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

06.10.03

Serotonergic Pathways

Tryp 5-HTP 5-HT

TPH

5-HTTLPR

5-HT2A

5-HT2C

5-HT1

Cellular

Response via

Signal

Transduction

Cascades

TP 5: Molecular Genetics/Pharmacogenetics

06.10.03

• Serotonin Transporter Gene: 5-HTTLPR44 bp Del/Ins polymorphism in the promoter region S- or L-allele changes in 5-HT expression

Candidate Genes for Affective Disorders I

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

TP 5: Molecular Genetics/Pharmacogenetics

06.10.03

• 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)

Candidate Genes for Affective Disorders II

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, Croatia2Institute for Legal Medicine, Ludwig-Maximilians-University Munich, Munich, Germany3Department of Forensic Medicine and Criminology,, Croatia4Department of Psychiatry, Ludwig-Maximilians-University Munich, Munich, Germany

TP 5: Molecular Genetics/Pharmacogenetics

06.10.03

• Serotonin Receptors

5-HT2A (T102C): associated with suicidal behavior (e.g. Arias et al. 2001, Du et

al. 2001)

5HT2C (Cys23Ser): associated with major depression (e.g. Lerer et al. 2001)

Candidate Genes for Affective Disorders III

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)

TP 5: Molecular Genetics/Pharmacogenetics

06.10.03

• Tryptophan Hydroxylase (TPH1)Numerous polymorphisms located over the entire gene

Candidate Genes for Affective Disorders IV

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

TP 5: Molecular Genetics/Pharmacogenetics

• Neuronal TPH (TPH2)Second TPH isoform which is exclusively present in the human brain

Candidate Genes for Affective Disorders V

06.10.03

0

40

80

120

160

200

Cortex

Thalam

us

Hippoc

ampu

s

Amygda

la

Hypoth

alamus

Heart

Lung

Liver

Duode

num

Adren

al Glan

d

Kidney

TP

H2

mR

NA

cop

ies

pe

r 10

E6

copi

es ß

2M m

RN

A

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)

TP 5: Molecular Genetics/Pharmacogenetics

06.10.03

• ß3 Subunit of G-Proteins (Gß3)C825T in exon 10 splice variant (Gß3-s) deletion of 41 amino acids biological active protein

Candidate Genes for Affective Disorders VI

Associated with: increased signal transduction and hypertension (Siffert et al. 1998)

Replicated by Kunugi et al. 2002 and Serretti et al.

2003

Replicated in own studies in an

increased patient sample

•

TP 5: Molecular Genetics/Pharmacogenetics

06.10.03

• Angiotensin Converting Enzyme (ACE)Del/Ins polymorphism of 287 bp in intron 16 D-allele associated with ACE concentration

Candidate Genes for Affective Disorders VII

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

TP 5: Molecular Genetics/Pharmacogenetics

06.10.03

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