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Table S2. Overview of studies investigating the effects of TPH2 polymorphisms on TPH2 expression and 5-HT function. Includes
papers published before January 2011.
SNP
Type of
Sample
Main effects on 5-HT
(alternative
study
name)
[location]
rs11178997
In vitro
Rats (5-HT neurons)
A allele associated with lower TPH2 transcriptional activity in
(T-473A)
MDD patients with a
primary 5-HT neurons in rats (22%) and in SHP-77 human cells
[promoter
history of suicide
(7%) 1
region]
attempts (SHP-77 cells)
No genotype difference in TPH2 expression in the dorsolateral PFC,
In vivo
Postmortem brains
neither an association between mRNA and T-473A and -8396GC
from patients with
haplotype 2
BPD, schizophrenia
and controls.
rs4570625
In vitro
Rats (5-HT neurons)
No genotypic differences in promoter activity 1.
(G-703T)
MDD patients with a
[promoter
history of suicide
region]
attempts (SHP-77 cells)
rs4131347
In vivo
BPD, MDD and
No association between genotype and CSF monoamine metabolite
(-C8347G)
controls
levels 3.
[promoter
region]
T-703G, TIn vitro
BPD patients (IMR-32 2-SNP (T-703G, T-473A) GA haplotype associated with lower
473A
and SH-Sy5Y cells)
TPH2 expression activity in SH-SY5Y and IMR-32 cell lines
relative to the other haplotypes 4.
Rats (RN46A cells),
T-703G and T-473A tended to have a synergic effect on gene
Humans (HEK-293
expression 5.
cells)
rs11178998
In vitro
Rats (RN46A cells)
In RN46A, the 90AG polymorphisms increased luciferase activity
(90AG)
Humans (HEK-293
and mRNA level. In HEK-293 cells the effect depends on the alleles
[exon 1]
cells)
at loci -703 and -473 5.
T-703G, T473A, 90AG
In vitro
C2775A
In vitro
[exon 2]
C74A, G223A In vitro
rs17110563
(P206S)
[exon 6, 7]
rs7305115
(G40237A)
[exon 7]
In vitro
C1473G
[exon 11]
In vitro
In vivo
In vivo
Rats (RN46A cells)
Humans (HEK-293
cells)
Rats (5-HT neurons)
MDD patients with a
history of suicide
attempts (SHP-77 cells)
BPD patients (SHSY5Y cells)
Rhesus monkeys (PC12
cells and HEK-293
cells)
Escherichia coli
Humans (HED 293
cells)
Postmortem sections of
rostral human pons
Mice PC12 cells
129X13SvJ and
BALB/cJ Mice
TTA haplotype has lowest TPH2 expression compared to the other
haplotypes in RN46A and HEK-293 cell lines 5.
TAG haplotype associated with lower TPH2 activity in 5-HT raphe
rat neurons and in human SHP-77 cells 20%, relative to the
wildtype haplotype 1.
C2775A: Amount of 5-HT in SY5Y cells expressing the TPH2-41Y
allele 36% lower than cells expressing the TPH2-41S allele 4.
AA haplotype had higher levels of TPH2 mRNA and protein, and
higher 5-HT production than the wildtype CG genotype in PC12
cells. Both C74A and G223A predicted to change mRNA secondary
structure. The wildtype CG mRNA degraded more quickly than
mRNA of the mutant haplotypes in both cell types 6.
Decreased thermal stability and solubility of the mutated enzyme in
E.coli 7, 8. Decreased TPH2 activity in HEK293 cells 8, 9.
G allele associated with lower levels of TPH2 mRNA expression in
human pons 10. Lower levels of TPH2 mRNA expression is
associated with the CTGTG combination of alleles and high levels
of expression with the TAAGA combination of alleles for the SNPs
rs2171363, rs4760815, rs7305115, rs6582078, rs9325202.
1473G mutation had 55% lower TPH2 activity in PC12 cells 12.
BALB/cJ mice (homozygous for 1473 G allele) have 50-70% lower
5-HT synthesis in frontal cortex and striatum and 40% reduction in
5-HT tissue concentrations compared to 129X13SvJ mice
(homozygous for 1473 C allele) 12.
In vivo
In vivo
In vitro
- C57BI/6 and BALB/c
mice congenic for the
TPH2 locus
1473G allele lowers 5-HT synthesis in C57BI/6 mice, no effect on
5-HT tissue content except for slight reduction (15%) in 5-HT tissue
in frontal cortex. In BALB/c mice, the 1473C allele increased 5-HT
synthesis but does not affect 5-HT tissue. 5-HIAA levels were
increased in BALB/c congenic mice; no effect of genotype on 5HIAA levels in C57BI/6 mice 13.
- B6-1473C vs B6-1473 Mice homozygous for the G allele had lower TPH2 activity in the
G mice; 10 strains with brain (± 30%) compared to mice homozygous for the C allele 11, 14.
CC vs. GG genotype 11
Cloned TPH2 from
P447R mutant decreased activity in E coli. (50%), no effect on
C57BL/6 mice
enzyme substrate specificity or stability 15.
In vivo
BALB/c and C57BL/6
mice
In vivo
DBA/2J, DNA/2N,
BALB/c, C57BL/6J
and C57BL/6N mice
In vivo
C57BL/6J, CBA/Ca,
129/SvHsd, BALB/C
BALB/c mice (homozygous for the G allele) had increased 5-HT
turnover in the striatum and hippocampus only following repeated
stress. C57BL36 mice (homozygous for the C allele) had increased
5-HT turnover following acute stress. TPH activity was decreased in
the brain stem and cortical regions following acute and chronic
stress in mice homozygous for the C allele, while this effect was not
seen in mice homozygous for the G allele 16.
DBA/2J, DNA/2N, BALB/c mice (carrying the 1473G allele) had
less dialysate 5-HT in the medial PFC and dorsal hippocampus (2040%) than C57BL/6J and C57BL/6N mice (carrying the 1473 C
allele). Citalopram raised extracellular 5-HT in mice carrying the
1473C allele and less in the mice carrying the G allele. 17
Mice homozygous for the 1473G allele had lower levels (35%) of 5HT in the medial PFC and ventral striatum compared to those
homozygous for the C allele. There were effects on DA or NE levels
18
.
G1473A
[exon 11]
rs1074815
[5`region]
In vitro
Humans (PC12 cells)
1463A (R441H) mutant has 80% reduction in enzyme activity in
PC12 cells 19.
In vivo
R439H knockin mice
In vivo
Suicide completers and
controls, postmortem
40-80% reduction in 5-HT synthesis in striatum, frontal cortex and
hippocampus in R439H mice (equivalent to 1463A allele) 20.
G allele associated with lower levels of mRNA in the ventral PFC
compared to the AA genotype 21.
Haplotype of
In vivo
Healthy controls
Lower 5-HIAA levels in individuals who are homozygous for
6-SNPs
haplotype ‘212121’ (`yin haplotype`), associated with suicidal
located in
behavior and anxiety/depression 22.
intron 5-8 (5
SNPs) and
exon 7 (1
SNP)
5-HT=5-hydroxytryptamine (serotonin). BPD=bipolar disorder, MDD=Major Depressive Disorder. PFC=prefrontal cortex.
CSF=cerebrospinal fluid. DA=dopamine. NE=Noradrenaline. 5-HIAA=5-Hydroxyindoleacetic acid.
1.
Scheuch K, Lautenschlager M, Grohmann M, Stahlberg S, Kirchheiner J, Zill P et al. Characterization of a functional promoter
polymorphism of the human tryptophan hydroxylase 2 gene in serotonergic raphe neurons. Biol Psychiatry 2007 Dec 1;
62(11): 1288-1294.
2.
De Luca V, Likhodi O, Van Tol HH, Kennedy JL, Wong AH. Tryptophan hydroxylase 2 gene expression and promoter
polymorphisms in bipolar disorder and schizophrenia. Psychopharmacology (Berl) 2005 Dec; 183(3): 378-382.
3.
Mann JJ, Currier D, Murphy L, Huang YY, Galfalvy H, Brent D et al. No association between a TPH2 promoter
polymorphism and mood disorders or monoamine turnover. J Affect Disord 2008 Feb; 106(1-2): 117-121.
4.
Lin YM, Chao SC, Chen TM, Lai TJ, Chen JS, Sun HS. Association of functional polymorphisms of the human tryptophan
hydroxylase 2 gene with risk for bipolar disorder in Han Chinese. Arch Gen Psychiatry 2007 Sep; 64(9): 1015-1024.
5.
Chen GL, Vallender EJ, Miller GM. Functional characterization of the human TPH2 5' regulatory region: untranslated region
and polymorphisms modulate gene expression in vitro. Hum Genet 2008 Jan; 122(6): 645-657.
6.
Chen GL, Miller GM. Rhesus monkey tryptophan hydroxylase-2 coding region haplotypes affect mRNA stability.
Neuroscience 2008 Aug 13; 155(2): 485-491.
7.
Cichon S, Winge I, Mattheisen M, Georgi A, Karpushova A, Freudenberg J et al. Brain-specific tryptophan hydroxylase 2
(TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder. Hum
Mol Genet 2008 Jan 1; 17(1): 87-97.
8.
McKinney JA, Turel B, Winge I, Knappskog PM, Haavik J. Functional properties of missense variants of human tryptophan
hydroxylase 2. Hum Mutat 2009 May; 30(5): 787-794.
9.
McKinney J, Johansson S, Halmoy A, Dramsdahl M, Winge I, Knappskog PM et al. A loss-of-function mutation in tryptophan
hydroxylase 2 segregating with attention-deficit/hyperactivity disorder. Mol Psychiatry 2008 Apr; 13(4): 365-367.
10.
Lim JE, Pinsonneault J, Sadee W, Saffen D. Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA
expression in human pons. Mol Psychiatry 2007 May; 12(5): 491-501.
11.
Kulikov AV, Osipova DV, Naumenko VS, Popova NK. Association between Tph2 gene polymorphism, brain tryptophan
hydroxylase activity and aggressiveness in mouse strains. Genes Brain Behav 2005 Nov; 4(8): 482-485.
12.
Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG. Tryptophan hydroxylase-2 controls brain serotonin
synthesis. Science 2004 Jul 9; 305(5681): 217.
13.
Siesser WB, Zhang X, Jacobsen JP, Sotnikova TD, Gainetdinov RR, Caron MG. Tryptophan hydroxylase 2 genotype
determines brain serotonin synthesis but not tissue content in C57Bl/6 and BALB/c congenic mice. Neurosci Lett 2010 Aug
30; 481(1): 6-11.
14.
Osipova DV, Kulikov AV, Popova NK. C1473G polymorphism in mouse tph2 gene is linked to tryptophan hydroxylase-2
activity in the brain, intermale aggression, and depressive-like behavior in the forced swim test. J Neurosci Res 2009 Apr;
87(5): 1168-1174.
15.
Sakowski SA, Geddes TJ, Kuhn DM. Mouse tryptophan hydroxylase isoform 2 and the role of proline 447 in enzyme function.
J Neurochem 2006 Feb; 96(3): 758-765.
16.
Browne CA, Clarke G, Dinan TG, Cryan JF. Differential Stress-induced Alterations in Tryptophan Hydroxylase Activity and
Serotonin Turnover in Two Inbred Mouse Strains. Neuropharmacology Dec 2.
17.
Calcagno E, Canetta A, Guzzetti S, Cervo L, Invernizzi RW. Strain differences in basal and post-citalopram extracellular 5-HT
in the mouse medial prefrontal cortex and dorsal hippocampus: relation with tryptophan hydroxylase-2 activity. J Neurochem
2007 Nov; 103(3): 1111-1120.
18.
Isles AR, Hathway GJ, Humby T, de la Riva C, Kendrick KM, Wilkinson LS. An mTph2 SNP gives rise to alterations in
extracellular 5-HT levels, but not in performance on a delayed-reinforcement task. Eur J Neurosci 2005 Aug; 22(4): 997-1000.
19.
Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB et al. Loss-of-function mutation in
tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 2005 Jan 6; 45(1): 11-16.
20.
Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC et al. Role of GSK3 beta in behavioral
abnormalities induced by serotonin deficiency. Proc Natl Acad Sci U S A 2008 Jan 29; 105(4): 1333-1338.
21.
Perroud N, Neidhart E, Petit B, Vessaz M, Laforge T, Relecom C et al. Simultaneous analysis of serotonin transporter,
tryptophan hydroxylase 1 and 2 gene expression in the ventral prefrontal cortex of suicide victims. Am J Med Genet B
Neuropsychiatr Genet Jun 5; 153B(4): 909-918.
22.
Zhou Z, Roy A, Lipsky R, Kuchipudi K, Zhu G, Taubman J et al. Haplotype-based linkage of tryptophan hydroxylase 2 to
suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations. Arch Gen Psychiatry
2005 Oct; 62(10): 1109-1118.