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Project 5: Molecular Genetics and Pharmacogenetics

Project 5: Molecular Genetics and Pharmacogenetics. W. Maier, M. Ackenheil, M. Rietschel. Recruitment of Samples in Project 5 Working Plan Steering Committee Genotyping Examples of Candidate Genes and First Results. Recruited Patients in Project 5. Sept 03.

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Project 5: Molecular Genetics and Pharmacogenetics

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  1. Project 5: Molecular Genetics and Pharmacogenetics W. Maier, M. Ackenheil, M. Rietschel

  2. Recruitment of Samples in Project 5 Working Plan Steering Committee Genotyping Examples of Candidate Genes and First Results

  3. Recruited Patients in Project 5 Sept 03

  4. Received Samples per Subproject SP 1.2 56 SP 1.2/1.5 131 SP 1.5 31 SP 2.1 154 SP 2.3 142 SP 3.8 131 SP 6.1 174 SP 6.1/6.2 64 Total Project 5 883 SP 1.2 Lithium-Intervention-Study SP 1.5 Neurobiology of Suicidal Behavior SP 2.1 Treatment of Mild and Subdiagnostic Depressions SP 2.3 Chronicity in Persons with Depression and Somatoform Disorder SP 3.8 Therapeutic Drug Monitoring of Antidepressants SP 6.1 Chronicity / Resistance / Suicidality SP 6.2 Comparison of Systematic Treatment Algorithms with Standard Treatment

  5. Recruitment of Samples in Project 5 Working Plan Steering Committee Genotyping Examples of Candidate Genes and First Results

  6. Received Samples per Center and Project SP 1.2 Lithium-Intervention-Study SP 1.5 Neurobiology of Suicidal Behavior SP 2.1 Treatment of Mild and Subdiagnostic Depressions SP 2.3 Chronicity in Persons with Depression and Somatoform Disorder SP 3.8 Therapeutic Drug Monitoring of Antidepressants SP 6.1 Chronicity / Resistance / Suicidality SP 6.2 Comparison of Systematic Treatment Algorithms with Standard Treatment

  7. Steering Committee "Genetics" Members: Applicants of Project 5PI of contributing projectsSpeaker of Network Tasks: Linkage between Genotype Data Bank  Clinical Data Bank  Core Data Bank Stimulation of investigations on genotype-phenotype relationships Provision of access to DNA bank, genotype bank Application for grants for genotyping Responsibilities and authorships for publications

  8. Genotyping in Candidate Genes of the KND Samples Bonn Munich Polymorphisms for genes coding for Glucocorticoid receptor Serotonin receptors/transporter Dopamine receptors/transporter Mineralocorticoid receptor Corticotropin hormone receptors Noradrenaline receptors/transporter MAO-A/-B Tryptophan hydroxylase COMT G-protein ß BDNF ACE Multidrug resistance Interleukine Interleukine Second messenger systemsGABA receptorsGSK3MPA3

  9. Investigated Polymorphisms (1) BDNFrs6265 (A/G) COMTrs4680 (G158A) rs737865 (C/T) rs165599 (A/G) 5-HT-2AT102C 5-HT-T 44 bp Ins./Del. VNTR (17 bp) MAO-A C936T VNTR (30 bp) MAO-B G/A Intron 13 MDR-1 C3435T

  10. Investigated Polymorphisms (2) KND Samples: SP 1.2/1.5, SP 3.8 CRHR1rs242925 (A/G) rs81189 (C/G) rs1396862 (C/T) rs173365 (C/T) GCCRTth111L (Promoter) rs860468 (A/G) rs2918419 (A/G) rs1866388 (A/G) rs6190 (G/A) rs6195 (A/G) MLRrs5534 (A/G) rs3733421 (G/A) rs5522 (A/G) rs2070951 (C/G)

  11. Recruitment of Samples in Project 5 Working Plan Steering Committee Genotyping Examples of Candidate Genes and First Results

  12. Corticotropin Releasing Hormone Receptor 1 (CRH-R1) Gene:Candidate Gene for Depression, Antidepressant Response, HPA Responsiveness CRH-binding sites (frontal cortex) in depression (Nemeroff et al., 1988) Knock-out mice: CRH-R1 mediates anxiety like behaviour(Timpl et al., 1998) Antisense technique (rats): CRH-R1 level   anxiety (Liebsch et al., 1999) CRH-R1 mRNA expression (locus coeruleus) in stressed rats (Zeng et al., 2003) Down-regulated CRH receptors (CRH test, DEX/CRH test) in depression (Gold, Holsboer, 1986) CRH antagonists: putative antidepressive effect(Zobel et al., 2000)

  13. The CRF-1 Receptor Gene and its Gene Product Genomic structure of human corticotropin releasing hormone receptor 1: Genomic size: 51 524 bp; mRNA size: 2 535 bp; 7-transmembrane segment hormone receptor Exon1 Exon13 rs1396862 rs242925 rs81189 rs173365 Intermarker distance 5.9kb 6.27kb 1.9kb

  14. The CRF-1 Receptor Gene and its Gene Product Genomic structure of human corticotropin releasing hormone receptor 1: Genomic size: 51 524 bp; mRNA size: 2 535 bp; 7-transmembrane segment hormone receptor Exon1 Exon13 rs1396862 rs242925 rs81189 rs173365 Intermarker distance 5.9kb 6.27kb 1.9kb

  15. Response to SSRI Treatment in 105 Inpatients (TDM Project) with Unipolar DepressionSubdivided by CRH1R – SNP rs81189 HAMD17 30 25 20 cc cg 15 gg 10 Day 28 Day 0 p = 0.02

  16. Response to SSRI Treatment in 105 Inpatients (TDM Project) with Unipolar DepressionSubdivided by COMT Genotype (V 158 M) HAMD17 30 25 20 15 10 Day 28 Day 0 p = 0.01 0

  17. Response to SSRI Treatment in 105 Inpatients (TDM Project) with Unipolar DepressionSubdivided by COMT Genotype (V 158 M) HAMD17 30 25 20 Val Val high activity Val Met 15 Met Met low activity 10 Day 28 Day 0 p = 0.01 0

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