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

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/ SP Total 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

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

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

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

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

Investigated Polymorphisms (1) BDNF rs6265 (A/G) COMT rs4680 (G158A) rs (C/T) rs (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

Investigated Polymorphisms (2) KND Samples: SP 1.2/1.5, SP 3.8 CRHR1 rs (A/G) rs81189 (C/G) rs (C/T) rs (C/T) GCCR Tth111L (Promoter) rs (A/G) rs (A/G) rs (A/G) rs6190 (G/A) rs6195 (A/G) MLR rs5534 (A/G) rs (G/A) rs5522 (A/G) rs (C/G)

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

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)

The CRF-1 Receptor Gene and its Gene Product Genomic structure of human corticotropin releasing hormone receptor 1: Genomic size: bp; mRNA size: bp; 7-transmembrane segment hormone receptor Exon1Exon13 rs242925rs81189rs rs Intermarker distance 5.9kb6.27kb1.9kb

The CRF-1 Receptor Gene and its Gene Product Genomic structure of human corticotropin releasing hormone receptor 1: Genomic size: bp; mRNA size: bp; 7-transmembrane segment hormone receptor Exon1Exon13 rs242925rs81189rs rs Intermarker distance 5.9kb6.27kb1.9kb

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

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

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