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. SP 1.2 Received Samples per Subproject SP 1.2/1.5 SP 1.5 SP 2.1 SP 3.8 SP 6.1 SP 6.1/6.2 56 31 154 142 131 174 131 SP 2.3 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. 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 Received Samples per Center and Project

7. Steering Committee "Genetics" Members: Tasks: Applicants of Project 5 PI of contributing projects Speaker of Network 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

9. Genotyping in Candidate Genes of the KND Samples BonnMunich Polymorphisms for genes coding for Glucocorticoid receptor Corticotropin hormone receptors MAO-A/-B COMT BDNF Multidrug resistance Interleukine Serotonin receptors/transporter Dopamine receptors/transporter Noradrenaline receptors/transporter Tryptophan hydroxylase ACE Interleukine Mineralocorticoid receptor Second messenger systems GABA receptors GSK3 MPA3 G-protein ß

10. Investigated Polymorphisms (1) BDNF rs6265 (A/G) COMT rs4680 (G158A) rs737865 (C/T) rs165599 (A/G) 5-HT-2A T102C 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

11. Investigated Polymorphisms (2) KND Samples: SP 1.2/1.5, SP 3.8 CRHR1 rs242925 (A/G) rs81189 (C/G) rs1396862 (C/T) rs173365 (C/T) GCCR Tth111L (Promoter) rs860468 (A/G) rs2918419 (A/G) rs1866388 (A/G) rs6190 (G/A) rs6195 (A/G) MLR rs5534 (A/G) rs3733421 (G/A) rs5522 (A/G) rs2070951 (C/G)

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

13. 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)

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 Exon1Exon13 rs242925rs81189rs173365 rs1396862 Intermarker distance 5.9kb6.27kb1.9kb

15. 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 Exon1Exon13 rs242925rs81189rs173365 rs1396862 Intermarker distance 5.9kb6.27kb1.9kb

16. 10 20 30 15 25 HAMD17 cc cg gg p = 0.02 Response to SSRI Treatment in 105 Inpatients (TDM Project) with Unipolar Depression Subdivided by CRH1R – SNP rs81189 Day 0 Day 28

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

18. 0 10 20 30 15 25 HAMD17 Val Val Met Met p = 0.01 Response to SSRI Treatment in 105 Inpatients (TDM Project) with Unipolar Depression Subdivided by COMT Genotype (V 158 M) Day 0 Day 28 high activity low activity