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TP 5: Molecular Genetics/Pharmacogenetics

TP 5: Molecular Genetics/Pharmacogenetics. Comptence Net Depression/Suicidality TP 5: Molecular Genetics/Pharmacogenetics M. Ackenheil, P. Zill. 06.10.03. TP 5: Molecular Genetics/Pharmacogenetics. Serotonergic Pathways. 5-HT1. TPH. 5-HT2A.

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TP 5: Molecular Genetics/Pharmacogenetics

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  1. TP 5: Molecular Genetics/Pharmacogenetics Comptence Net Depression/Suicidality TP 5: Molecular Genetics/Pharmacogenetics M. Ackenheil, P. Zill 06.10.03

  2. TP 5: Molecular Genetics/Pharmacogenetics Serotonergic Pathways 5-HT1 TPH 5-HT2A Cellular Response via Signal Transduction Cascades Tryp 5-HTP 5-HT 5-HT2C 5-HTTLPR 06.10.03

  3. TP 5: Molecular Genetics/Pharmacogenetics Candidate Genes for Affective Disorders I • Serotonin Transporter Gene: 5-HTTLPR 44 bp Del/Ins polymorphism in the promoter region  S- or L-allele  changes in 5-HT expression Associated with:suicidality (e.g. Joiner et al. 2002),unipolar depression(e.g. Hauser et al. 2003) and depression in relation to stress (Caspi et al. 2003) Replicated in a meta anlysis by Anguelova et al. 2003 06.10.03

  4. TP 5: Molecular Genetics/Pharmacogenetics Candidate Genes for Affective Disorders II • Serotonin Receptors 5-HT1A (C-1018G): associated with major depression(e.g . Arias et al. 2002) 5HT1B (G861C): associated with major depression(e.g. Huang et al. 2003) and suicidality(New et al. 2001) Serotonin 1B (5HT-1B) receptor polymorphism (G861C) in suicide victims: association study in German and Slavic population American Journal of Medical Genetics (in press) Jasminka Stefulj,1 Andreas Büttner,2 Milovan Kubat,3 Peter Zill,4 Melita Balija,5 Wolfgang Eisenmenger,2 Brigitta Bondy,4 Branimir Jernej1 1Laboratory of Neurochemistry and Molecular Neurobiology, Zagreb, Croatia 2Institute for Legal Medicine, Ludwig-Maximilians-University Munich, Munich, Germany 3Department of Forensic Medicine and Criminology,, Croatia 4Department of Psychiatry, Ludwig-Maximilians-University Munich, Munich, Germany 06.10.03

  5. TP 5: Molecular Genetics/Pharmacogenetics Candidate Genes for Affective Disorders III • Serotonin Receptors 5-HT2A (T102C): associated withsuicidal behavior(e.g. Arias et al. 2001, Du et al. 2001) 5HT2C (Cys23Ser): associated with major depression(e.g. Lerer et al. 2001) 5HT-2C receptor polymorphism in suicide victims: association studies in German and Slavic population Jasminka Stefulj,1 Andreas Büttner,2 Milovan Kubat,3 Peter Zill,4 Melita Balija,5 Wolfgang Eisenmenger,2 Brigitta Bondy,4 Branimir Jernej1(International cooperation Munich-Zagreb) 06.10.03

  6. TP 5: Molecular Genetics/Pharmacogenetics Candidate Genes for Affective Disorders IV • Tryptophan Hydroxylase (TPH1) Numerous polymorphisms located over the entire gene Associated with:suicidality, but not convincingly confirmed results(e.g. Lalovic et al. 2002, Rujescu et al. 2003),antidepressant treatment response(e.g. Serretti et al. 2003) and major depression (Tan et al. 2003) Own association studies between several polymorphisms in the TPH1 gene and completed suicide provided no evidence for association 06.10.03

  7. TP 5: Molecular Genetics/Pharmacogenetics Candidate Genes for Affective Disorders V • Neuronal TPH (TPH2) Second TPH isoform which is exclusively present in the human brain Located on chromosome 12, 77% homology to TPH1 (Walther et al. 2003) TPH2 is exclusively present in the human brain and not in peripheral tissues (Zill et al. 2003) SNPs in the TPH2 gene show an association with completed suicide (Zill et al. 2003) 06.10.03

  8. TP 5: Molecular Genetics/Pharmacogenetics Candidate Genes for Affective Disorders VI • ß3 Subunit of G-Proteins (Gß3) C825T in exon 10  splice variant (Gß3-s)  deletion of 41 amino acids  biological active protein Associated with:increased signal transduction and hypertension (Siffert et al. 1998) • Replicated in own studies in an increased patient sample Replicated by Kunugi et al. 2002 and Serretti et al. 2003 06.10.03

  9. TP 5: Molecular Genetics/Pharmacogenetics Candidate Genes for Affective Disorders VII • Angiotensin Converting Enzyme (ACE) Del/Ins polymorphism of 287 bp in intron 16  D-allele associated with ACE concentration Associated with:mycardial infarction, arteriosclerosis, hypertension and affective disorders (Arinami et al. 1996) Baghai TC, Schule C, Zwanzger P, Minov C, Schwarz MJ, de Jonge S, Rupprecht R, Bondy B. Mol Psychiatry. 2001 May;6(3):258-9 06.10.03

  10. TP 5: Molecular Genetics/Pharmacogenetics Future Aspects • Subgrouping according to clinical and pharmacological parameters • SNP Haplotyping by High Throughput Techniques • Search for new Candidate Genes by Functional Genomics and Proteomics 06.10.03

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