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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. Serotonergic Pathways. 5-HT1. TPH. 5-HT2A. - PowerPoint PPT Presentation
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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