The contribution of common and rare variants to the complex genetics of psychiatric disorders [Elektronische Ressource] / vorgelegt von Sandra Schulz

Sandra Batlle-Nelson

Sujets

• Naturwissenschaften

Informations

• Publié par: julius-maximilians-universitat_wurzburg
• Publié le: 01 janvier 2010
• Nombre de lectures: 26
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

THE CONTRIBUTION OF COMMON AND RARE
VARIANTS TO THE COMPLEX GENETICS OF
PSYCHIATRIC DISORDERS




Dissertation zur Erlangung des
naturwissenschaftlichen Doktorgrades
der Julius-Maximilians-Universität Würzburg




vorgelegt von
Sandra Schulz


geboren am 29. April 1981 in Nürnberg




Würzburg, 2010












Eingereicht am: ……………………………………………………………………………………....




Mitglieder der Promotionskomission:
Vorsitzender: …………………………………………………………………………………………
Gutachter: ……………………………………………………………………………………………
Gutachter: ……………………………………………………………………………………………

Tag des Promotionskolloquiums: ………………………………………………………………...

Doktorurkunde ausgehändigt am : ……………………………………………………………… The present work was accomplished within the Graduate Programme 1156 “From Synaptic Plasticity
to Behavioural Modulation in Genetic Model Organisms” (Speaker: Prof. Dr. M. Heisenberg) of the
International Graduate School of Life Sciences in the Department of Psychiatry, Psychosomatics and
Psychotherapy of the Julius-Maximilians University, Würzburg from August 2005 until July 2009 under
supervision of Prof. Dr. K.P. Lesch.


Dekan: Prof. Dr. Martin Müller
Lehrstuhl für Pharmazeutische Biologie
der Julius-Maximilians-Universität Würzburg
Julius-von-Sachs-Platz 2, 97082 Würzburg

Erstgutachter: Prof. Dr. Klaus-Peter Lesch
Klinik für Psychiatrie, Psychosomatik und
Psychotherapie
der Julius-Maximilians-Universität Würzburg
Füchsleinstrasse 15, 97080 Würzburg

Zweitgutachter: PH Dr. Bertram Gerber
Lehrstuhl für Genetik und Neurobiologie
der Julius-Maximilians-Universität Würzburg
Biozentrum, Am Hubland, 97074 Würzburg

Kooperationspartner: PH Dr. Reinhard Ullmann
Lehrstuhl für Molekulare Zytogenetik
des Max-Planck-Instituts für Molekulare Genetik
Ihnestrasse 63-73, 14195 Berlin

III
Chapter A INDEX
A. INDEX

A INDEX IV
B LIST OF SCIENTIFIC PUBLICATIONS IX
C LECTURES X
D PRESENTATIONS AT CONFERENCES XI
E CURRICULUM VITAE XII
F ABSTRACT XIV
G ZUSAMMENFASSUNG XVI

I. INTRODUCTION

1. ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD) 1
1.1. CLINICAL PHENOTYPE 1
1.2. TREATMENT 2
1.3. NEUROBIOLOGICAL FUNDAMENTALS 2
PREFRONTAL CORTEX 4
DORSAL ANTERIOR CINGULATED CORTEX 4
STRIATUM 4
CEREBELLUM 5
CORPUS CALLOSUM 5
2. CANDIDATE GENES 6
2.1. DOPAMINERGIC SYSTEM 6
2.2. DOPAMINERGIC GENES 11
DOPAMINE TRANSPORTER 1 11
DOPAMINE RECEPTOR 1 11
DOPAMINE RECEPTOR 4 12

IV
Chapter A INDEX
DOPAMINE RECEPTOR 5 13
DOPAMINE Β-HYDROXYLASE 13
2.3. NORADRENERGIC SYSTEM 14
NOREPINEPHRINE TRANSPORTER 17
ADRENERGIC RECEPTOR 2A 17
2.4. SEROTONERGIC SYSTEM 18
2.5. SEROTONERGIC GENES 21
SEROTONIN TRANSPORTER 21
SEROTONIN RECEPTOR 1B 21
TRYPTOPHAN HYDROXYLASE 2 22
2.6. NEUROPEPTIDES 22
NEUROPEPTIDE Y 22
LATROPHILIN 3 23
2.7. OTHER CANDIDATE GENES 24
MONOAMINE OXIDASE ISOENZYME A 24
SYNAPTOSOMAL ASSOCIATED PROTEIN 25 24
3. MEGALOENCEPHALIC LEUKOENCEPHALOPATHY WITH 25
SUBCORTICAL CYSTS
3.1. CLINICAL FEATURE 25
3.2. FINDINGS 25

II. MATERIAL & METHODS

1. MATERIAL 28
2. METHODS 41
2.1. BASAL MOLECULAR GENETIC METHODS 41
POLYMERASE-CHAIN REACTION 41

V
Chapter A INDEX
REVERSE TRANSCRIPTASE POLYMERASE-CHAIN 43
REACTION OLIGONUCLEOTIDE PRIMER
AGAROSE GEL ELECTROPHORESIS 45
DNA PRECIPITATION 45
DNA CUTTING BY RESTRICTION ENDONUCLEASES 45
2.2. IN SITU HYBRIDIZATION 46
2.3. IMMUNOHISTOCHEMISTRY 48
2.4. ARRAY COMPARATIVE GENOMIC HYBRIDIZATION 50
(ARRAY CGH)
2.5. HIGH THROUGHPUT SNP GENOTYPING USING 58
MALDI-TOF MASS SPECTROMETRY
2.6. TARGETING VECTOR CONSTRUCTION FOR 63
KNOCKOUT MICE
LIGATION 64
TRANSFORMATION 65
SELECTION OF POSITIVE CLONES VIA COLONY 66
SCREENING
ELECTROPORATION 67

III. RESULTS

1. GENOMIC COPY NUMBER VARIATIONS IN ADHD 68
1.1. ARRAY COMPARATIVE GENOMIC HYBRIDIZATION 68
1.2. PHENOTYPE OF THE 7Q15 DUPLICATION IN A 74
MULTIGENERATIONAL PEDIGREE
2. LINKAGE ANALYSES 81
2.1. GLUCOSETRANSPORTER 3 AND 6 81
2.2. GENOTYPING OF PLEKHB1, RAB6A AND PDE4D 84
2.3. THE SYNAPYIC VESICLE PROTEIN 2C 92


VI
Chapter A INDEX
3. IMMUNOHISTOCHEMICAL ANALYSIS OF LPHN3 96
3.1. REGIONAL DISTRIBUTION OF LPHN3 mRNA IN THE 96
MURINE BRAIN USING ISH
3.2. CELLULAR AND REGIONAL DISTRIBUTION PATTERN 98
OF LPHN3 PROTEIN IN HUMAN AND MURINE BRAIN
SECTIONS
4. RESEARCHES IN MLC 100
4.1. GENOTYPING OF MLC1 POLYMORPHISMS FOR 100
ASSOCIATIONS WITH PERIODIC CATATONIA
4.2. MLC1KNOCKOUT PLASMID VECTOR 103

IV. DISCUSSION

1. NEW ADHD CANDIDATE GENES BY ARRAY CGH 106
1.1. NEUROPEPTIDE Y 106
1.2. GLUCOSETRANSPORTER 3 AND 6 109
1.3. CUB AND SUSHIE MULTIBLE DOMAINS 1 112
1.4. BUTYRYLCHOLINESTERASE 112
1.5. PLEKHB1, RAB6A AND PDE4D 114
1.6. SYNAPTIC VESICLE PROTEIN 2C 116
1.7. FURTHER CANDIDATE GENES 117
2. DISTRIBUTION OF LPHN3 mRNA IN CNS 118
3. NEW FINDINGS OF MLC 119
3.1. MLC1 POLYMORPHISMS ARE ASSOCIATED WITH 119
PERIODIC CATATONIA
3.2. GENERATION OF A KNOCKOUT MOUSE BY GENE 121
TARGETING




VII
Chapter A INDEX
V. APPENDIX

1. REFERENCES 122
2. LIST OF FIGURES AND TABLES 137
3. LIST OF ABBREVIATIONS 141
4. ACKNOWLEDGEMENT 149
5. DECLARATION / ERKLÄRUNG 150


VIII
Chapter B LIST OF SCIENTIFIC PUBLICATIONS
B. LIST OF SCIENTIFIC PUBLICATIONS

1. Selch S, Strobel A, Haderlein J, Meyer J, Jacob CP, Schmitt A, Lesch KP, Reif A.
(2007). “MLC1 polymorphisms are specifically associated with periodic
catatonia, a subgroup of chronic schizophrenia.” Biol Psychiatry 61 (10): 1211-4.

2. Veenema AH, Reber SO, Selch S, Obermeier F, Neumann ID. (2008). “Early life
stress enhances the vulnerability to chronic psychosocial stress and
experimental colitis in adult mice.” Endocrinology 149 (6): 2727-36.

3. Lesch KP*, Selch S*, Renner TJ*, Jacob C, Nguyen TT, Romanos M, Shoichet S,
Dempfle A, Heine M, Boreatti-Hümmer A, Walitza S, Romanos J, Zerlaut H, Allolio B,
Fassnacht M, Wultsch T, Reif A, Schäfer H, Warnke A, Ropers HH, Ullmann R.
(2010) “Genome-wide copy number variation analysis in ADHD: association
with neuropeptide Y gene dosage in an extended pedigree.” Mol Psychiatry
(Epub ahead of print)
* Equal contribution


IX
Chapter C LECTURES
C. LECTURES

nd1. Selch S. (Dec 2005) “Behavioral Phenotyping.” 2 Würzburg Brain and Behaviour
Days: A critical evaluation of available method, meeting of the Graduate College
(GRK) 1156 “From Synaptic Plasticity to Behavioural Modulation in Genetic Model
Organisms” within the International Graduate School of Life Science.
2. Selch S. (Apr 2007) “A genomwide duplication and deletion analysis on patients
thwith ADHD.“ 4 Würzburg Brain and Behaviour Days: Presentation of the latest
results, meeting of the Graduate College (GRK) 1156: “From Synaptic Plasticity to
Behavioural Modulation in Genetic Model Organisms” within the International
Graduate School of Life Science.
3. Selch S. (May 2007) “Untersuchungen zu ADHS mit Hilfe des Microarray-based
comparative genomic hybridization (a-CGH).” Scientific neurobiological meeting,
Department of Psychiatry, Psychosomatics and Psychotherapy, University of
Würzburg.
4. Selch S. (Dec 2007) “Molekularbiologische Untersuchungen zu MLC1 – ein
Kandidatengen für Schizophrenie.“ Scientific neurobiological meeting, Department
of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg.


X