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Entity | Breast Cancer |
Note | TPH1 was analyzed in histological samples to learn about the possible relationship between changing 5HT synthesis and human breast cancer progression. TPH1 is evenly distributed in the epithelial stroma in normal breast tissue and epithelial TPH1 is markedly stained. Compared to healthy breast cell lines, TPH1 staining intensity increased significantly in cancerous cell lines (Pai et al. 2009). |
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Entity | Alzheimer's disease (AD) |
Note | It was observed that the amount of serotonin increased 4 times in raphe cell bodies and decreased 0.4-fold in amygdala synaptic ends in Alzheimer's disease (AD) cases compared to controls. As a result of the accumulation of oxidative metabolites of serotonin and reduced transport of TPH to the axon terminals, TPH and its products are accumulated in the perikarya of raphe neurons, which may lead to the degeneration of serotonergic neurons in AD (Lukiw and Rogaev, 2017). In one study, fifty percent of patients showed agitation/aggression in response to the NPI screening question. A significant relationship was observed between agitation/aggression in male subjects carrying the C allele of the TPH1 gene. A218C polymorphism in this gene is linked to aggression and irritability in men. Given this, it was concluded that the agitated and aggressive behavior in AD is associated with the polymorphic variation in the TPH1 gene in men. According to these results, TPH (TPH1, chr11p15.1, and TPH2, chr12q21.1) gene is considered as one of the six genes frequently seen in AD and aggression (Lukiw and Rogaev, 2017). |
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Entity | Suicidal behavior (SB) |
Note | Three polymorphisms of the TPH1 gene, a potential GATA transcription factor binding site A218C, A779C located in intron 7, and A6526G located in the promoter region, were studied in patients with suicide attempts (Mirkovic et al. 2016). The A allele of A218C was found to be more common in suicide attempts than in patients who did not attempt suicide (Mirkovic et al. 2016). AA genotypes in the intron 7 and promoter region were associated with increased suicide attempts (Galfalvy et al. 2009). A relationship between the C allele of A218C and suicidal behavior (SB) was found only in people over 65 years of age (Stefulj et al. 2006). A significant relationship between suicide risk and AA218C SNP allele has been reported in Caucasian populations (Bellivier et al. 2004). There is a strong relationship between SB and A779C / A218C polymorphisms in both European and Asian populations (Mirkovic et al. 2016). The prevalence of TPH1 A218C polymorphism was evaluated in a Turkish population and a significant relationship was found between the A allele and SB (Beden et al. 2016). It was shown that not only the AA genotype but also the CC genotype was significantly associated with suicide risk and depression (Zalsman et al. 2001). On the other hand, some studies have reported that A218C genotypes are not related to the suicide attempt. A multi-center case-control study and meta-analysis showed that the A218/A779 locus increased sensitivity to schizophrenia and contributed to psychiatric disorders characterized by high suicide rates rather than affecting suicide (Beden et al. 2016). Although it was not associated with SB, there was a significant relationship between bipolar disorder (BPD) and small alleles of A218C in individuals with psychiatric disorders (Beden et al. 2016). |
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Entity | Schizophrenia |
Note | A study conducted with 837 Scandinavian schizophrenic patients and 1473 healthy individuals revealed that three of the five SNPs tested are associated with schizophrenia sensitivity including A218C and A779C polymorphisms (Saetre et al. 2010). However, it has been shown that there is no difference in the allele frequencies of these loci among people who have attempted suicide at least once and have no history of a suicide attempt (Saetre et al. 2010). Although TPH1 is expressed mainly in peripheral tissues, its variants have been reported to be frequently associated with psychiatric disorders. The TPH1 gene, shown in Figure 3, is a strong candidate gene for schizophrenia (Halmøy et al. 2010). |
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| Figure 3. Representation of TPH1 and other Schizophrenia-associated candidate genes (green-colored) located on Chromosome 11 (http://www.szgene.org/chromo.asp?c=11). |
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Entity | Aggressive Behavior |
Note | The A218C and A779C SNPs (usually called U/top and L/bottom alleles) found in the intron of the TPH1 gene are associated with different aggression evaluated by interview and self-reporting questionnaires (Rujescu et al. 2002). Lower cerebrospinal fluid (CSF) 5-Hydroxyindoleacetic acid (5-HIAA) levels were observed in healthy men with the U allele (Jonsson et al. 1997), while the lowest CSF 5-HIAA levels were observed in LL carriers diagnosed with antisocial alcoholism (Nielsen et al. 1994). Both U and L alleles were thought to be associated with different types of aggressiveness (Quadros et al. 2010). Individuals with a UU allele have been shown to have more aggressive hostility but slightly lower neurotic hostility (New et al. 1998). Individuals with a UU allele have been shown to have more aggressive hostility but slightly lower neurotic hostility (New et al. 1998). A higher level of impulsivity was found in tests that focused on neurotic hostility for LL homozygous individuals (Hennig et al. 2005). Genetic studies show that the polymorphism in both alleles (L and U) of the TPH1 gene is associated with human aggression, but each allele is associated with a different type of aggression (Quadros et al. 2010). |
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Entity | Major depressive disorder (MDD) |
Note | The frequency of TPH1 C allele and CC homozygous in patients with Major depressive disorder (MDD) was higher than healthy individuals with the same genotype. According to the results of the verbal aggression and aggression questionnaire, TPH1 CC homozygotes in the MDD group scored significantly higher than the A carrier genotypes. It has been revealed that there is a relationship between the frequency of this polymorphism, aggression, and MDD (Frodl, 2016). Vitamin D activates a series of processes that are critical for maintaining normal healthy neurons, also preventing the onset of depression. Where vitamin D enters the nucleus, it joins with the retinoid X receptor (RXR) and then binds to the vitamin D response element (VDRE) found on a large number of genes. Eventually, Ca2+ homeostasis is maintained by inducing the expression of the calcium-binding proteins (calbindin and parvalbumin), SLC8A1 (Na2+/Ca2+ exchanger1 NCX1) and cell membrane Ca2+ ATPase (PMCA) pump (ATP2B1 to 4 genes). Besides, vitamin D regulates Ca2+ levels by reducing the expression of the voltage-dependent calcium channel CaV1.2. In this case, TPH1 is suppressed and serotonin formation is controlled by increasing the TPH2 level. Reduced expression of inflammatory cytokines diminishes inflammation as well (Figure 4). By binding to its receptor ( VDR), vitamin D also regulates the expression of many mitochondrial proteins that maintain mitochondrial respiration (Berridge, 2017). |
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| Figure 4. Vitamin D signaling affecting TPH1 expression in depression (Simplified from https://www.wikipathways.org/index.php/Pathway:WP4698). |
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Entity | Somatoform Disorders |
Note | Genes in the serotonergic hypofunction and serotonergic pathway were thought to be associated with symptoms of somatoform disorders (Frodl, 2016). This hypothesis has been studied using a variety of serotonin-related gene polymorphisms to determine whether the undifferentiated somatoform disorder is associated with specific serotonin-related gene pathways. 102 patients with the undifferentiated somatoform disorder and 133 healthy individuals were examined. It was emphasized that patients with undifferentiated somatoform disorder had a higher frequency of TPH1 (A218C) C-allele than healthy controls, but this difference was not significant after Bonferroni correction. These findings indicate that serotonin-related gene pathways are unlikely to be genetic risk factors for the undifferentiated somatoform disorder (Frodl, 2016). |
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Entity | Middle Insomnia |
Note | A study found a relationship between TPH1 and middle insomnia. The serotonergic pathway plays an important role in the regulation of circadian rhythm, sleep, and wakefulness. Serotonergic axon release is high during wakefulness, decreases during non-rapid eye movement (NREM) sleep, and is absent during rapid eye movement (REM) sleep (Ursin R, 2002). TPH activity is most abundant in brain raphe, gut, and pineal gland where N-acetyltransferase converts serotonin to melatonin (Patel et al. 2004). Therefore, the polymorphism of TPH1 may affect the synthesis of serotonin and melatonin, so that depressed patients with this polymorphism are more prone to middle insomnia (Myung et al. 2012). |
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Entity | Bipolar Disorder (BPD) |
Note | Emotional disorders (MDD and BPD) and alcohol dependence are common psychiatric disorders. Nine studies involving 1951 cases and 2161 control subjects were conducted to investigate the relationship between TPH1 A218C polymorphism and BPD risk (Chen et al. 2012). Of these, 4 studies with 416 cases and 596 control subjects were conducted in Asians, whereas 5 studies with 1535 cases and 1565 controls were conducted in Caucasians. A nominally significant relationship was observed in the homozygous model of Asian populations and homozygous and recessive models of Caucasian populations. It was found that the relationship between this polymorphism and the risk of BPD and alcohol dependence varies according to ethnicity, and the 218A variant homozygous genotype is an important risk factor for BPD and alcohol dependence in the Caucasians (Chen et al. 2012). A significant relationship has been reported between A218C polymorphism of TPH1 intron 7 and BPD in the French population (Lai et al. 2005). There was a positive relationship between BD and TPH1 polymorphism (rs1800532) in CC genotype, but no relation was found between other genotypes and alleles (Hormozi et al. 2019). |
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Entity | Inflammation, Crohn's Disease (CD), and Inflammatory Bowel Disease (IBD) |
Note | TPH1 catalyzes serotonin biosynthesis in EC, the main source of 5HT (Shajib et al. 2019). The secreted 5HT regulates gut functions through a variety of 5HT receptor (5HTR) families. In inflammatory bowel disease (IBD), the mucosal 5HT signal is altered, including upregulated EC cell numbers and 5HT levels. The two major forms of IBD are Crohn's disease (CD) and ulcerative colitis (UC) which are described by long-lasting and recurrent inflammatory lesions throughout the digestive tract (Shajib et al. 2019). Through TPH1, EC produces 5HT from dietary tryptophan (Shajib and Khan et al. 2015). This 5HT can then be released into the intestinal lumen and surrounding tissue that can enter the bloodstream through the dense capillary bed of lamina propria (Shajib et al. 2019). 5HT has been evaluated in IBD and animal colitis models. TPH1-deficient mice have reduced 5HT content in the gut and low inflammatory cytokine production has been observed (Ghia et al. 2009). Besides, pharmacological blocking of peripheral 5HT synthesis reduced the severity of both chemical and infection-related gut inflammation. In colon biopsy samples from CD patients, TPH1, HTR3A, mucosal HTR4, and HTR7 expressions were upregulated, whereas serotonin transporter (5HTT) expression was downregulated in inflammation. Besides, colonic TPH1 expression was found to be significantly higher in inflamed areas compared to non-inflamed areas and controls (Shajib et al. 2019). Other important factors such as gut microbiota, may also affect host 5HT production in IBD. The role of gut microbiota in 5-HT production, via the regulation of TPH1, has been shown (Yano et al. 2015). The increase in TPH1 expression was thought to be associated with dysbiosis observed in IBD. In particular, a study showed that a 5HT increase due to 5HTT deficiency was associated with dysbiosis. As a result, CD and inflammation are associated with increasing the mucosal 5HT signal, characterized by the upregulation of TPH1 expression and downregulation of 5HTT expression (Shajib et al. 2019). Furthermore, high expression of IL13, a cytokine associated with increased 5HT production, is noteworthy. Increased 5HT availability due to its increased production and impaired clearance is thought to play an important role in maintaining intestinal inflammation and associated symptoms (Shajib et al. 2019). |
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TPH1 A218 allele is associated with suicidal behavior in Turkish population |
Beden O, Senol E, Atay S, Ak H, Altintoprak AE, Kiyan GS, Petin B, Yaman U, Aydin HH |
Leg Med (Tokyo) 2016 Jul;21:15-8 |
PMID 27497328 |
|
Association between the TPH gene A218C polymorphism and suicidal behavior: a meta-analysis |
Bellivier F, Chaste P, Malafosse A |
Am J Med Genet B Neuropsychiatr Genet 2004 Jan 1;124B(1):87-91 |
PMID 14681922 |
|
Vitamin D and Depression: Cellular and Regulatory Mechanisms |
Berridge MJ |
Pharmacol Rev 2017 Apr;69(2):80-92 |
PMID 28202503 |
|
Association between the TPH1 A218C polymorphism and risk of mood disorders and alcohol dependence: evidence from the current studies |
Chen D, Liu F, Yang C, Liang X, Shang Q, He W, Wang Z |
J Affect Disord 2012 Apr;138(1-2):27-33 |
PMID 21601290 |
|
Localization of human tryptophan hydroxylase (TPH) to chromosome 11p15 |
Craig SP, Boularand S, Darmon MC, Mallet J, Craig IW |
3----p14 by in situ hybridization Cytogenet Cell Genet |
PMID 2055111 |
|
Whole-Exome Sequencing Reveals Increased Burden of Rare Functional and Disruptive Variants in Candidate Risk Genes in Individuals With Persistent Attention-Deficit/Hyperactivity Disorder |
Demontis D, Lescai F, Børglum A, Glerup S, Østergaard SD, Mors O, Li Q, Liang J, Jiang H, Li Y, Wang J, Lesch KP, Reif A, Buitelaar JK, Franke B |
J Am Acad Child Adolesc Psychiatry 2016 Jun;55(6):521-3 |
PMID 27238071 |
|
The two faces of serotonin in bone biology |
Ducy P, Karsenty G |
J Cell Biol 2010 Oct 4;191(1):7-13 |
PMID 20921133 |
|
Do (epi)genetics impact the brain in functional neurologic disorders? Handb Clin Neurol |
Frodl T |
2016;139:157-165 doi: 10 |
PMID 27719836 |
|
Increased risk of suicide attempt in mood disorders and TPH1 genotype |
Galfalvy H, Huang YY, Oquendo MA, Currier D, Mann JJ |
J Affect Disord 2009 Jun;115(3):331-8 |
|
The serotonin signaling system: from basic understanding to drug development for functional GI disorders |
Gershon MD, Tack J |
Gastroenterology 2007 Jan;132(1):397-414 |
PMID 17241888 |
|
Focus on the essentials: tryptophan metabolism and the microbiome-gut-brain axis |
Gheorghe CE, Martin JA, Manriquez FV, Dinan TG, Cryan JF, Clarke G |
Curr Opin Pharmacol 2019 Oct;48:137-145 |
PMID 31610413 |
|
Serotonin has a key role in pathogenesis of experimental colitis |
Ghia JE, Li N, Wang H, Collins M, Deng Y, El-Sharkawy RT, Côté F, Mallet J, Khan WI |
Gastroenterology 2009 Nov;137(5):1649-60 |
PMID 19706294 |
|
Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome bowel habit subtypes |
Grasberger H, Chang L, Shih W, Presson AP, Sayuk GS, Newberry RD, Karagiannides I, Pothoulakis C, Mayer E, Merchant JL |
Am J Gastroenterol 2013 Nov;108(11):1766-74 |
PMID 24060757 |
|
Attention-deficit/hyperactivity disorder symptoms in offspring of mothers with impaired serotonin production |
Halmøy A, Johansson S, Winge I, McKinney JA, Knappskog PM, Haavik J |
Arch Gen Psychiatry 2010 Oct;67(10):1033-43 |
PMID 20921119 |
|
Two types of aggression are differentially related to serotonergic activity and the A779C TPH polymorphism |
Hennig J, Reuter M, Netter P, Burk C, Landt O |
Behav Neurosci 2005 Feb;119(1):16-25 |
PMID 15727508 |
|
Association study of TPH1 (rs1800532) and TPH2 (rs4570625) Polymorphisms in Type 1 Bipolar Disorder in Iran |
Hormozi M, Zarei F, Rasouli A, Salimi S, Taji O, Narooie-Nejad M. |
Gene Cell Tissue. In Press(In Press):e86109. |
|
Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers |
Jönsson EG, Goldman D, Spurlock G, Gustavsson JP, Nielsen DA, Linnoila M, Owen MJ, Sedvall GC |
Eur Arch Psychiatry Clin Neurosci 1997;247(6):297-302 |
PMID 9477008 |
|
Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis |
Kwon YH, Wang H, Denou E, Ghia JE, Rossi L, Fontes ME, Bernier SP, Shajib MS, Banskota S, Collins SM, Surette MG, Khan WI |
Cell Mol Gastroenterol Hepatol 2019;7(4):709-728 |
PMID 30716420 |
|
Polymorphism screening and haplotype analysis of the tryptophan hydroxylase gene (TPH1) and association with bipolar affective disorder in Taiwan |
Lai TJ, Wu CY, Tsai HW, Lin YM, Sun HS |
BMC Med Genet 2005 Mar 31;6:14 |
PMID 15799788 |
|
Platelet-derived serotonin mediates liver regeneration |
Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA |
Science 2006 Apr 7;312(5770):104-7 |
PMID 16601191 |
|
Genetics of Aggression in Alzheimer's Disease (AD) |
Lukiw WJ, Rogaev EI |
Front Aging Neurosci 2017 Apr 10;9:87 |
PMID 28443016 |
|
Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients |
Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J |
Am J Psychiatry 1997 Oct;154(10):1451-3 |
PMID 9326831 |
|
Serotonin regulates mammary gland development via an autocrine-paracrine loop |
Matsuda M, Imaoka T, Vomachka AJ, Gudelsky GA, Hou Z, Mistry M, Bailey JP, Nieport KM, Walther DJ, Bader M, Horseman ND |
Dev Cell 2004 Feb;6(2):193-203 |
PMID 14960274 |
|
Genetic Association Studies of Suicidal Behavior: A Review of the Past 10Years, Progress, Limitations, and Future Directions |
Mirkovic B, Laurent C, Podlipski MA, Frebourg T, Cohen D, Gerardin P |
Front Psychiatry 2016 Sep 23;7:158 |
PMID 27721799 |
|
Genetic association study of individual symptoms in depression |
Myung W, Song J, Lim SW, Won HH, Kim S, Lee Y, Kang HS, Lee H, Kim JW, Carroll BJ, Kim DK |
Psychiatry Res 2012 Aug 15;198(3):400-6 |
PMID 22429480 |
|
Tryptophan hydroxylase genotype is associated with impulsive-aggression measures: a preliminary study |
New AS, Gelernter J, Yovell Y, Trestman RL, Nielsen DA, Silverman J, Mitropoulou V, Siever LJ |
Am J Med Genet 1998 Feb 7;81(1):13-7 |
PMID 9514581 |
|
Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism |
Nielsen DA, Goldman D, Virkkunen M, Tokola R, Rawlings R, Linnoila M |
Arch Gen Psychiatry 1994 Jan;51(1):34-8 |
PMID 7506517 |
|
Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival |
Pai VP, Marshall AM, Hernandez LL, Buckley AR, Horseman ND |
Breast Cancer Res 2009;11(6):R81 |
PMID 19903352 |
|
Robust and tissue-specific expression of TPH2 versus TPH1 in rat raphe and pineal gland |
Patel PD, Pontrello C, Burke S |
Biol Psychiatry 2004 Feb 15;55(4):428-33 |
PMID 14960297 |
|
Serotonin and Aggression |
Quadros M I, Aki Takahashi A, Miczek K A. |
Handbook of Behavioral Neurobiology of Serotonin Copyright 2010 Elsevier B.V. All rights reserved ISBN 978-0-12-374634-4 |
|
Microbial tryptophan catabolites in health and disease |
Roager HM, Licht TR |
Nat Commun 2018 Aug 17;9(1):3294 |
PMID 30120222 |
|
Association of anger-related traits with SNPs in the TPH gene |
Rujescu D, Giegling I, Bondy B, Gietl A, Zill P, Möller HJ |
Mol Psychiatry 2002;7(9):1023-9 |
PMID 12399958 |
|
The tryptophan hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: a multi-centre case-control study and meta-analysis |
Saetre P, Lundmark P, Wang A, Hansen T, Rasmussen HB, Djurovic S, Melle I, Andreassen OA, Werge T, Agartz I, Hall H, Terenius L, Jönsson EG |
Am J Med Genet B Neuropsychiatr Genet 2010 Mar 5;153B(2):387-396 |
PMID 19526457 |
|
Characterization of Serotonin Signaling Components in Patients with Inflammatory Bowel Disease |
Shajib MS, Chauhan U, Adeeb S, Chetty Y, Armstrong D, Halder SLS, Marshall JK, Khan WI |
J Can Assoc Gastroenterol 2019 Aug;2(3):132-140 |
PMID 31294376 |
|
The role of serotonin and its receptors in activation of immune responses and inflammation |
Shajib MS, Khan WI |
Acta Physiol (Oxf) 2015 Mar;213(3):561-74 |
PMID 25439045 |
|
TPH gene polymorphism and aging: indication of combined effect on the predisposition to violent suicide |
Stefulj J, Kubat M, Balija M, Jernej B |
Am J Med Genet B Neuropsychiatr Genet 2006 Mar 5;141B(2):139-41 |
PMID 16389591 |
|
Tryptophan hydroxylase gene polymorphism (A218C) and suicidal behaviors |
Tsai SJ, Hong CJ, Wang YC |
Neuroreport 1999 Dec 16;10(18):3773-5 |
PMID 10716208 |
|
Complex phenotype of dyskeratosis congenita and mood dysregulation with novel homozygous RTEL1 and TPH1 variants |
Ungar RA, Giri N, Pao M, Khincha PP, Zhou W, Alter BP, Savage SA |
Am J Med Genet A 2018 Jun;176(6):1432-1437 |
PMID 29696773 |
|
Serotonin and sleep |
Ursin R |
Sleep Med Rev 2002 Feb;6(1):55-69 |
PMID 12531142 |
|
Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum |
Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G |
Cell 2008 Nov 28;135(5):825-37 |
PMID 19041748 |
|
Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis |
Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY |
Cell 2015 Apr 9;161(2):264-76 |
PMID 25860609 |
|
Case control and family-based studies of tryptophan hydroxylase gene A218C polymorphism and suicidality in adolescents |
Zalsman G, Frisch A, King RA, Pauls DL, Grice DE, Gelernter J, Alsobrook J, Michaelovsky E, Apter A, Tyano S, Weizman A, Leckman JF |
Am J Med Genet 2001 Jul 8;105(5):451-7 |
PMID 11449398 |
|