Project 5:Project 5:

Molecular Genetics Molecular Genetics and Pharmacogeneticsand 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 6.1/6.2

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 BehaviorSP 2.1 Treatment of Mild and Subdiagnostic DepressionsSP 2.3 Chronicity in Persons with Depression and

Somatoform Disorder

SP 3.8 Therapeutic Drug Monitoring of AntidepressantsSP 6.1 Chronicity / Resistance / SuicidalitySP 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

Center Total 1.2 1.2/1.5 1.5 2.1 2.3 3.8 6.1 6.1/6.2Berlin 89 15 3 2 13 56Bonn 157 30 29 98Dresden 50 50Düsseldorf 28 20 8Gabersee 4 4Haar 23 23LMU Munich 293 21 154 118Lübeck 44 41 3Mainz 29 29Marburg 142 142MPI Munich 24 24Total TP 5 883 56 131 31 154 142 131 174 64

SP 1.2 Lithium-Intervention-Study SP 1.5 Neurobiology of Suicidal BehaviorSP 2.1 Treatment of Mild and Subdiagnostic DepressionsSP 2.3 Chronicity in Persons with Depression and

Somatoform Disorder

SP 3.8 Therapeutic Drug Monitoring of AntidepressantsSP 6.1 Chronicity / Resistance / SuicidalitySP 6.2 Comparison of Systematic Treatment Algorithms

with Standard Treatment

Received Samples per Center and Project

Steering Committee "Genetics"

Members:

Tasks:

Applicants of Project 5PI of contributing projectsSpeaker 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

Bonn Munich

Polymorphisms for genes coding for

Glucocorticoid receptor

Corticotropin hormone receptorsMAO-A/-B

COMTBDNF

Multidrug resistanceInterleukine

Serotonin receptors/transporterDopamine receptors/transporter

Noradrenaline receptors/transporter

Tryptophan hydroxylase

ACE

Interleukine

Mineralocorticoid receptor

Second messenger systemsGABA receptors

GSK3MPA3

G-protein ß

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 C936TVNTR (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 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)

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: 51 524 bp; mRNA size: 2 535 bp; 7-transmembrane segment hormone receptor

Exon1 Exon13

rs242925

rs81189

rs173365

rs1396862

Intermarker distance 5.9kb 6.27kb 1.9kb

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

rs242925

rs81189

rs173365

rs1396862

Intermarker distance 5.9kb 6.27kb 1.9kb

10

20

30

15

25

HAMD17

cccg

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

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

0

10

20

30

15

25

HAMD17

Val ValVal Met

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