht aus Seminaren und Workshops mit ergänzender Sommerschule, Master Class, Symposien und nationalen oder internationalen Praktika. Diese vermitteln und trainieren relevante Inhalte und Methoden, Schlüsselqualifikationen und Soft Skills. Mentoring und Coaching optimieren die persönliche Weiterentwicklung.

BMBF - Bundesministerium für Bildung und Forschung 01EW1904: EMBED Impact of Early life MetaBolic and psychosocial strEss on susceptibility to mental Disorders; from converging epigenetic signatures to novel targets for therapeutic intervention. 06/2019-05/2022.

Nearly 40% of the EU population each year suffers from a mental disorder. Adverse experiences early in life can produce important physiological changes, which become embedded biological traces leading to increased vulnerability for later depression. There is now robust evidence indicating that early metabolic challenges impinge upon energy balance regulatory systems, which, in many cases, overlap with stress-response systems. EMBED will identify informative DNA methylation differences associated with prenatal psychological and metabolic stressors in genes that are relevant for mood disorders. These will be related to shared biomarkers to define common biological substrates between early life stress and maternal obesity for prevention and treatment. We will also determine whether intervention strategies can reverse such epigenetic marks and related biomarkers. The relationship between DNA methylation pattern in human peripheral samples (cord blood) and brain will be studied in animal models and brain post-mortem samples from depressive patients. EMBED brings together leading researchers with complementary expertise to exploit existing clinical data sets, including biomaterial collections from previous collaborative proposals, that will be analyzed in an original and innovative way to study the role of different, but often co-occurring, adverse prenatal conditions on individual risk/resilience to develop mental disorders in adulthood. This research may lead not only to a better understanding of the risk architecture of Major psychiatric disorders, but could also enable preventive measures in risk opulations, new diagnostics and, potentially, therapeutic approaches since, in contrast to genetic variations, epigenetic effects on the transcriptome may be reversed, also in adulthood.

DFG - Deutsche Forschungsgemeinschaft TRR 265/1 TP S01 : Losing and Regaining Control over Drug Intake: from trajectories to mechanisms to interventions. 06/2019-05/2022.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 031L0190A : Target-OXY - Towards Targeted Oxytocin Treatment in Alcohol Addiction. 06/2019-05/2022.

Worldwide two billion people drink regularly alcohol. A major health consequence is alcohol addiction that is characterized by chronic relapses. Preventing relapse is the main Treatment goal. Current pharmacological treatments have limited effectiveness and there is a large heterogeneity in the treatment response. Better treatments and prediction approaches that can be easily translated into the clinical situation are warranted. In our e:Med funded SysMedAlcoholism consortium we have identified early warning signs and drinking profiles that predict future relapse behavior and treatment response of clinically used anti-relapse medications. We have also identified in a multi-omics approach alterations in the oxytocin (OXY) system in alcoholic patients suggesting OXY as a candidate medication to reduce relapse. Here our Goals are (i) to demonstrate the clinical applicability of OXY and (ii) to computationally predict elapse and identify treatment responsive individuals. For the demonstration of the clinical applicability of OXY, we propose a new module in the drug development process, namely a preclinical multicenter placebo controlled trial in rats with a step-wise translation into a naturalistic pilot trial with ambulatory assessment in alcoholic patients. As a comparator, we will use datasets from previous trials where we tested placebo vs acamprosate – which is a clinically effective medication. These data will be contrasted with a 3-arm design in male and female alcohol addicted rats where two doses of intranasally applied OXY will be tested against placebo in a well-validated rat model for alcohol addiction. From this preclinical trial we will obtain intensive longitudinal data (ILD) sets on drinking and activity. Using new in silico approaches we will then be able to identify early warnings signs and drinking clusters for relapse and OXY treatment responsive individuals. This preclinical work will guide our naturalistic Trial with ambulatory assessment in alcoholic patients.

DFG - Deutsche Forschungsgemeinschaft WI 3439/3-2: Neurobiology of affective disorders: A translational perspective on brain structure and function, WP5: (Epi-)Genetics/ gene expression . 12/2018-11/2021.

DFG - Deutsche Forschungsgemeinschaft RI 908/11-2: Neurobiology of affective disorders: A translational perspective on brain structure and function, WP5: (Epi-)Genetics/ gene expression. 08/2018-07/2021.

Rietschel M. BMBF - Bundesministerium für Bildung und Forschung 01EW1810: SYNSCHIZ: WP1 (Gen-Identifizierung) und WP5 (Innovation, Schutz geistigen Eigentums, kommerzielle Verwertung):. 08/2018-07/2021.

Das SYNSCHIZ Projekt stellt eine Zusammenarbeit von Experten aus Norwegen, Deutschland, der Schweiz, Finnland, Rumänien, und den Niederlanden dar, mit dem Ziel synaptische Dysfunktion als Risikomechanismus der Schizophrenie (SCZ) zu untersuchen. WP5 hat das Ziel die kommerzielle Verwertung der in SYNSCHIZ gewonnen Erkenntnisse sicherzustellen und damit einen entscheidenden Beitrag zum translationalen Aspekt von SYNSCHIZ zu leisten. Wir gehen davon aus, dass mehrere Forschungsergebnisse von hohem Wert für die Forschungsgemeinschaft erzielt werden. Insbesondere die Entwicklung eines in vitro Modells für SCZ kann im Bereich Wirkstoffscreening und dem Testen neuer Pharmazeutika von großem Wert sein.Die kommerzielle Auswertung kann sowohl durch die Ausgründungen von Firmen oder durch Lizenzvereinbarungen mit Pharmafirmen erfolgen.

BMBF - Bundesministerium für Bildung und Forschung 01EE1406C: TP7 Verbund Aerial im Forschungsnetz für psychische Erkrankungen - Mechanismen von Suchterkrankungen: Sozialer Ausschluss, Vorhersage von Erkrankungsrisiken und Widerstandsfähigkeit und angepasste Therapien. 02/2015-02/2020.

Rietschel M. BMBF - Bundesministerium für Bildung und Forschung 01EE1409C: Verbund ASD-Net: Service Module - (Epi)Genetics and imaging genetics in ASD. 02/2015-12/2019.

Evidence implicates genetic and environmental factors as playing a substantial role in the aetiology of ASD1-3. The contribution of environmental factors may partially be mediated by epigenetic mechanisms, such as DNA methylation. Oxytocin (OXT) as well as genetic variation and methylation differences in genes related to the OXT pathway modulate human social behaviour and play a substantial role in the treatment of the core deficits in individuals with ASD4. However, little is known about the molecular mechanisms of how OXT impacts on a behavioural and/or neural level. In the light of the individual variability of OXT response, the consideration of individual factors like gender, genetic and epigenetic variations in studies investigating the efficacy of OXT administration in treatment of ASD are warranted5. In this project, we aim to identify which genetic and epigenetic factors are a) predictive at baseline for the patients’ treatment [OXT, social skills training (SST)+placebo, SST+OXT] outcome and b) associated with the response to acute and long-term OXT administration. By identifying implicated genetic factors and methylation changes, we will c) gain new insights into the molecular mechanisms underlying ASD and the OXT response. Data at baseline and after treatment will be analyzed not only with respect to the categorical diagnoses but also regarding behavioural and imaging subphenotypes. To verify highquality data management and assessment of the neuroimaging data across sites, the service module will also implement standard routines and protocols for quality assurance.

BMBF - Bundesministerium für Bildung und Forschung 01ZX1611A: e.Med II - SPs 1: Central Resource I:Epigenomics and genomics platform. 01/2017-12/2018.

SP2 provides central resources to the consortium. These include genomic and epigenomic information from case/control samples. Together with contributing international groups the PIs of SP2 are currently performing a world-wide meta-analysis of all available GWAS datasets of alcohol addicted patients. The resultant candidate gene list will be forwarded to SP6 for use in convergent data analysis and mathematical modelling to better predict risk profiles. In addition to this ongoing work, a pathway analysis of our NGFN-derived GWAS dataset was completed and replicated in independent samples. The most frequent gene was XRCC5. In a subsequent step, we were able to confirm the influence of XRCC5 on alcohol-related traits in both Drosophila (SP9) and in our platform for experimental human studies (SP12) (Juraeva et al., 2015). In collaboration with SP10, GWAS for specific endophenotypes were performed, and we were able to show that variants in glutamatergic genes are associated with altered cue-induced brain activation, craving and relapse risk (Bach et al., 2015).

BMBF - Bundesministerium für Bildung und Forschung 01ZX1614G: e:Med Integrament II TP 2: Central patient resource and bridging between genotype and phenotype. 01/2017-12/2018.

Schizophrenie (SCZ), bipolare Störung (BD) und unipolare Depression (MD) sind heterogene Erkrankungen mit einer multifaktoriellen Verursachung. Da die zugrundeliegenden biologischen Mechanismen nur unzureichend geklärt sind, gibt es bisher weder ein biologisch fundiertes Klassifikationssystem noch gibt es valide Biomarker zur Unterstützung der Diagnosestellung oder Prädiktion des Krankheitsverlaufes. Die Diagnosen werden stattdessen anhand von Symptomkatalogen erstellt, zur Diagnosestellung sind bestimmte Symptome in einer Mindestdauer notwendig. Patienten mit der gleichen Diagnose können sich bezüglich der klinischen Symptome und dem Krankheitsverlauf erheblich unterscheiden. Darüber hinaus überlappen die verwendeten diagnostischen Kriterien auf klinischer und - wie wir und andere zeigen konnten - auch auf molekularer Ebene. Das übergeordnete Ziel von Teilprojekt 2 (TP2) ist es, die Entwicklung eines biologisch geleiteten Klassifikationssystems für SCZ, BD und MD durch die Identifikation robuster Zusammenhänge von Genotypen und Phänotypen zu erleichtern und Einblicke in die Ursachen der Krankheitsentstehung zu erlangen. Hierfür verfolgt TP2 folgende drei Teilziele: 1.) Systematische Untersuchung von Genotyp-Phänotyp Assoziationen in großen Patientenkollektiven sowohl innerhalb als auch über die diagnostischen Kategorien hinweg. Dies geschieht in enger Zusammenarbeit mit den anderen Teilprojekten insbesondere TP1, TP3, TP4, TP5 und TP6. 2.) Bereitstellung und weiterer Ausbau der zentralen Patientenressource für das IntegraMent Konsortium. Die Verfügbarkeit von großen und gut charakterisierten Kollektiven von Patienten und Kontrollen stellt eine Voraussetzung für die Arbeiten in TP2, TP3, TP4, TP5, TP6, TP9 und TP10 dar. Die Kollektive, die TP2 als zentrale Plattform zur Verfügung stellt, zählen mit zu den größten weltweit und werden in Rahmen von IntegraMent kontinuierlich erweitert und teilweise auch longitudinal verfolgt. Die Phänotypcharakterisierung schließt die Erhebung von klinischen Symptomen, Endophänotypen, wie z.B. Kognition, Krankheitsverlauf, Pharmakoresponse (siehe Abbildung), und Umwelteinflüssen mit ein. 3.) Verstetigung und Erweiterung dieser Kollektive durch Einbindung weiterer deutscher klinisch-psychiatrischer Zentren außerhalb des Konsortiums. Dies wird durch eine von uns initiierte Initiative durch die Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN-Patienten Kohorte) unterstützt.

Deuschle M. Dietmar Hopp Stiftung gGmbH 23011216: PreSchooler: Young Children's Health and Enviroment. 10/2014-09/2017.

Fragestellungen / Ziele - Persistieren die epigenetischen Merkmale von Geburt (Nabelschnurblut) oder 6 Monaten nach Geburt bis zum Alter von 4 Jahren? Sind psychosoziale Risiken der ersten 4 Lebensjahre mit spezifischen Veränderungen epigenetischer Marker assoziiert? - Lassen sich Auffälligkeiten in Verhaltenstests im Alter von 4 Jahren durch epigenetische Merkmale bei Geburt oder der Mutter-Kind-Interaktion im 6. Monat vorhersagen? - Können Stressoren in Schwangerschaft und früher Kindheit bzw. epigenetische Merkmale die Hirnentwicklung bis zum 4. Lebensjahr prognostizieren? - Stehen Auffälligkeiten in Verhaltenstests im Alter von 4 Jahren in Verbindung mit „Infektions-Historie“ (Antikörper im Speichel) oder der Darmflora?

DFG - Deutsche Forschungsgemeinschaft RI 908/12-1: Initiation of International Collaboration: Identification of genetic and environmental risk factors for psychiatric disorders in Turkish multiplex pedigrees and comparison with respective data from other populations.. 09/2016-08/2017.

The overall aim is to establish a long-term collaboration between the Central Institute of Mental Health, Mannheim, Germany and the Departments of Psychiatry and Bioinformatics, Medical Faculty of Akdeniz University, Antalya, Turkey – two leading institutes of biomedicine in the field of psychiatry and genetics. Within the collaboration, we aim at investigating the genetic as well as epigenetic and environmental risk factors involved in the etiology of schizophrenia and affective disorders and the interplay of these risk factors in large extensively characterized multiplex families from Turkey. It is hoped that some of the findings will provide new aetiologically based, more efficient, better tolerated treatments which will also be reducing the burden of the schizophrenia and affective disorders. We will jointly apply for adequate external funding, develop the study design and implement ethical requirements and logistics. The German partners will train the Turkish partners in data assessment methods and a small pilot study will be performed under German supervision. Turkish researchers will gain insights and knowledge of the modern methods used in genomic studies in psychiatric disorders through their visit in Germany. In the long term, a national Turkish biobank for psychiatric disorders will be established and specific genetic and environmental risk factors in Turkish population will be identified. Turkish genomic data will be integrated into the MooDS unified European genomic data base. At this stage, Turkish researchers will gain access to international science networks and biomedical advancements.

DFG - Deutsche Forschungsgemeinschaft RI 908/11-1: WP6 "Integrierte Analyse genetischer, epigenetischer und umweltbedingter Vulnerabilitätsfaktoren in affektiven Störungen. 04/2014-04/2017.

WP6 RESEARCH PROJECT Integrative analyses of genetic, epigenetic, and environmental vulnerability factors for affective disorders Prof. Dr. Marcella Rietschel1, Dr. Stephanie Witt1, Dr. Axel Krug2, 1University of Heidelberg, Central Institute of Mental Health (ZI) Mannheim, 2University of Marburg, Department of Psychiatry Summary The aim of this workpackage is to identify how genetic, epigenetic, and environmental factors impact on the etiology of affective disorders. This will be achieved by correlating these factors with each other, with categorial diagnoses, and with endophenotypes. The latter will be assessed in magnetic resonance imaging (MRI) and immunological studies performed in WP1 and WP3. To ensure stateof- the-art coverage of all variants known to be of importance to psychiatric disorders, subjects will be genotyped with the PsychChip, a custom 20,000 probe multiplex array that is specific for psychiatricdisorders. For the statistical analyses, a convergent approach will be applied in collaboration with WP7. This will comprise multimarker-, polygenic score based-, and pathway analytical methods, and will take into account environmental factors. The results of our analyses will provide data concerning diagnosis-specific factors, as well as factors which are of relevance across diagnostic boundaries. Background and own previous work: The heritability of bipolar disorder (BD) has been reported to be as high as 80%, while that of major depressive disorder (MDD) ranges between 40 and 70%. However, the scientific community is calling the conceptualisation of these two disorders as separate entities increasingly into question 317. Formal- and molecular genetic studies also indicate a substiantial overlap in their etiology. The number of identified vulnerability genes for affective disorder is increasing, and our group has contributed substantially to these findings 20,22,318. Identification of the first vulnerability genes has identified various neurobiological mechanisms in the etiology of affective disorders 11,319, and the use of more refined phenotypes is likely to generate further insights. For example, a growing number of studies, including studies performed by our group, are demonstrating the important impact of environmental factors on affective disorders. In a GxE study, we found that BDNF variation moderated the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms 38. Given that affective disorders are heterogeneous clinical conditions, it is unlikely that single genetic variants are associated with categorial disease. A more plausible hypothesis is that such variants are associated with sub-dimensions. Therefore, an important prerequisite for understanding why particular individuals will develop the disease whereas others will not, is to elucidate the influence of genetic variation at the level of clinical subdimensions and/or endophenotypes, e.g. MRI or immunological data. With respect to clinical subimensions, we recently found that a genome-wide significant association between BD and a variant in NCAN 22 was due to an association with an overactivity dimension that is also present in MDD 11. Interestingly, NCAN deficient mice displayed a similar behavioral phenotype, rendering them a novel animal model for pharmacological testing of this clinically relevant subdimension. With respect to endophenotypes, the imaging genetic approach has proven to be most successful in terms of delineating the possible mechanisms of action of vulnerability genes 174,280,320,321. This approach will moreover help to elucidate how known environmental risk factors act on the level of individuals 115. Besides genetic factors, epigenetic modifications – which do not alter the genetic code, but regulate gene expression – modulate the susceptibility to psychiatric disorders 50,53,322. Such modifications include DNA methylation. In a recent study, we demonstrated that maternal prenatal stress led to differential methylation in a large number of genes in the newborn. In a collaborative conver- 24 gent approach (with Moshe Syf, Univ. Montreal), which included use of primate animal models, we detected a novel and reliable vulnerability gene for stress-related disorders 323. Most of the genetic studies of affective disorders performed to date have analysed single markers. Using multi-marker approaches, such as pathway/gene set based analysis or polygenic score-based analysis, information contained in many small association signals throughout the genome which is too weak to be detected by single marker tests can be cumulated. This is also a powerful approach for testing shared genetic liability across categorial diagnoses 324,325, as well as across symptom dimensions or sub-groups defined according to more refined phenotypes. Work Program: Genes of interests will be analysed throughout the course of the FOR, once a substantial number of the study subjects have been characterized with the PsychChip. The two genes of interest (NCAN, BDNF) will also be analysed in the animal model (WP2), and were selected because of the following criteria: confirmed association with affective disorders; feasible for use in animal studies (WP2); expressed in the synapse to be a gene of interest for WP4; and of relevance to the immunological hypotheses addressed in WP3. Genotyping and methylation studies will commence at the end of year 1 with n=500 subjects and will be ongoing. Analyses will start as soon as the first findings are available. Data will be replicated in the full cohort, once recruitment is complete. In year 1, we will also conduct feasibility studies to determine which sub-phenotypes are useful and whether the proposed data mining technique is feasible. 1. Genotyping of subjects recruited in WP1 for NCAN and BDNF. 2. Methylation analysis of NCAN and BDNF (pyro-sequencing). 3. Genotyping with the PsychChip (Illumina custom array), which is being developed by the Psychiatric Genomic Consortium. The PsychChip contains 20,000 SNPs and CNVs of relevance to psychiatric disease. SNP selection focuses on top hits from GWAS and meta-analyses, exome SNPs, SNPs from the MHC region, and CNVs implicated in psychiatric disease. 4. Polygenic analyses to quantify the impact of aggregated genetic variation on sub- and endophenotypes in collaboration with WP7. Using an integrative approach, all results from the genotyping and methylation analyses will be combined. Multimarker-, polygenic, and pathway analyses will then be performed to identify as yet undetected genotype-, GxE, and phenotype relationships. One of the available data mining techniques is used in retail market research. Our group recently adapted this method by developing the new software tool RUDI (RUle Discoverer) in order to identify frequent and characteristic genotype patterns showing strong association to phenotype clusters (http://rudi-genetics.net). Outlook: In the second funding period, we will perform genome-wide association studies (GWAS), genome-wide methylation studies in extreme groups, e.g. therapy outcome (good vs. bad responders), and high/low risk groups and transition to disease. We will also take into account environmental factors, such as stress (assessed via questionnaires and biological parameters, i.e. hair cortisol levels). Project specific references Miró X, Meier S, Dreisow ML, Frank J, Strohmaier J, Breuer R, Schmäl C, Albayram Ö, Pardo-Olmedilla MT, Mühleisen TW, Degenhardt FA, Mattheisen M, Reinhard I, Bilkei-Gorzo A, Cichon S, Seidenbecher C, Rietschel M, Nöthen MM, Zimmer A. Studies in humans and mice implicate neurocan in the etiology of mania. Am J Psychiatry. 2012 Sep;169(9):982-90. Rietschel M, et al. Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression. Biol Psychiatry. 2010 Sep 15;68(6):578-85. Krug A, Krach S, Jansen A, Nieratschker V, Witt SH, Shah NJ, Nöthen MM, Rietschel M, Kircher T. The Effect of Neurogranin on Neural Correlates of Episodic Memory Encoding and Retrieval. Schizophr Bull, in press. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011 Sep 18;43(10):969-76. doi: 10.1038/ng.940. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet. 2011 Sep 18;43(10):977-83.

DFG - Deutsche Forschungsgemeinschaft WI 3439/3-1: WP6 Integrierte Analyse genetischer, epigenetischer und umweltbedingter Vulnerabilitästsfaktoren in affektiven Störungen . 04/2014-04/2017.

WP6 RESEARCH PROJECT Integrative analyses of genetic, epigenetic, and environmental vulnerability factors for affective disorders Prof. Dr. Marcella Rietschel1, Dr. Stephanie Witt1, Dr. Axel Krug2, 1University of Heidelberg, Central Institute of Mental Health (ZI) Mannheim, 2University of Marburg, Department of Psychiatry Summary The aim of this workpackage is to identify how genetic, epigenetic, and environmental factors impact on the etiology of affective disorders. This will be achieved by correlating these factors with each other, with categorial diagnoses, and with endophenotypes. The latter will be assessed in magnetic resonance imaging (MRI) and immunological studies performed in WP1 and WP3. To ensure stateof- the-art coverage of all variants known to be of importance to psychiatric disorders, subjects will be genotyped with the PsychChip, a custom 20,000 probe multiplex array that is specific for psychiatricdisorders. For the statistical analyses, a convergent approach will be applied in collaboration with WP7. This will comprise multimarker-, polygenic score based-, and pathway analytical methods, and will take into account environmental factors. The results of our analyses will provide data concerning diagnosis-specific factors, as well as factors which are of relevance across diagnostic boundaries. Background and own previous work: The heritability of bipolar disorder (BD) has been reported to be as high as 80%, while that of major depressive disorder (MDD) ranges between 40 and 70%. However, the scientific community is calling the conceptualisation of these two disorders as separate entities increasingly into question 317. Formal- and molecular genetic studies also indicate a substiantial overlap in their etiology. The number of identified vulnerability genes for affective disorder is increasing, and our group has contributed substantially to these findings 20,22,318. Identification of the first vulnerability genes has identified various neurobiological mechanisms in the etiology of affective disorders 11,319, and the use of more refined phenotypes is likely to generate further insights. For example, a growing number of studies, including studies performed by our group, are demonstrating the important impact of environmental factors on affective disorders. In a GxE study, we found that BDNF variation moderated the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms 38. Given that affective disorders are heterogeneous clinical conditions, it is unlikely that single genetic variants are associated with categorial disease. A more plausible hypothesis is that such variants are associated with sub-dimensions. Therefore, an important prerequisite for understanding why particular individuals will develop the disease whereas others will not, is to elucidate the influence of genetic variation at the level of clinical subdimensions and/or endophenotypes, e.g. MRI or immunological data. With respect to clinical subimensions, we recently found that a genome-wide significant association between BD and a variant in NCAN 22 was due to an association with an overactivity dimension that is also present in MDD 11. Interestingly, NCAN deficient mice displayed a similar behavioral phenotype, rendering them a novel animal model for pharmacological testing of this clinically relevant subdimension. With respect to endophenotypes, the imaging genetic approach has proven to be most successful in terms of delineating the possible mechanisms of action of vulnerability genes 174,280,320,321. This approach will moreover help to elucidate how known environmental risk factors act on the level of individuals 115. Besides genetic factors, epigenetic modifications – which do not alter the genetic code, but regulate gene expression – modulate the susceptibility to psychiatric disorders 50,53,322. Such modifications include DNA methylation. In a recent study, we demonstrated that maternal prenatal stress led to differential methylation in a large number of genes in the newborn. In a collaborative conver- 24 gent approach (with Moshe Syf, Univ. Montreal), which included use of primate animal models, we detected a novel and reliable vulnerability gene for stress-related disorders 323. Most of the genetic studies of affective disorders performed to date have analysed single markers. Using multi-marker approaches, such as pathway/gene set based analysis or polygenic score-based analysis, information contained in many small association signals throughout the genome which is too weak to be detected by single marker tests can be cumulated. This is also a powerful approach for testing shared genetic liability across categorial diagnoses 324,325, as well as across symptom dimensions or sub-groups defined according to more refined phenotypes. Work Program: Genes of interests will be analysed throughout the course of the FOR, once a substantial number of the study subjects have been characterized with the PsychChip. The two genes of interest (NCAN, BDNF) will also be analysed in the animal model (WP2), and were selected because of the following criteria: confirmed association with affective disorders; feasible for use in animal studies (WP2); expressed in the synapse to be a gene of interest for WP4; and of relevance to the immunological hypotheses addressed in WP3. Genotyping and methylation studies will commence at the end of year 1 with n=500 subjects and will be ongoing. Analyses will start as soon as the first findings are available. Data will be replicated in the full cohort, once recruitment is complete. In year 1, we will also conduct feasibility studies to determine which sub-phenotypes are useful and whether the proposed data mining technique is feasible. 1. Genotyping of subjects recruited in WP1 for NCAN and BDNF. 2. Methylation analysis of NCAN and BDNF (pyro-sequencing). 3. Genotyping with the PsychChip (Illumina custom array), which is being developed by the Psychiatric Genomic Consortium. The PsychChip contains 20,000 SNPs and CNVs of relevance to psychiatric disease. SNP selection focuses on top hits from GWAS and meta-analyses, exome SNPs, SNPs from the MHC region, and CNVs implicated in psychiatric disease. 4. Polygenic analyses to quantify the impact of aggregated genetic variation on sub- and endophenotypes in collaboration with WP7. Using an integrative approach, all results from the genotyping and methylation analyses will be combined. Multimarker-, polygenic, and pathway analyses will then be performed to identify as yet undetected genotype-, GxE, and phenotype relationships. One of the available data mining techniques is used in retail market research. Our group recently adapted this method by developing the new software tool RUDI (RUle Discoverer) in order to identify frequent and characteristic genotype patterns showing strong association to phenotype clusters (http://rudi-genetics.net). Outlook: In the second funding period, we will perform genome-wide association studies (GWAS), genome-wide methylation studies in extreme groups, e.g. therapy outcome (good vs. bad responders), and high/low risk groups and transition to disease. We will also take into account environmental factors, such as stress (assessed via questionnaires and biological parameters, i.e. hair cortisol levels). Project specific references Miró X, Meier S, Dreisow ML, Frank J, Strohmaier J, Breuer R, Schmäl C, Albayram Ö, Pardo-Olmedilla MT, Mühleisen TW, Degenhardt FA, Mattheisen M, Reinhard I, Bilkei-Gorzo A, Cichon S, Seidenbecher C, Rietschel M, Nöthen MM, Zimmer A. Studies in humans and mice implicate neurocan in the etiology of mania. Am J Psychiatry. 2012 Sep;169(9):982-90. Rietschel M, et al. Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression. Biol Psychiatry. 2010 Sep 15;68(6):578-85. Krug A, Krach S, Jansen A, Nieratschker V, Witt SH, Shah NJ, Nöthen MM, Rietschel M, Kircher T. The Effect of Neurogranin on Neural Correlates of Episodic Memory Encoding and Retrieval. Schizophr Bull, in press. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011 Sep 18;43(10):969-76. doi: 10.1038/ng.940. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet. 2011 Sep 18;43(10):977-83.

Rietschel M. BMBF - Bundesministerium für Bildung und Forschung 01ZX1314G: e:Med Integrament, Integrierte Untersuchungen von Ursachen und Mechanismen psychiatrischer Störungen. 01/2014-12/2016.

1. Vorhabenziel Teilprojekt 2 (ZP2) verfolgt die Ziele der Identifikation von Phenotyp-Phänotyp-Assoziationen, der Bereitstellung von großen Patientenstichproben sowie der Ausweitung der Patientenressource des Konsortiums auf eine deutschlandweite multizentrische Kohorte. In TP4 und TP5 stehen die Identifizierung und Validierung neuer Marker (Bildgebung/Imaging, Genetik, Klinik, Umwelteinflüsse) für Schizophrenie (SCZ) sowie Unipolare und Bipolare Störung (MD) im Vordergrund. Es sollen computationale Netzwerk-Modelle zur Darstellung der dynamischen Abläufe im Gehirn, vor allem des präfrontalen Cortex, von Patienten mit SCZ und MD erarbeitet werden (TP10). Es ist folgende Gliederung einzuhalten: 1. Vorhabenziel, 2. Arbeitsplanung 2. Arbeitsplanung TP2: Identifizierung robuster Genotyp-Phänotypmuster mittels Genomsequenzierung und ggf. Patienten-Wiederbegutachtung. TP4 und 5: Etablierung der Bioinformatik-Infrastruktur, Marker-Identifizierung und –Validierung, Festlegen prädiktiver Marker. TP 10: Statistische Beschreibung zellulärer und synaptischer Transferfunktionen bei Kandidatengenen (CACNA1C, NCAN) und anschließende Netzwerk-Darstellung. 3. Ergebnisverwertung Ein vertieftes Verständnis der Pathophysiologie psychiatrischer Erkrankungen wir mittel- und langfristig zur Entwicklung von neuen und besser wirkenden Behandlungsstrategien und Medikamenten führen.

Meyer-Lindenberg A, Rietschel M. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP B03: Plasticity in prefrontal circuits in the human: Genetic variation, cellular. 01/2012-12/2015.

In the previous funding period, repetitive transcranial magnetic stimulation (rTMS) was shown to induce plasticity in prefrontal circuits for executive function and working memory, and genome-wide significant variants for psychosis were found to impact on these circuits, as well as on prefrontal regulation of the limbic system. In the present project, plasticity in prefrontal circuits will be further dissected by three experiments: (a) a genetic association study examining the effects of genome-wide significant common variants for psychosis on modulation of prefrontal circuit plasticity by rTMS, (b) an experiment in healthy controls relating prefrontal plasticity to a direct cellular assay of synaptic and glutamatergic function by using neuronally-differentiated induced pluripotent stem cells (iPS cells) together with multimodal imaging and rTMS, and (c) an experiment in healthy controls to directly modulate prefrontal circuit (connectivity) features and dependent cognition through real-time-fMRI based neurofeedback. The experiments are independent, but subjects for experiments (b) and (c) will be subsamples of the group investigated in (a) If successful, these experiments will identify genetic variants linking prefrontal plasticity and risk for psychosis, establish a cellular model for systems-level plasticity in humans and provide a first cognitive approach to induce plasticity in connected brain circuits relevant for mental disorders.

Rietschel M. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP Z04: Molecular Genetic core facility for genotype-phenotype delineation. 01/2012-12/2015.

As a core project Z03 will give methodological support to those studies within the SFB, that use diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), including real-time fMRI, and magnetic resonance spectroscopy (MRS) at 3.0T as well as advanced imaging and MRS methods at 9.4T. Methods to directly compare functional connectivity and spatiotemporal dynamics acquired with BOLD and regional cerebral blood volume (rCBV)-weighted fMRI in anesthetized rats at the 9.4T scanner will be established. Various MRS editing techniques will be optimized for glutamine, GABA, glutathione, and NAAG detection. Another goal of project Z03 is to combine structural connection maps determined by DTI tractography and/or diffusion spectrum imaging (DSI) with brain network analysis of fMRI data to gain insight into the patterning and dynamics of brain networks and to determine how structural connectivity relates to functional and effective connectivity of the brain. Concepts from graph theory will be used to analyze connection maps and brain network properties. These network properties such as clustering coefficients, characteristic path length or global efficiency can then be quantified and translated to clinical applications.

Rietschel M. EU - Europäische Union 279227: CRESTAR: Pharmacogenomic biomarkers as clinical decision making tools for clozapine treatment of schizophrenia. 11/2011-10/2015.

Treatment resistant schizophrenia (TRS) is the most disabling of all psychiatric illnesses, affecting about 1/3 of patients (~1 million Europeans), a considerable economic and social burden. First-line treatments include atypical (e.g. olanzapine) and typical (e.g. haloperidol) antipsychotics. The original atypical, clozapine, is a final option, and although it is the only antipsychotic shown to be effective in TRS, about half of TRS patients are also resistant to clozapine. CRESTAR is an SME-driven projected, focusing on the development of pharmacogenomic biomarkers for schizophrenia. It aims to develop tools to predict i) who will NOT respond to usual antipsychotics, indicating treatment with clozapine as early as possible, ii) the 1% of patients who will develop potentially fatal side effects, agranulocytosis, which is the main factor limiting clozapine use, and diabetic ketoacidosis, occurring in up to 2% of patients, and often fatal. We will also predict patients likely to be non-responders to all antipsychotics, i.e. extreme TRS, so that they can be stratified in clinical trials. CRESTAR will address these questions by examining genome-wide association data, genome sequence, epigenetic biomarkers and epidemiological data in European patient cohorts characterized for treatment response, and adverse drug reaction using data from clozapine therapeutic drug monitoring and linked National population medical and pharmacy databases, alongside existing European projects (e.g. PSYCNVs and EU-GEI) national initiatives (e.g. UK10K genome sequencing) to identify predictive factors. In parallel CRESTAR will perform health economic research on potential benefits, and ethics and patient-centered research with stakeholders. The outcome of CRESTAR will be a genomic test and associated clinical decision making tools, designed to improve pharmacological treatment of schizophrenia in both efficacy and safety, piloted with existing and new clinical trials such as OPTiMiSE.

Bohus M, Rietschel M. DFG - Deutsche Forschungsgemeinschaft BO 1487/12-1: KFO 256 CP 2: Central Recruitment and Assessment. 01/2012-12/2014.

Wüst S, Flor H, Rietschel M. DFG - Deutsche Forschungsgemeinschaft WU392/7-1: Genetische Grundlagen des Phantomschmerzes: Aufbau einer nationalen Forschungsressource. 05/2010-04/2014.

Nach Amputation eines Körperglieds leidet die Mehrheit aller Patienten unter Phantomschmerzen und den damit einhergehenden erheblichen psychosozialen Folgen. Die neurobiologischen Grundlagen des Phantomschmerzes sind bisher nur in Ansätzen verstanden, man weiß jedoch, dass zentralnervösen Prozessen eine große Bedeutung zukommt. Die Erforschung des Phantomschmerzes hat unmittelbare klinische Bedeutung und ist auch ein Zugang zur Untersuchung der generellen neurobiologischen Grundlagen der Wahrnehmung des eigenen Körpers. Human- und Tierstudien weisen darauf hin, dass genetische Faktoren für die Entstehung von Phantomschmerzen bedeutsam sind, bislang stehen für die Erforschung der molekulargenetischen Grundlagen aber keine ausreichend großen und gut charakterisierten Patientenkollektive zur Verfügung. In dieser Situation bietet nun das im 7. Rahmenprogramm vom Europäischen Forschungsrat (ERC) geförderte „PHANTOMMIND“ Projekt (Leitung: Prof. Flor), in dem 6.000 Patienten mit Amputationen untersucht werden, eine einmalige Chance. Ziel des hier vorgeschlagenen „PHANTOMGENE“ Projektes ist die Erweiterung des PHANTOMMIND Projektes um den Aufbau einer DNA-Bank als nationaler Forschungsressource. Im Rahmen der Rekontaktierung der Patienten soll u.a. auch eine vertiefende Phänotypisierung erfolgen. Anschließend sind genomweite Untersuchungen zu den molekularen Ursachen von Phantomschmerzen geplant.

Deuschle M, Laucht M, Rietschel M. Dietmar Hopp Stiftung gGmbH : POSSIBLE: Prenatal, Obstetric and Social Stress, mother-infant Interaction, Breastfeeding: Lasting Epigenetic effects on Health in Neonates. 10/2010-02/2014.

Den häufigen „Volkskrankheiten“ (z.B. Diabetes, Herz-Kreislauferkrankungen, Adipositas, Depression) liegen sowohl genetische als auch Lebensstil-Faktoren zugrunde, die jedoch jeweils isoliert betrachtet meist nur einen geringen Anteil der Wahrscheinlichkeit des Auftretens dieser Erkrankungen erklären. Epidemiologische Untersuchungen zeigen, dass pränatale und frühkindliche Stressoren das Risiko für diese häufigen Erkrankungen Jahrzehnte später signifikant beeinflussen können. Zum Beispiel hatte der Hungerwinter 1944/45 ein vermehrtes Auftreten von Diabetes zur Folge (pränatal), ein Verlust der Eltern vor dem 10. Lebensjahr erhöht das Risiko, im Verlauf des Lebens an einer Depression zu erkranken. Ziel des Vorhabens Prospektive Charakterisierung von 200 Müttern und Neugeborenen hinsichtlich: • Pränatalen Stressoren (z.B. Hyperemesis, Erkrankung, Rauchen, Ernährung der Schwangeren, psychische Erkrankung, Schwangerschaftserleben, belastende Lebensereignisse) • Perinatalen Risiken (z.B. Asphyxie, Sectio, Frühgeburt, niedriges Geburtsgewicht) • Psychosozialen Stressoren (z.B. alleinerziehend, Armut, Wochenbettdepression, belastende Lebensereignisse) • Einstellungen zum Kind (Bonding), Stillen, Temperament des Kindes • Mutter-Kind-Interaktion (standardisierte Verhaltensbeobachtung)

Rietschel M. DFG - Deutsche Forschungsgemeinschaft KR 3822/2-1: Bildgebungskorrelate von molekulargenetischen Risikovarianten der Schizophrenie und bipolaren Störung. 01/2011-12/2013.

Schizophrenia is a common and severe disorder with an onset in early adulthood. Its aetiology, symptom clusters, and course are heterogeneous and are known to be under genetic control. A meta-analysis of 12 twin studies estimated heritability in liability to schizophrenia at 81%. In addition to genetic risk, there is also evidence for important gene by environment interactions contributing to overall liability. Linkage studies have identified a series of chromosomal regions that are likely to contain susceptibility genes, and highly promising association findings have been obtained for several genes in these regions (e.g. neuregulin 1 [NRG1], disrupted in schizophrenia gene 1 [DISC1], Catechol-O-methyl transferase [COMT], D-amino acid oxidase activator [DAOA also known as G72], dystrobrevin-binding protein 1 [DTNBP1] and regulator of G-protein signaling 4 [RGS4]). Among those candidates, several have also been implicated in bipolar disorder, such as NRG1, DISC1 and G72. Previous work of the investigators has found that the disorder related variants have an influence on general cognition, personality profiles, neural activation levels and brain structure in healthy individuals which is, in many cases, highly similar to the patterns found when comparing patients with schizophrenia to healthy controls. The project aims at extending these results in patients. As several susceptibility genes seem to have an influence on schizophrenia as well as bipolar disorder - thus in part questioning the established strict diagnostic boundaries- it is intended to include these two diagnostic groups in these investigations in order to explore the commonalities as well as specificities of the genotype-phenotype associations across the two disorders. The phenotypes to be investigated include neuropsychological variables, personality profiles, neural activations during several cognitive and social-cognitive paradigms, whole brain and area specific morphometry as well as structural and functional connectivity. Candidate genes to be investigated will include – among others – the above mentioned variants NRG1, DISC1, G72, DTNBP1, and RGS4, but also new candidates emerging from genome-wide associations studies such as e.g. CACNA1C, ZNF804A, Neurogranin and TCF4. The aim of the proposal is to gain a deeper understanding of the pathogenetic pathways as well as the specificity of these susceptibility genes and the sensitivity of the methods employed to detect their influence in healthy subjects and patients.

Rietschel M. DFG - Deutsche Forschungsgemeinschaft RI 908/8-1: HeiDE: Heidelberger Langzeitstudie zu Risikofaktoren und Diagnose chronischer Erkrankungen . 09/2011-12/2013.

Durchschnittlich 20 Jahre nach der Erhebung von psychosozialen Faktoren und Variablen des Lebensstils an ursprünglich 5.133 Personen beiderlei Geschlechts sollen in dem hier beantragten Vorhaben zum zweiten Mal Nacherhebungen an der HeiDE-Kohorte vorgenommen werden. Diese richten sich zentral auf die Gesundheit bzw. Krankheit der Teilnehmer. Für die Erhebungen stehen prinzipiell noch jene 4.010 Personen aus der damaligen Stichprobe zur Verfügung, die bereits an einer ersten Nacherhebung mit einem Follow-up-Intervall von ca. 8 Jahren teilgenommen hatten (85% der damals noch Lebenden). Wichtige Ergebnisse bestanden darin, dass emotionale Labilität mit koronaren Herzerkrankungen in Beziehung stand, hingegen Krebserkrankungen mit keinem Persönlichkeitsmerkmal assoziiert waren. Des Weiteren wurden mehrere Persönlichkeits- und psychosozialen Variablen als Prädiktoren für Asthma identifiziert, genetisches Material asserviert und die kognitive Funktion bei den über 70-jährigen Personen erhoben. In dem nunmehr beantragten Vorhaben wird das Alter der Befragungspersonen wischen 60 und 85 Jahren liegen. Erneut interessieren besonders die in der Zwischenzeit neu aufgetretenen Erkrankungen sowie die Todesursachen bei den Verstorbenen; erstere werden mittels eines selbst auszufüllenden Fragebogens erfasst, letztere über die Gesundheitsämter. Die erhaltenen Informationen werden mit dem Einverständnis der Befragungspersonen durch Angaben der behandelnden Ärzte validiert. Um darüber hinaus untersuchen zu können, welche epigenetische Veränderungen im Verlauf der Erhebung aufgetreten sind, soll erneut genetisches Material asserviert werden. Gestützt auf die damit vorliegenden psychologischen, genetischen und epigenetischen Variablen sollen deren bivariate Korrelationen und unabhängige Effekte für das Auftreten und den Verlauf chronischer Krankheiten ermittelt werden, wobei Krebs, kardiovaskuläre Erkrankungen, psychische Störungen, Abbau bzw. Erhaltung kognitiver Funktionen, Diabetes und Asthma im Vordergrund stehen.

Strohmaier J. Universität Heidelberg : Exzellenzinitiative II, Zukunftskonzept. 01/2013-12/2013.

Depression zählt weltweit zu den häufigsten, in ihrer Schwere regelmäßig unterschätzen Erkrankungen. Unterschiedlichste Faktoren (z. B. Stress, genetische Veranlagung, körperliche Erkrankungen) können das Krankheitsrisiko erhöhen. Das klinische Erscheinungsbild ist heterogen – es können Symptome wie Antriebslosigkeit und Traurigkeit oder aber auch allgemeines Unwohlsein und Erschöpfung im Vordergrund stehen. Diese starke klinische und biologische Heterogenität stellt das größte Problem bei der Identifikation kausaler Pathomechanismen dar und verhindert bislang die Entwicklung dringend benötigter kausaler Therapien. Das konkrete Ziel dieses internationalen Kooperationsprojekts ist es genetische und umweltbedingte Risiko-/Resilienzfaktoren, die bei der Entwicklung depressiver Störungen eine Rolle spielen, zu identifizieren. Die Gruppe am QIMR untersucht seit Jahren erfolgreich die genetischen und umweltbedingten Ursachen komplexer Volkskrankheiten (z. B. Asthma, Krebs, Alkoholismus) an großen über Jahrzehnte hinweg klinisch ausführlich charakterisierten Zwillingskollektiven. Da sie für die Untersuchungen dieser somatischen Erkrankungen bereits umfangreiche genomweite genetische, epigenetische und Telomerdaten generiert haben, können diese Daten im Hinblick auf die Entwicklung depressiver Störungen sofort ausgewertet werden. Für weiterführende Untersuchungen liegen in Subkollektiven bildgebende Daten der Gehirnfunktion, Metabolomdaten und biologische Daten der Stressverarbeitung (z. B. Kortisol) vor. In unseren großen deutschen, neuropsychologisch intensiv untersuchten Kollektiven, liegen bislang nur teilweise genomweite und biologische Daten vor. Durch gezielte Untersuchung der Befunde, die wir durch Auswertung der australischen Daten finden, können diese validiert und weiterführende Endophänotypuntersuchungen durchgeführt werden. Die Kombination der psychiatrisch genetischen Expertise des ZI gepaart mit der Expertise des QIMR bei der Erforschung komplexer genetischer Mechanismen sowie die Fülle der dort bereits vorhandenen klinisch, genetischen und epigenetischen Daten eröffnet durch die optimale Nutzung der gemeinsamen Ressourcen eine unvergleichliche Chance biologische und klinische Depressionsmarker zu identifizieren.

Treutlein J. DFG - Deutsche Forschungsgemeinschaft TR 920/2-1: Zusammenspiel genetischer und umweltbedingter Einflussfaktoren auf das Rauchverhalten. 10/2012-09/2013.

Rauchen gehört zu den größten vermeidbaren Gesundheitsrisiken weltweit und auch das Passivrauchen ist gesundheitsschädlich. Das Rauchverhalten (u. a. Rauchbeginn, Rauchmenge, Nikotinabhängigkeit, Nikotinabstinenz) wird von genetischen und umweltbedingten Faktoren beeinflusst. Seit 2007 wurden durch genomweiten Assoziationsuntersuchungen (GWAS) erstmals systematisch robust replizierbare genetische Varianten identifiziert, die mit dem Rauchverhalten assoziiert sind. In dem hier beantragten Projekt sollen diese und weitere in der Literatur berichtete Risikovarianten genotypisiert und die kombinierten Effekte dieser genetischen Risikovarianten und bekannter Risikofaktoren (u. a. Alter bei Rauchbeginn, psychische Erkrankungen, Familiengeschichte für psychische Erkrankungen, Ausbildungsstand, Geburtskohorte, Geschlecht) auf das Rauchverhalten in zwei bereits vorhandenen gut charakterisierten Kohorten aus der Normalbevölkerung (N=1143 und N=1199) untersucht werden. Das Ziel ist, Konstellationen von Risikofaktoren zu identifizieren, die das Risiko für Tabakkonsum und abhängiges Rauchverhalten besonders stark erhöhen. Hierdurch soll die Entwicklung von präventiven Maßnahmen für Gruppen von Individuen mit einem besonders hohen Risiko ermöglicht werden.

Rietschel M. BMBF - Bundesministerium für Bildung und Forschung 01GS08152: NGFN Plus GENALC TP11: GWA studies in alcohol dependent patients and replicant studies. 06/2011-05/2013.

Rietschel M. EU - Europäische Union 224330 : ADAMS: Genomic variations underlying common neuropsychiatric diseases. 10/2009-12/2012.

The main objective of the ADAMS project is to promote the industrial exploitation and enhancement of the MARTE and other relevant standards for the development of real-time and embedded systems using both, model and component design paradigms. The approach to achieve this objective is basically to promote and create a comunity around the technical solutions provided by these standards and feed-back their concerns into the standardization efforts. The project addresses in first person two very active industrial communities: the automotive and the avionics embedded systems development, and integration. This will be achieved by creating two corresponding groups of experts in the field, one for automotive and other for avionis, which despite their different bussines models, share the necessity of basic technologies for the validation and verification of the non-functional properties involved in the embedded systems life cycle. Then, ADAMS will focus on promoting the usage of the OMG’s MARTE standard for MDD in both avionics and automotive domains. But at the same time capturing the concourse of the research comunity at large by promoting the visibility of MARTE in the various basic research forums that deal with the different aspects of the embedded distributed systems development.

Rietschel M, Banaschewski T. EU - Europäische Union 037286: IMAGEN WP4: Reinforcement-related behaviour in normal brain function and psychopathology: Recruitment and characterisation. 02/2007-07/2012.

Workpackage WP 04 will develop the procedure by which the human participants will be recruited and characterised on a cognitive, behavioural and clinical level. This WP will provide rationale for the target population (14 year old adolescents) and the methods necessary to successfully recruit young people to participate in the research. This WP also works closely with an SME (Delosis) to develop a new web-based system of collecting confidential cognitive and behavioural information from youth and their parents. Cognitive measures were selected to closely overlap with neuropsychological processes measured in WP 06 and WP 04 and reward-related brain processes in the animal research WP 03. This workpackage will also provide an assessment of cognitive and behavioural processes under different experimental conditions to further elaborate on the role of reward-related mechanisms in more complex psychological processes. It will provide a comprehensive assessment of youth psychosocial functioning and psychiatric symptoms and the progression toward greater behavioural and emotional problems at later stages of adolescence. Such a comprehensive battery will enable us to associate both genes and brain structure/function to behavioural and psychiatric profile. Finally, assessment of family environment and parental psychopathology and substance use will allow us to investigate gene-environment interaction at the level of both brain and behaviour. Specific objectives: 1. Develop an assessment battery to provide a comprehensive cognitive, behavioural, psychiatric and environmental characterisation of each adolescent participant. 2. Assure that all assessment procedures are piloted and validated for use in English, French and Germanspeaking adolescent populations. 3. Develop a manual-based standard operating procedure for recruitment of participants and assessment of participants at two time points (at age 14 and ages 15-17) (in collaboration with SME NNL). 4. Development of educational programmes to implement operating procedures for recruitment and clinical assessment of subjects Europewide. 5. Recruitment and behavioural/clinical characterisation of 2000 adolescent subjects. 6. Complete follow-up assessments in year 4 on all 2000 adolescent subjects.

Rietschel M. EU - Europäische Union 037286: IMAGEN WP9: Reinforcement-related behaviour in normal brain function and psychopathology: Ethics IMAGEN. 02/2007-07/2012.

Research to identify the genetic underpinnings of personality and psychiatric disturbances is aligned with a variety of ethical problems and challenges. Some of the problems which may arise within the context of the IMAGEN project (e.g. ethical issues concerning privacy and confidentiality, psychological impact on participating individuals, biobanking, data protection, etc.) have been addressed within the ELSI projects of the Human Genome Project. While standards have been set for certain aspects (e.g. biobanking and data protection) unforeseen ethical problems may emerge during the IMAGEN study. Since this project involves adolescents and deals with such sensitive issues as psychological deviance and genetics it is necessary to offer researchers the possibility of reacting to problems in an ethically appropriate manner. We will act in accordance with existing ethical guidelines and clinical practicability to address these problems. Problems and suggested strategies for solving them will be made available to all other researchers via an internal webpage. In addition, we will hold Annual Meetings with the External Ethics Council in order to discuss the most relevant ethical issues. The results of these Consensus Meetings will be disseminated internationally. The advantages are thus two-fold: Firstly, as outlined in ELSI projects, we can scurtinize possible emerging ethical problems for their relevance in a multinational EU study. Secondly, we will elaborate and disseminate strategies and models for decision making processes and solutions in research and clinical pratice of this kind. These models can then be used as an example for future multinational EU projects.

Rietschel M. DFG - Deutsche Forschungsgemeinschaft RI 908/7-1: ConLiGen: Genome-wide association study of response to lithium treatment in bipolar disorder using the international Consortium on Lithium Genetics sample. 11/2010-04/2012.

For more than half a century, lithium has been used as a first-line mood stabilizer in bipolar disorder. Apart from its proven antimanic and prophylactic effects, considerable evidence suggests that lithium has antisuicidal and antidepressant effects in affective disorders. Lithium is also used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In marked contrast to its wide use all over the world, the neurobiological underpinnings of lithium action remain vastly unknown. Pharmacogenetic studies of lithium response are comparatively sparse, and these studies are generally characterized by small sample size and varying definitions of response. Within the framework of the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org), we spearheaded an initiative to change this by creating the international Consortium on Lithium Genetics (www.ConLiGen.org). The combined sample size comprises 1252 individuals with bipolar disorder stringently characterized for lithium response with around 40% of individuals showing excellent response. We propose a genome-wide association study (GWAS) of lithium response in this sample. Currently available bipolar samples do not provide phenotypic information allowing a pharmacogenetic study of lithium response. The ConLiGen sample is unique in its thorough phenotypic assessment of lithium response and its sample size. We will thus be able to perform the first and largest GWAS of an internationally established and highly reliable measure of lithium response. This study will put lithium at the forefront of pharmacogenetic studies in psychiatry. It will contribute to a more personalized treatment of bipolar disorder by identifying genetic predictors of response and adverse events in lithium treatment.

Rietschel M. Rheinische Friedrich-Wilhelms-Universität Bonn 01ER1001C: Nationale cohort – pilot. 09/2010-04/2012.

Registration of neurocognitiv and neuropsychological phenotypes in the Helmholtz-cohort: feasibilty study


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