Skip to main content

Advertisement

SpringerLink
Log in

TPH2 and TPH1: Association of Variants and Interactions with Heroin Addiction

  • Original Research
  • Published:
Behavior Genetics Aims and scope Submit manuscript

Abstract

The tryptophan hydroxylase 2 gene (TPH2) was resequenced at the 5′ upstream, coding, and 3′ downstream regions, including all 11 exons in 185 subjects. Twenty-three novel and 14 known variants were identified. In a cohort of 583 consecutively ascertained subjects, including normal volunteers and those with specific addictive diseases, six common TPH2 and one TPH1 variant were genotyped. Allele frequencies of three TPH2 variants and the TPH1 variant varied significantly among the four ethnic groups within the control subjects. Of these subjects, 385 who met heroin addiction or control criteria and were of Caucasian, African-American, or Hispanic ethnicity were examined for potential association with vulnerability to develop heroin addiction. At the two locus genotype level in Hispanics, the TPH1 rs1799913 variant was found to significantly interact with the TPH2 rs7963720 variant and heroin addiction (P = 0.022), and with the TPH2 rs4290270 variant and heroin addiction (P = 0.011). In the African-American group, a significant association of a specific TPH2 haplotype with heroin addiction also was found (SNPHAP, P = 0.004; PHASE P = 0.036).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abecasis GR, Cookson WO (2000) GOLD – graphical overview of linkage disequilibrium. Bioinformatics 16:182–183

    Article  PubMed  CAS  Google Scholar 

  • Aubert R, Betoulle D, Herbeth B, Siest G, Fumeron F (2000) 5-HT2A receptor gene polymorphism is associated with food and alcohol intake in obese people. Int J Obes Relat Metab Disord 24:920–924

    Article  PubMed  CAS  Google Scholar 

  • Bach-Mizrachi H, Underwood MD, Kassir SA, Bakalian MJ, Sibille E, Tamir H, Mann JJ, Arango V (2006) Neuronal tryptophan hydroxylase mRNA expression in the human dorsal and median raphe nuclei: major depression and suicide. Neuropsychopharmacology 31:814–824

    Article  PubMed  CAS  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 57:289–300

    Google Scholar 

  • Boldrini M, Underwood MD, Mann JJ, Arango V (2005) More tryptophan hydroxylase in the brainstem dorsal raphe nucleus in depressed suicides. Brain Res 1041:19–28

    Article  PubMed  CAS  Google Scholar 

  • Brown GL, Ballenger JC, Minichiello MD, Goodwin FK (1979) Human aggression and its relationship to cerebrospinal fluid 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol, and homovanilic acid. In: Sandler M (ed) Psychopharmacology of aggression. Raven Press, New York, pp 131–148

    Google Scholar 

  • Brown HJ, Henderson LA, Keay KA (2006) Hypotensive but not normotensive haemorrhage increases tryptophan hydroxylase-2 mRNA in caudal midline medulla. Neurosci Lett 398:314–318

    Article  PubMed  CAS  Google Scholar 

  • Canli T, Congdon E, Gutknecht L, Constable RT, Lesch KP (2005) Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation. J Neural Transm 112:1479–1485

    Article  PubMed  CAS  Google Scholar 

  • Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3:285–298

    Article  PubMed  CAS  Google Scholar 

  • Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR (2003) ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res 31:3568–3571

    Article  PubMed  CAS  Google Scholar 

  • Chung IW, Kim H, Sribney W, Hong JB, Lee CH, Lee KY, Nan HM, Kim YS, Manowitz P (2005) Tryptophan hydroxylase polymorphism is associated with age of onset of alcoholism related behaviors. Alcohol 36:1–3

    Article  PubMed  CAS  Google Scholar 

  • Coon H, Dunn D, Lainhart J, Miller J, Hamil C, Battaglia A, Tancredi R, Leppert MF, Weiss R, McMahon W (2005) Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2). Am J Med Genet B Neuropsychiatr Genet 135:42–46

    PubMed  Google Scholar 

  • Cooper JR, Melcer I (1961) The enzymatic oxidation of tryptophan to 5-hydroxytryptophan in the biosynthesis of serotonin. J Pharmacol Exp Ther 132:265–268

    PubMed  CAS  Google Scholar 

  • De Luca V, Likhodi O, Van Tol HH, Kennedy JL, Wong AH (2005) Tryptophan hydroxylase 2 gene expression and promoter polymorphisms in bipolar disorder and schizophrenia. Psychopharmacology (Berl) 183:378–382

    Article  CAS  Google Scholar 

  • Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (2003) Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 12:205–216

    Article  PubMed  CAS  Google Scholar 

  • Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927

    PubMed  CAS  Google Scholar 

  • Fehr C, Grintschuk N, Szegedi A, Anghelescu I, Klawe C, Singer P, Hiemke C, Dahmen N (2000) The HTR1B 861G > C receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy. Psychiatry Res 97:1–10

    Article  PubMed  CAS  Google Scholar 

  • Forrest D, Hallbook F, Persson H, Vennstrom B (1991) Distinct functions for thyroid hormone receptors alpha and beta in brain development indicated by differential expression of receptor genes. EMBO J 10:269–275

    PubMed  CAS  Google Scholar 

  • Gade R, Muhleman D, Blake H, MacMurray J, Johnson P, Verde R, Saucier G, Comings DE (1998) Correlation of length of VNTR alleles at the X-linked MAOA gene and phenotypic effect in Tourette syndrome and drug abuse. Mol Psychiatry 3:50–60

    Article  PubMed  CAS  Google Scholar 

  • Garriock HA, Allen JJ, Delgado P, Nahaz Z, Kling MA, Carpenter L, Burke M, Burke W, Schwartz T, Marangell LB, Husain M, Erickson RP, Moreno FA (2005) Lack of association of TPH2 exon XI polymorphisms with major depression and treatment resistance. Mol Psychiatry 10:976–977

    Article  PubMed  CAS  Google Scholar 

  • Gerra G, Garofano L, Santoro G, Bosari S, Pellegrini C, Zaimovic A, Moi G, Bussandri M, Moi A, Brambilla F, Donnini C (2004) Association between low-activity serotonin transporter genotype and heroin dependence: behavioral and personality correlates. Am J Med Genet 126B:37–42

    Article  PubMed  CAS  Google Scholar 

  • Gerra G, Garofano L, Zaimovic A, Moi G, Branchi B, Bussandri M, Brambilla F, Donnini C (2005) Association of the serotonin transporter promoter polymorphism with smoking behavior among adolescents. Am J Med Genet 35:73–78

    Article  Google Scholar 

  • Glatt CE, Carlson E, Taylor TR, Risch N, Reus VI, Schaefer CA (2005) Response to Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16. Neuron 48:704–705

    Article  PubMed  CAS  Google Scholar 

  • Hallikainen T, Saito T, Lachman HM, Volavka J, Pohjalainen T, Ryynanen OP, Kauhanen J, Syvalahti E, Hietala J, Tiihonen J (1999) Association between low activity serotonin transporter promoter genotype and early onset alcoholism with habitual impulsive violent behavior. Mol Psychiatry 4:385–388

    Article  PubMed  CAS  Google Scholar 

  • Hammoumi S, Payen A, Favre JD, Balmes JL, Benard JY, Husson M, Ferrand JP, Martin JP, Daoust M (1999) Does the short variant of the serotonin transporter linked polymorphic region constitute a marker of alcohol dependence? Alcohol 17:107–112

    Article  PubMed  CAS  Google Scholar 

  • Harlan RE, Shivers BD, Romano GJ, Howells RD, Pfaff DW (1987) Localization of preproenkephalin mRNA in the rat brain and spinal cord by in situ hybridization. J Comp Neurol 258:159–184

    Article  PubMed  CAS  Google Scholar 

  • Harvey M, Shink E, Tremblay M, Gagne B, Raymond C, Labbe M, Walther DJ, Bader M, Barden N (2004) Support for the involvement of TPH2 gene in affective disorders. Mol Psychiatry 9:980–981

    Article  PubMed  CAS  Google Scholar 

  • Hasegawa Y, Higuchi S, Matsushita S, Miyaoka H (2002) Association of a polymorphism of the serotonin 1B receptor gene and alcohol dependence with inactive aldehyde dehydrogenase-2. J Neural Transm 109:513–521

    Article  PubMed  CAS  Google Scholar 

  • He X, Treacy MN, Simmons DM, Ingraham HA, Swanson LW, Rosenfeld MG (1989) Expression of a large family of POU-domain regulatory genes in mammalian brain development. Nature 340:35–41

    Article  PubMed  CAS  Google Scholar 

  • Herman AI, Philbeck JW, Vasilopoulos NL, Depetrillo PB (2003) Serotonin transporter promoter polymorphism and differences in alcohol consumption behaviour in a college student population. Alcohol Alcohol 38:446–449

    PubMed  CAS  Google Scholar 

  • Herrmann MJ, Huter T, Muller F, Muhlberger A, Pauli P, Reif A, Renner T, Canli T, Fallgatter AJ, Lesch KP (2007) Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing. Cereb Cortex 17(5):1160–1163

    Article  PubMed  Google Scholar 

  • Hill EM, Stoltenberg SF, Bullard KH, Li S, Zucker RA, Burmeister M (2002) Antisocial alcoholism and serotonin-related polymorphisms: association tests. Psychiatr Genet 12:143–153

    Article  PubMed  Google Scholar 

  • Hsu YP, Loh EW, Chen WJ, Chen CC, Yu JM, Cheng AT (1996) Association of monoamine oxidase A alleles with alcoholism among male Chinese in Taiwan. Am J Psychiatry 153:1209–1211

    PubMed  CAS  Google Scholar 

  • Hsu YP, Tai JJ, Seow SV, Chen CC, Yu JM, Cheng AT (1998) Allelic association of tryptophan hydroxylase with alcoholism in five Taiwanese ethnic groups. Mol Psychiatry 3:213–214

    Article  PubMed  CAS  Google Scholar 

  • Huang YY, Oquendo MA, Friedman JM, Greenhill LL, Brodsky B, Malone KM, Khait V, Mann JJ (2003) Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism. Neuropsychopharmacology 28:163–169

    Article  PubMed  CAS  Google Scholar 

  • Hwu HG, Chen CH (2000) Association of 5HT2A receptor gene polymorphism and alcohol abuse with behavior problems. Am J Med Genet 96:797–800

    Article  PubMed  CAS  Google Scholar 

  • Ishiguro H, Saito T, Akazawa S, Mitushio H, Tada K, Enomoto M, Mifune H, Toru M, Shibuya H, Arinami T (1999a) Association between drinking-related antisocial behavior and a polymorphism in the serotonin transporter gene in a Japanese population. Alcohol Clin Exp Res 23:1281–1284

    PubMed  CAS  Google Scholar 

  • Ishiguro H, Saito T, Shibuya H, Toru M, Arinami T (1999b) The 5’ region of the tryptophan hydroxylase gene: mutation search and association study with alcoholism. J Neural Transm 106:1017–1025

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa H, Ohtsuki T, Ishiguro H, Yamakawa-Kobayashi K, Endo K, Lin YL, Yanagi H, Tsuchiya S, Kawata K, Hamaguchi H, Arinami T (1999) Association between serotonin transporter gene polymorphism and smoking among Japanese males. Cancer Epidemiol Biomarkers Prev 8:831–833

    PubMed  CAS  Google Scholar 

  • Ito H, Hamajima N, Matsuo K, Okuma K, Sato S, Ueda R, Tajima K (2003) Monoamine oxidase polymorphisms and smoking behaviour in Japanese. Pharmacogenetics 13:73–79

    Article  PubMed  CAS  Google Scholar 

  • Kreek MJ, LaForge KS, Butelman E (2002) Pharmacotherapy of addictions. Nat Rev Drug Discov 1:710–726

    Article  PubMed  CAS  Google Scholar 

  • Kreek MJ, Schlussman SD, Bart G, LaForge KS, Butelman ER (2004) Evolving perspectives on neurobiological research on the addictions: celebration of the 30th anniversary of NIDA. Neuropharmacology 47(Suppl 1):324–344

    Article  PubMed  CAS  Google Scholar 

  • Lappalainen J, Long JC, Eggert M, Ozaki N, Robin RW, Brown GL, Naukkarinen H, Virkkunen M, Linnoila M, Goldman D (1998) Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch Gen Psychiatry 55:989–994

    Article  PubMed  CAS  Google Scholar 

  • Leander P, Vrang N, Moller M (1998) Neuronal projections from the mesencephalic raphe nuclear complex to the suprachiasmatic nucleus and the deep pineal gland of the golden hamster (Mesocricetus auratus). J Comp Neurol 399:73–93

    Article  PubMed  CAS  Google Scholar 

  • Lerman C, Caporaso NE, Bush A, Zheng YL, Audrain J, Main D, Shields PG (2001) Tryptophan hydroxylase gene variant and smoking behavior. Am J Med Genet 105:518–520

    Article  PubMed  CAS  Google Scholar 

  • Liang J, Wessel JH III, Iuvone PM, Tosini G, Fukuhara C (2004) Diurnal rhythms of tryptophan hydroxylase 1 and 2 mRNA expression in the rat retina. Neuroreport 15:1497–1500

    Article  PubMed  CAS  Google Scholar 

  • Lichtermann D, Hranilovic D, Trixler M, Franke P, Jernej B, Delmo CD, Knapp M, Schwab SG, Maier W, Wildenauer DB (2000) Support for allelic association of a polymorphic site in the promoter region of the serotonin transporter gene with risk for alcohol dependence. Am J Psychiatry 157:2045–2047

    Article  PubMed  CAS  Google Scholar 

  • Lim JE, Pinsonneault J, Sadee W, Saffen D (2007) Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons. Mol Psychiatry 12:491–501

    PubMed  CAS  Google Scholar 

  • Linnoila M, Virkkunen M, Scheinin M, Nuutila A, Rimon R, Goodwin FK (1983) Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from nonimpulsive violent behavior. Life Sci 33:2609–2614

    Article  PubMed  CAS  Google Scholar 

  • Lucki I (1998) The spectrum of behaviors influenced by serotonin. Biol Psychiatry 44:151–162

    Article  PubMed  CAS  Google Scholar 

  • Marchini J, Cutler D, Patterson N, Stephens M, Eskin E, Halperin E, Lin S, Qin ZS, Munro HM, Abecasis GR, Donnelly P (2006) A comparison of phasing algorithms for trios and unrelated individuals. Am J Hum Genet 78:437–450

    Article  PubMed  CAS  Google Scholar 

  • Matsushita S, Yoshino A, Murayama M, Kimura M, Muramatsu T, Higuchi S (2001) Association study of serotonin transporter gene regulatory region polymorphism and alcoholism. Am J Med Genet 105:446–450

    Article  PubMed  CAS  Google Scholar 

  • McKinney EF, Walton RT, Yudkin P, Fuller A, Haldar NA, Mant D, Murphy M, Welsh KI, Marshall SE (2000) Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers. Pharmacogenetics 10:483–491

    Article  PubMed  CAS  Google Scholar 

  • McLellan AT, Luborsky L, Woody GE, O’Brien CP (1980) An improved diagnostic evaluation instrument for substance abuse patients. The Addiction Severity Index. J Nerv Ment Dis 168:26–33

    Article  PubMed  CAS  Google Scholar 

  • Miguez JM, Martin FJ, Aldegunde M (1994) Effects of single doses and daily melatonin treatments on serotonin metabolism in rat brain regions. J Pineal Res 17:170–176

    Article  PubMed  CAS  Google Scholar 

  • Mossner R, Walitza S, Geller F, Scherag A, Gutknecht L, Jacob C, Bogusch L, Remschmidt H, Simons M, Herpertz-Dahlmann B, Fleischhaker C, Schulz E, Warnke A, Hinney A, Wewetzer C, Lesch KP (2005) Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive-compulsive disorder. Int J Neuropsychopharmacol 1–6

  • Mossner R, Walitza S, Geller F, Scherag A, Gutknecht L, Jacob C, Bogusch L, Remschmidt H, Simons M, Herpertz-Dahlmann B, Fleischhaker C, Schulz E, Warnke A, Hinney A, Wewetzer C, Lesch KP (2006) Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive-compulsive disorder. Int J Neuropsychopharmacol 9:437–442

    Article  PubMed  CAS  Google Scholar 

  • Munafo MR, Lingford-Hughes AR, Johnstone EC, Walton RT (2005) Association between the serotonin transporter gene and alcohol consumption in social drinkers. Am J Med Genet B Neuropsychiatr Genet 135:10–14

    PubMed  Google Scholar 

  • Nakamura T, Matsushita S, Nishiguchi N, Kimura M, Yoshino A, Higuchi S (1999) Association of a polymorphism of the 5HT2A receptor gene promoter region with alcohol dependence. Mol Psychiatry 4:85–88

    Article  PubMed  CAS  Google Scholar 

  • Nakamura K, Sugawara Y, Sawabe K, Ohashi A, Tsurui H, Xiu Y, Ohtsuji M, Lin QS, Nishimura H, Hasegawa H, Hirose S (2006) Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels. J Neurosci 26:530–534

    Article  PubMed  CAS  Google Scholar 

  • Nielsen DA, Dean M, Goldman D (1992) Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism. Am J Hum Genet 51:1366–1371

    PubMed  CAS  Google Scholar 

  • Nielsen DA, Goldman D, Virkkunen M, Tokola R, Rawlings R, Linnoila M (1994) Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch Gen Psychiatry 51:34–38

    PubMed  CAS  Google Scholar 

  • Nielsen DA, Jenkins GL, Stefanisko KM, Jefferson KK, Goldman D (1997) Sequence, splice site and population frequency distribution analyses of the polymorphic human tryptophan hydroxylase intron 7. Mol Brain Res 45:145–148

    Article  PubMed  CAS  Google Scholar 

  • Nielsen DA, Virkkunen M, Lappalainen J, Eggert M, Brown GL, Long JC, Goldman D, Linnoila M (1998) A tryptophan hydroxylase gene marker for suicidality and alcoholism. Arch Gen Psychiatry 55:593–602

    Article  PubMed  CAS  Google Scholar 

  • Patel PD, Pontrello C, Burke S (2004) Robust and tissue-specific expression of TPH2 versus TPH1 in rat raphe and pineal gland. Biol Psychiatry 55:428–433

    Article  PubMed  CAS  Google Scholar 

  • Peters EJ, Slager SL, McGrath PJ, Knowles JA, Hamilton SP (2004) Investigation of serotonin-related genes in antidepressant response. Mol Psychiatry 9:879–889

    Article  PubMed  CAS  Google Scholar 

  • Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155:945–959

    PubMed  CAS  Google Scholar 

  • Proudnikov D, LaForge KS, Hofflich H, Levenstein M, Gordon D, Barral S, Ott J, Kreek MJ (2006) Association analysis of polymorphisms in serotonin 1B receptor gene and heroin addiction: a comparison of molecular and statistically estimated haplotypes. Pharmacogenet Genomics 16:25–36

    Article  PubMed  CAS  Google Scholar 

  • Ranade K, Chang MS, Ting CT, Pei D, Hsiao CF, Olivier M, Pesich R, Hebert J, Chen YD, Dzau VJ, Curb D, Olshen R, Risch N, Cox DR, Botstein D (2001) High-throughput genotyping with single nucleotide polymorphisms. Genome Res 11:1262–1268

    PubMed  CAS  Google Scholar 

  • Rettig RA, Yarmolinsky A (eds) (1995) Federal regulation of methadone treatment. Washington DC, National Academy Press

    Google Scholar 

  • Reuter M, Hennig J (2005) Pleiotropic effect of the TPH A779C polymorphism on nicotine dependence and personality. Am J Med Genet B Neuropsychiatr Genet 134:20–24

    PubMed  CAS  Google Scholar 

  • Rosenthal NE, Davenport Y, Cowdry RW, Webster MH, Goodwin FK (1980) Monoamine metabolites in cerebrospinal fluid of depressive subgroups. Psychiatry Res 2:113–119

    Article  PubMed  CAS  Google Scholar 

  • Rotondo A, Schuebel KE, Bergen AW, Aragon R, Virkkunen M, Linnoila M, Goldman D, Nielsen DA (1999) Identification of four variants in the tryptophan hydroxylase promoter and association to behavior. Mol Psychiatry 4:360–368

    Article  PubMed  CAS  Google Scholar 

  • Roy A, Adinoff B, Linnoila M (1988) Acting out hostility in normal volunteers: negative correlation with levels of 5HIAA in cerebrospinal fluid. Psychiatry Res 24:187–194

    Article  PubMed  CAS  Google Scholar 

  • Sander T, Harms H, Lesch KP, Dufeu P, Kuhn S, Hoehe M, Rommelspacher H, Schmidt LG (1997) Association analysis of a regulatory variation of the serotonin transporter gene with severe alcohol dependence. Alcohol Clin Exp Res 21:1356–1359

    PubMed  CAS  Google Scholar 

  • Schug J, Overton GC (1977) TESS: transcription element search software on the WWW. Philadelphia, Computational Biology and Informatics Laboratory, School of Medicine, University of Pennsylvania

    Google Scholar 

  • Sheehan K, Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M, Hawi Z (2005) Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD. Mol Psychiatry 10:944–949

    Article  PubMed  CAS  Google Scholar 

  • Soubrie P (1986) Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Sci 9:319–364

    Article  Google Scholar 

  • Stephens M, Donnelly P (2003) A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:1162–1169

    Article  PubMed  CAS  Google Scholar 

  • Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

    Article  PubMed  CAS  Google Scholar 

  • Stoll J, Goldman D (1991) Isolation and structural characterization of the murine tryptophan hydroxylase gene. J Neurosci Res 28:457–465

    Article  PubMed  CAS  Google Scholar 

  • Stoltenberg SF, Glass JM, Chermack ST, Flynn HA, Li S, Weston ME, Burmeister M (2006) Possible association between response inhibition and a variant in the brain-expressed tryptophan hydroxylase-2 gene. Psychiatr Genet 16:35–38

    Article  PubMed  Google Scholar 

  • Sugden D (2003) Comparison of circadian expression of tryptophan hydroxylase isoform mRNAs in the rat pineal gland using real-time PCR. J Neurochem 86:1308–1311

    Article  PubMed  CAS  Google Scholar 

  • Sullivan PF, Jiang Y, Neale MC, Kendler KS, Straub RE (2001) Association of the tryptophan hydroxylase gene with smoking initiation but not progression to nicotine dependence. Am J Med Genet 105:479–484

    Article  PubMed  CAS  Google Scholar 

  • Sun HF, Chang YT, Fann CS, Chang CJ, Chen YH, Hsu YP, Yu WY, Cheng AT (2002) Association study of novel human serotonin 5-HT(1B) polymorphisms with alcohol dependence in Taiwanese Han. Biol Psychiatry 51:896–901

    Article  PubMed  CAS  Google Scholar 

  • Tan EC, Yeo BK, Ho BK, Tay AH, Tan CH (1999) Evidence for an association between heroin dependence and a VNTR polymorphism at the serotonin transporter locus. Mol Psychiatry 4:215–217

    Article  PubMed  CAS  Google Scholar 

  • Turker T, Sodmann R, Goebel U, Jatzke S, Knapp M, Lesch KP, Schuster R, Schutz H, Weiler G, Stober G (1998) High ethanol tolerance in young adults is associated with the low-activity variant of the promoter of the human serotonin transporter gene. Neurosci Lett 248:147–150

    Article  PubMed  CAS  Google Scholar 

  • Van Den Bogaert A, De Zutter S, Heyrman L, Mendlewicz J, Adolfsson R, Van Broeckhoven C, Del-Favero J (2005) Response to loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16. Neuron. 48:704

    Google Scholar 

  • Walitza S, Renner TJ, Dempfle A, Konrad K, Wewetzer C, Halbach A, Herpertz-Dahlmann B, Remschmidt H, Smidt J, Linder M, Flierl L, Knolker U, Friedel S, Schafer H, Gross C, Hebebrand J, Warnke A, Lesch KP (2005) Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 10:1126–1132

    Article  PubMed  CAS  Google Scholar 

  • Walther DJ, Bader M (2003) A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 66:1673–1680

    Article  PubMed  CAS  Google Scholar 

  • Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, Bader M (2003) Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299:76

    Article  PubMed  CAS  Google Scholar 

  • Westfall P, Young S (1993) Resampling-based multiple testing: examples and methods for p-value adjustment. John Wiley & Sons, Inc., New York

    Google Scholar 

  • Whitcombe D, Brownie J, Gillard HL, McKechnie D, Theaker J, Newton CR, Little S (1998) A homogeneous fluorescence assay for PCR amplicons: its application to real-time, single-tube genotyping. Clin Chem 44:918–923

    PubMed  CAS  Google Scholar 

  • Williams RG, Dockray GJ (1983) Distribution of enkephalin-related peptides in rat brain: immunohistochemical studies using antisera to met-enkephalin and met-enkephalin Arg6Phe7. Neuroscience 9:563–586

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Gainetdinov RR, Beaulieu J-M, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan KRR, Caron MG (2005a) Response to correspondence: loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 48:705–706

    Article  CAS  Google Scholar 

  • Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan KR, Caron MG (2005b) Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45:11–16

    Article  PubMed  CAS  Google Scholar 

  • Zhou Z, Peters EJ, Hamilton SP, McMahon F, Thomas C, McGrath PJ, Rush J, Trivedi MH, Charney DS, Roy A (2005a) Response to Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16. Neuron 48:702–703

    Article  PubMed  CAS  Google Scholar 

  • Zhou Z, Roy A, Lipsky RH, Kuchipudi K, Zhu G, Taubman J, Enoch M-A, Virkkunen M, Goldman D (2005b) Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations. Arch Gen Psychiatry 62:1109–1118

    Article  PubMed  CAS  Google Scholar 

  • Zill P, Baghai TC, Zwanzger P, Schule C, Eser D, Rupprecht R, Moller HJ, Bondy B, Ackenheil M (2004a) SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 9(11):1030–1036

    Google Scholar 

  • Zill P, Buttner A, Eisenmenger W, Moller HJ, Bondy B, Ackenheil M (2004b) Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol Psychiatry 56:581–586

    Article  PubMed  CAS  Google Scholar 

  • Zill P, Buttner A, Eisenmenger W, Moller H-J, Ackenheil M, Bondy B (2007) Analysis of tryptophan hydroxylase I and II mRNA expression in the human brain: a post-mortem study. J Psychiatr Res 41(1–2):168–173

    Google Scholar 

Download references

Acknowledgements

We thank Kathy Bell, R.N., Elizabeth Ducat, R.N., Dorothy Melia, R.N., Lisa Borg, M.D., Pauline McHugh, M.D., James Schluger, M.D., and Heather Hofflich, D.O. for recruiting, screening, and assessment of study subjects, Matthew Randesi for sequencing assistance, and Bronson E. Oosterhuis and Julia Allen for re-reading of the sequencing electropherograms. We are grateful to Vadim Yuferov, Ph.D., Stefan Schlussman, Ph.D., Orna Levran, Ph.D., and K. Steven LaForge, Ph.D. for critical review of this manuscript. We thank Susan Russo for help in manuscript preparation. This study was supported by NIH-NIDA Grants K05-DA00049 (M.J.K.) and RO1-DA12848 (M.J.K.), NIH-RR UL1RR024143 (B.C.), NIH-MH R01-44292 (J.O.), and NSFC grant 30730057 from the Chinese Government (J.O.).

Author information

Authors and Affiliations

  1. Laboratory of Biology of the Addictive Diseases, The Rockefeller University, Box 171, 1230 York Avenue, New York, NY, 10065, USA

    David A. Nielsen, Dmitri Proudnikov, Scott Kellogg, Ann Ho & Mary Jeanne Kreek

  2. Gertrude H. Sergievsky Center, Columbia University, New York, NY, 10032, USA

    Sandra Barral

  3. Laboratory of Statistical Genetics, The Rockefeller University, New York, NY, 10065, USA

    Jurg Ott

  4. Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China

    Jurg Ott

Authors
  1. David A. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra Barral
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dmitri Proudnikov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Scott Kellogg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ann Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jurg Ott
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mary Jeanne Kreek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Nielsen.

Additional information

Edited by Tatiana Foroud.

Appendix

Appendix

Table A Primary ascertainment categories of additional study subjects with addiction diseases not studied herein
Full size table
Table B Primers used for the amplification of the TPH2 gene
Full size table
Table C Sequencing primers used to sequence the TPH2 amplicons
Full size table
Table D TaqMan® primers and probes
Full size table
Table E Additional TPH2 variants identified by resequencing
Full size table
Table F Interaction of the TPH2 variants with the TPH1 rs1799913 variant in Hispanics
Full size table
Table G Pairwise linkage disequilibrium between the six TPH2 variants in the control groups of the four major ethnic groups
Full size table

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nielsen, D.A., Barral, S., Proudnikov, D. et al. TPH2 and TPH1: Association of Variants and Interactions with Heroin Addiction. Behav Genet 38, 133–150 (2008). https://doi.org/10.1007/s10519-007-9187-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10519-007-9187-7

Keywords

Search

Navigation