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Genetics of Bipolar Disorder

Susanne Bengesser and Eva Reininghaus

The high hereditary factor of Bipolar Disorder has been proven by many twin-, adoption- and family-studies already decades ago. Concordance rates between monozygotic twins are even as high as 40-70%. Children of two affected parents have a lifetime-risk of 50-65% to fall ill with Bipolar Disorder, while children with one affected parent show a risk of 25% to get Bipolar Disorder. Therefore psychiatric genetics is highly important to detect the genetic blueprint of Bipolar Disorder to invent prevention strategies, as well as individualized pharmacotherapy and new medication targets. Interestingly top susceptibility genes belong to the ion channel group, growth hormones, clock genes, neurotransmitter systems, Lithium sensitive pathway and other important groups. A detailed and exciting description is given by the authors within this book. Furthermore basic principles of genetics, gene-environment-interactions and genetic overlaps between psychiatric diseases are described to picture the whole painting of Genetics of Bipolar Disorder.

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Preface .................................................................................................................. 5 Abstract ................................................................................................................. 7 Acknowledgements ............................................................................................... 9 1. Introduction ................................................................................................... 17 1.1 Bipolar Affective Disorder ................................................................... 17 1.1.1 History and Symptomatology of Bipolar Disorder .................. 17 1.1.2 Pharmacotherapy ..................................................................... 18 Mood Stabilization ................................................................... 19 Lithium .............................................................................. 19 Antiepileptics .................................................................... 21 Atypical Antipsychotics .................................................... 22 Antidepressant Therapy ........................................................... 23 Selective Serotonin Reuptake Inhibitors (SSRI) ............... 24 NASSA (Noradrenaline and Serotonin Specific Antidepressant) ................................................................. 24 SNRI (Serotonin and Noradrenaline Reuptake Inhibitor) ........................................................................... 25 NARI (Noradrenaline Reuptake Inhibitor) ....................... 25 SRE (Serotonin Reuptake Enhancer) ................................ 25 NDRI (Noradrenaline and Dopamine Reuptake Inhibitor) ........................................................................... 25 Tricyclic Antidepressants .................................................. 26 Tetracyclic Antidepressants .............................................. 26 MAO Inhibitors ................................................................. 26 DSA (Dual Serotonergic Antidepressant) ......................... 26 Bright Light Therapy ........................................................ 27 1.1.3 Epidemiology of Bipolar Disorder .......................................... 27 1.2 Basic Principles of Genetics ................................................................. 27 1.2.1 Structure of DNA ..................................................................... 27 12 1.2.2 Gene Expression- from DNA to Proteins ................................ 28 Transcription ............................................................................ 29 Initiation of Transcription ................................................. 30 Elongation of Transcription .............................................. 31 Termination of Transcription ............................................ 31 Proteinbiosynthesis (Translation): ........................................... 32 Initiation of Protein Biosynthesis in Eukaryotes ............... 33 Elongation ......................................................................... 34 Termination ....................................................................... 35 1.2.3 Replication ............................................................................... 35 Initiation of Replication ........................................................... 35 1.2.4 Epigenetics ............................................................................... 36 1.2.5 Mutations ................................................................................. 36 Gene mutations ........................................................................ 36 Point mutations ................................................................. 36 Insertions, Deletions, Duplications and Repeat Polymorphisms ................................................................. 37 Chromosomal mutations .......................................................... 37 Structural Chromosomal Mutations .................................. 37 Chromosome Number Aberrations ................................... 37 1.2.6 Methods of Molecular Bipolar Disorder Research .................. 38 Association Studies .................................................................. 38 Genome Wide Association Studies (GWAS) .................... 38 Linkage studies ................................................................. 39 2. Methods ......................................................................................................... 41 3. Genetics of Bipolar Disorder ........................................................................ 43 3.1 Heritability of Bipolar Disorder ........................................................... 43 3.2 Candidate Genes at One View ............................................................. 43 3.3 Genes of the Serotonergic System ....................................................... 60 3.3.1 Serotonin Receptor Genes ....................................................... 60 5-HT1 Receptor Genes ............................................................ 60 HTR1A .............................................................................. 60 HTR1B and HTR1D ......................................................... 62 5-HT2 Receptor...

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