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Influence of Genetic Variants on Serotonergic Neurotransmission

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Influence of Genetic Variants on Serotonergic Neurotransmission Influence of genetic variants on serotonergic neurotransmission Doctoral thesis at the Medical University of Vienna in the program of Applied Medical Sciences N790 thematic program Clinical Neurosciences (CLINS) for obtaining the medical degree DOCTOR OF MEDICAL SCIENCE submitted by Pia Baldinger, MD supervised by Rupert Lanzenberger, Assoc. Prof, PD, MD Functional, Molecular and Translational Neuroimaging Lab – PET & MRI Department of Psychiatry and Psychotherapy Medical University of Vienna Währinger Gürtel 18-20, 1090 Vienna, Austria http://www.meduniwien.ac.at/neuroimaging/ Vienna, 03/2015 DECLARATION This thesis project was conducted at the Functional, Molecular and Translational Neuroimaging Lab – PET & MRI (head: Assoc. Prof. PD Dr. med. Rupert Lanzenberger) at the Department of Psychiatry and Psychotherapy (head: o.Univ.-Prof. Dr. h.c.mult. Dr. med. Siegfried Kasper), Clinical Division of Biological Psychiatry, Medical University of Vienna, Austria (www.meduniwien.ac.at/neuroimaging). Positron emission tomography measurements were performed at the Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine (head: Univ. Prof. Dr. med. Markus Hacker), former Department of Nuclear Medicine (heads: o.Univ. Prof. Dr. med. Robert Dudczak and ao. Univ. Prof. Dr. med. Helmut Sinzinger), Medical University of Vienna, Austria Synthesis of radioligands was done by the working group of Radiopharmaceutical Sciences (www.radiopharmaceutical-sciences.net), Department of Nuclear Medicine, Medical University of Vienna, Austria (head: Assoc. Prof. PD Mag. Dr. Wolfgang Wadsak and PD Mag. Dr. Markus Mitterhauser). Genotyping of DNA samples was conducted at the Genetics Research Center (head: Prof. Dr. med. Dan Rujescu), Department of Psychiatry and Psychotherapy (head: Prof. Dr. med. Peter Falkai), Ludwig-Maximilians-University, Munich, Germany (www.klinikum.uni-muenchen/Klinik- undPoliklinik-fuer-Psychiatrie-und-Psychotherapie/forschung/genetics/index.html). i TABLE OF CONTENT ABSTRACT (english) iv ABSTRACT (Deutsch) v PUBLICATIONS ARISING FROM THIS THESIS vii ABBREVIATIONS ix PROJECT FUNDING AND ACKNOWLEDGEMENTS x 1. INTRODUCTION 1 1.1. General Introduction 1 1.1.1. New developments in the field of genetics 1 1.1.2. Psychiatric genetics 4 1.1.3. The role of serotonin in psychiatry 7 1.1.4. Relevant genetic variations 10 1.1.5. Positron emission tomography and imaging genetics 15 1.2. Aims of the thesis 18 2. MATERIALS AND METHODS 19 3. RESULTS 21 3.1. First publication: Impact of COMT genotype on serotonin-1A receptor binding investigated with PET 21 3.1.1. Abstract 22 3.1.2. Introduction 23 3.1.3. Materials and Methods 25 3.1.4. Results 28 3.1.5. Discussion 30 3.1.6. Conclusions 34 3.1.7. References 36 3.1.8. Tables and Figures 45 ii 3.2. Second publication: Exploring the impact of BDNF Val66Met genotype on serotonin transporter and serotonin-1A receptor binding 50 3.2.1. Abstract 51 3.2.2. Introduction 52 3.2.3. Methods 54 3.2.4. Results 58 3.2.5. Discussion 59 3.2.6. Limitations 61 3.2.7. References 63 3.2.8. Tables and Figures 68 3.3. Third publication: Interaction between 5-HTTLPR and 5-HT1B genotype status enhances cerebral 5-HT1A receptor binding 73 3.3.1. Abstract 74 3.3.2. Introduction 75 3.3.3. Methods and Material 77 3.3.4. Results 81 3.3.5. Discussion 83 3.3.6. References 88 3.3.7. Tables and Figures 94 4. DISCUSSION 99 4.1. General discussion 99 4.2. Conclusion and further prospects 103 5. REFERENCES 104 6. APPENDIX 117 iii ABSTRACT (english) Influence of genetic variants on serotonergic neurotransmission Psychiatric disorders were shown to be highly inheritable, for instance with rates of 40-50 % for depressive disorder. The manifestation of a mental illness underlies multifactorial conditions including environment factors and the interplay of multiple gene variants, notably single- nucleotide-polymorphisms (SNPs), where each mutation taken individually is supposed to exert only a marginal effect. Genetic association studies including genome-wide investigations have led to the characterization of a multitude of risk genes thought to increase vulnerability for psychiatric disorders. In mood and anxiety disorders, main focus has been led on the exploration of the serotonergic neurotransmitter system and related gene variants, notably as drugs modulating the serotonin system have proven effective in the treatment of these diseases. To date, the classification of psychiatric disorders is based on the observation and description of psychopathologic symptoms without taking into account etiologic factors. In biological psychiatry, to mitigate the issue of clinical heterogeneity, the concept of endophenotypes represents an attempt to reconcile genetic factors with measurable neurobiological correlates thought to underlie a certain clinical phenotype. In order to assess the implications of gene variants on serotonergic neurotransmission, we conducted three investigations using an imaging genetics approach combining allelic distribution patterns of genes of interest with imaging data retrieved from positron emission tomography studies investigating the serotonin-1A (5-HT1A) receptor and the serotonin transporter (SERT), two major players in the modulation of the serotonin system. In the first study, we could determine an effect of catechol-O-methyltransferase gene variant (rs4680) on 5-HT1A receptor binding, where the high-activity allele (GG) is associated with higher receptor binding in healthy controls (HC). Secondly, we were able to replicate previous findings showing no effect of brain-derived-neurotrophic-factor Val66Met (rs6265) variant on 5-HT1A receptor in HC and SERT binding in both depressed and HC. Finally, we could establish a gene x gene interaction between a length polymorphism in SERT gene promoter region (5-HTTLPR) and a serotonin-1B receptor gene SNP (rs6296) affecting 5-HT1A receptor binding in HC with highest receptor densities in LL (5-HTTLPR) x CC (rs6296) carriers. The publications arising from this thesis substantiate and expand our knowledge on the influence of SNPs on serotonergic neurotransmission using a promising research approach in the field of imaging genetics. Further studies are needed to confirm the gene-binding relationship and its role in the pathogenesis of psychiatric disorders. These studies represent a valuable step in search for a biologically-based classification of psychiatric disorders. iv ABSTRACT (Deutsch) Einfluss genetischer Varianten auf die serotonerge Neurotransmission Psychische Erkrankungen weisen eine hohe Heredität auf, beispielsweise mit Raten von 40- 50% bei der depressiven Störung. Die Ausprägung einer psychischen Störung ist multifaktoriell bedingt. Eine Rolle spielen Umweltfaktoren und das Zusammenspiel einer Vielzahl von genetischen Varianten, insbesondere Einzelnukleotid-Polymorphismen (SNPs), wobei jede einzelne Mutation jeweils nur einen marginalen Effekt ausübt. Genetische Assoziationsstudien einschließlich genomweiter Analysen haben zur Charakterisierung einer Vielzahl von Risikogenen geführt, die mutmaßlich mit einer erhöhten Vulnerabilität für psychische Erkrankungen einhergehen. In der Erforschung affektiver Störungen und Angststörungen wurde ein Schwerpunkt auf die Untersuchung des Serotoninsystems und damit verbundener Genvarianten gelegt, da Medikamente, die in dieses Neurotransmittersystem eingreifen, effektiv in der Behandlung dieser Erkrankungen sind. Zum heutigen Zeitpunkt beruht die Klassifikation psychischer Erkrankungen auf der Beobachtung und Beschreibung psychopathologischer Symptome ohne Berücksichtung ätiologischer Faktoren. Um das Problem der klinischen Heterogenität zu minimieren, hat sich im Bereich der biologischen Psychiatrie das Konzept der Endophänotypen durchgesetzt: Es handelt sich hierbei um einen Versuch, genetische Faktoren mit messbaren neurobiologischen Korrelaten in Verbindung zu bringen, die mutmaßlich bestimmten psychischen Störungen zugrunde liegen. Wir haben drei Studien durchgeführt, um die Effekte genetischer Varianten auf die serotonerge Neurotransmission, genauer gesagt auf den Serotonin-1A (5-HT1A) Rezeptor und den Serotonintransporter (SERT), zwei wesentliche Akteure des Serotoninsystems, zu erfassen. Die Studien bedienen sich des Ansatzes der Imaging genetics, der auf der Kombination von Expressionsmustern genetischer Varianten und quantitativer Bildgebungsdaten, die mittels Positronen-Emissions-Tomographie erfasst wurden, beruht. In der ersten Studie konnten wir zeigen, dass eine Variante des Catechol-O-Methyltransferase Gens (rs4680) einen Effekt auf das 5-HT1A Rezeptorbindungspotenzial bei Gesunden hat. Das Allel, das mit einer höheren enzymatischen Aktivität einhergeht (GG) ist mit einem höheren Bindungspotenzial vergesellschaftet. In der zweiten Studie konnten wir frühere Ergebnisse replizieren und zeigen, dass eine Variante des Brain-Derived-Neurotrophic-Factor Gens (Val66Met, rs6265) weder einen Einfluss auf das 5-HT1A Rezeptorbindungspotenzial in Gesunden noch auf das SERT Bindungspotenzial bei depressiven Patienten und gesunden Kontrollprobanden hat. Drittens, konnten wir eine Gen x Geninteraktion zwischen dem Längenpolymorphismus der Promoterregion des SERT Gens (5-HTTLPR) und einer Variante v des Serotonin-1B Rezeptors (rs6296) etablieren, welche einen Einfluss auf das 5-HT1A Rezeptorbindungspotenzial ausübt. Eine hohe Rezeptorbindung konnte für jene Probanden festgestellt werden, die sowohl homozygote L (5-HTTLPR) und C (rs6296) Träger sind. Die Publikationen, die aus diesem
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