Advertisement

Human Genetics

, 119:233 | Cite as

Further clarification of the contribution of the tryptophan hydroxylase (TPH) gene to suicidal behavior using systematic allelic and genotypic meta-analyses

  • Dawei Li
  • Lin HeEmail author
Review Article

Abstract

Suicide is a major public health issue, especially in western countries, accounting for approximately 1 million deaths every year throughout the world. The tryptophan hydroxylase (TPH) gene has been extensively studied as a candidate for suicidal behavior due to its role in serotonergic neurotransmission. Since the first study associating the gene with schizophrenia, there have been many attempts to replicate it. However, a number of these studies have produced contrary results, possibly reflecting inadequate statistical power and the use of different populations. Association data relating European and, more particularly, Asian populations has become increasingly available in recent years. To examine whether the aggregate data provide evidence of statistical significance, the current meta-analysis has combined all the published studies up to July 2005, and examined the polymorphisms (A779C, A218C, A-6526G) in the context of varied suicidal behaviors by analyzing the studies in total and in subsets. Compared with the inconsistent results of previous studies, the current results (22 references) confirm a strong overall association between suicidal behavior and the A779C/A218C polymorphisms, supporting the involvement of TPH in the pathogenesis of suicidal behavior.

Keywords

Meta-analysis Association Suicide Tryptophan hydroxylase (TPH

Notes

Acknowledgements

This work was supported by grants from the Ministry of Education, PRC, the national 973 and 863 programs, the National Natural Science Foundation of China, and the Shanghai Municipal Commission for Science and Technology.

Supplementary material

439_2005_113_MOESM1_ESM.pdf (501 kb)
Supplementary material

References

  1. Abbar M, Courtet P, Amadeo S, Caer Y, Mallet J, Baldy-Moulinier M, Castelnau D, Malafosse A (1995) Suicidal behaviors and the tryptophan hydroxylase gene. Arch Gen Psychiatry 52:846–849PubMedGoogle Scholar
  2. Abbar M, Courtet P, Bellivier F, Leboyer M, Boulenger JP, Castelhau D, Ferreira M, Lambercy C, Mouthon D, Paoloni-Giacobino A, Vessaz M, Malafosse A, Buresi C (2001) Suicide attempts and the tryptophan hydroxylase gene. Mol Psychiatry 6:268–273PubMedCrossRefGoogle Scholar
  3. Arango V, Huang YY, Underwood MD, Mann JJ (2003) Genetics of the serotonergic system in suicidal behavior. J Psychiatr Res 37:375–386PubMedCrossRefGoogle Scholar
  4. Bellivier F, Chaste P, Malafosse A (2004) Association between the TPH gene A218C polymorphism and suicidal behavior: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 124:87–91CrossRefGoogle Scholar
  5. Bellivier F, Leboyer M, Courtet P, Buresi C, Beaufils B, Samolyk D, Allilaire JF, Feingold J, Mallet J, Malafosse A (1998) Association between the tryptophan hydroxylase gene and manic-depressive illness. Arch Gen Psychiatry 55:33–37PubMedCrossRefGoogle Scholar
  6. Bennett PJ, McMahon WM, Watabe J, Achilles J, Bacon M, Coon H, Grey T, Keller T, Tate D, Tcaciuc I, Workman J, Gray D (2000) Tryptophan hydroxylase polymorphisms in suicide victims. Psychiatr Genet 10:13–17PubMedGoogle Scholar
  7. Courtet P, Picot MC, Bellivier F, Torres S, Jollant F, Michelon C, Castelnau D, Astruc B, Buresi C, Malafosse A (2004) Serotonin transporter gene may be involved in short-term risk of subsequent suicide attempts. Biol Psychiatry 55:46–51PubMedCrossRefGoogle Scholar
  8. Du L, Bakish D, Hrdina PD (2001) Tryptophan hydroxylase gene 218A/C polymorphism is associated with somatic anxiety in major depressive disorder. J Affect Disord 65:37–44PubMedCrossRefGoogle Scholar
  9. Du L, Faludi G, Palkovits M, Bakish D, Hrdina PD (2000) Tryptophan hydroxylase gene 218A/C polymorphism is not associated with depressed suicide. Int J Neuropsychopharmacol 3:215–220PubMedCrossRefGoogle Scholar
  10. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedGoogle Scholar
  11. Faludi G, Du L, Palkovits M, Antal B, Sotonyi P, Hrdina PD (2000) Serotonin transporter, serotonin-2A receptor and tryptophan hydroxilase gene polymorphisms in depressed suicide victims. Neurobiology (Bp) 8:269–271Google Scholar
  12. Furlong RA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC (1998) No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behaviour in major affective disorder. Am J Med Genet 81:245–247PubMedCrossRefGoogle Scholar
  13. Geijer T, Frisch A, Persson ML, Wasserman D, Rockah R, Michaelovsky E, Apter A, Jonsson EG, Nothen MM, Weizman A (2000) Search for association between suicide attempt and serotonergic polymorphisms. Psychiatr Genet 10:19–26PubMedCrossRefGoogle Scholar
  14. Gelernter J, Kranzler H, Lacobelle J (1998) Population studies of polymorphisms at loci of neuropsychiatric interest (tryptophan hydroxylase (TPH), dopamine transporter protein (SLC6A3), D3 dopamine receptor (DRD3), apolipoprotein E (APOE), mu opioid receptor (OPRM1), and ciliary neurotrophic factor (CNTF)). Genomics 52:289–297PubMedCrossRefGoogle Scholar
  15. Han L, Nielsen DA, Rosenthal NE, Jefferson K, Kaye W, Murphy D, Altemus M, Humphries J, Cassano G, Rotondo A, Virkkunen M, Linnoila M, Goldman D (1999) No coding variant of the tryptophan hydroxylase gene detected in seasonal affective disorder, obsessive-compulsive disorder, anorexia nervosa, and alcoholism. Biol Psychiatry 45:615–619PubMedCrossRefGoogle Scholar
  16. Ho LW, Furlong RA, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC (2000) Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder. Am J Med Genet 96:36–42PubMedCrossRefGoogle Scholar
  17. Hong CJ, Tsai SJ, Wang YC (2001) Association between tryptophan hydroxylase gene polymorphism (A218C) and schizophrenic disorders. Schizophr Res 49:59–63PubMedCrossRefGoogle Scholar
  18. Jernej B, Stefulj J, Hranilovic D, Balija M, Skavic J, Kubat M (2004) Intronic polymorphism of tryptophan hydroxylase and serotonin transporter: indication for combined effect in predisposition to suicide. J Neural Transm 111:733–738PubMedCrossRefGoogle Scholar
  19. Kirov G, Owen MJ, Jones I, McCandless F, Craddock N (1999) Tryptophan hydroxylase gene and manic-depressive illness. Arch Gen Psychiatry 56:98–99PubMedCrossRefGoogle Scholar
  20. Kunugi H, Ishida S, Kato T, Sakai T, Tatsumi M, Hirose T, Nanko S (1999) No evidence for an association of polymorphisms of the tryptophan hydroxylase gene with affective disorders or attempted suicide among Japanese patients. Am J Psychiatry 156:774–776PubMedGoogle Scholar
  21. Lalovic A, Turecki G (2002) Meta-analysis of the association between tryptophan hydroxylase and suicidal behavior. Am J Med Genet 114:533–540PubMedCrossRefGoogle Scholar
  22. Mann JJ, Brent DA, Arango V (2001) The neurobiology and genetics of suicide and attempted suicide: a focus on the serotonergic system. Neuropsychopharmacology 24:467–477PubMedCrossRefGoogle Scholar
  23. Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J (1997) Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients. Am J Psychiatry 154:1451–1453PubMedGoogle Scholar
  24. Marshall SE, Bird TG, Hart K, Welsh KI (1999) Unified approach to the analysis of genetic variation in serotonergic pathways. Am J Med Genet 88:621–627PubMedCrossRefGoogle Scholar
  25. New AS, Gelernter J, Yovell Y, Trestman RL, Nielsen DA, Silverman J, Mitropoulou V, Siever LJ (1998) Tryptophan hydroxylase genotype is associated with impulsive-aggression measures: a preliminary study. Am J Med Genet 81:13–17PubMedCrossRefGoogle Scholar
  26. 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 51:34–38PubMedGoogle Scholar
  27. 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. Brain Res Mol Brain Res 45:145–148PubMedCrossRefGoogle Scholar
  28. 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 55:593–602PubMedCrossRefGoogle Scholar
  29. Ohtani M, Shindo S, Yoshioka N (2004) Polymorphisms of the tryptophan hydroxylase gene and serotonin 1A receptor gene in suicide victims among Japanese. Tohoku J Exp Med 202:123–133PubMedCrossRefGoogle Scholar
  30. Ono H, Shirakawa O, Nishiguchi N, Nishimura A, Nushida H, Ueno Y, Maeda K (2000) Tryptophan hydroxylase gene polymorphisms are not associated with suicide. Am J Med Genet 96:861–863PubMedCrossRefGoogle Scholar
  31. Paik I, Toh K, Kim J, Lee C (2000) TPH gene may be associated with suicidal behavior, but not with schizophrenia in the Korean population. Hum Hered 50:365–369PubMedCrossRefGoogle Scholar
  32. Paoloni-Giacobino A, Mouthon D, Lambercy C, Vessaz M, Coutant-Zimmerli S, Rudolph W, Malafosse A, Buresi C (2000) Identification and analysis of new sequence variants in the human tryptophan hydroxylase (TpH) gene. Mol Psychiatry 5:49–55PubMedCrossRefGoogle Scholar
  33. Pooley EC, Houston K, Hawton K, Harrison PJ (2003) Deliberate self-harm is associated with allelic variation in the tryptophan hydroxylase gene (TPH A779C), but not with polymorphisms in five other serotonergic genes. Psychol Med 33:775–783PubMedCrossRefGoogle Scholar
  34. Rotondo A, Schuebel K, Bergen A, Aragon R, Virkkunen M, Linnoila M, Goldman D, Nielsen D (1999) Identification of four variants in the tryptophan hydroxylase promoter and association to behavior. Mol Psychiatry 4:360–368PubMedCrossRefGoogle Scholar
  35. Roy A, Rylander G, Forslund K, Asberg M, Mazzanti CM, Goldman D, Nielsen DA (2001) Excess tryptophan hydroxylase 17 779C allele in surviving cotwins of monozygotic twin suicide victims. Neuropsychobiology 43:233–236PubMedCrossRefGoogle Scholar
  36. Rujescu D, Giegling I, Bondy B, Gietl A, Zill P, Moller HJ (2002) Association of anger-related traits with SNPs in the TPH gene. Mol Psychiatry 7:1023–1029PubMedCrossRefGoogle Scholar
  37. Rujescu D, Giegling I, Sato T, Hartmann AM, Moller HJ (2003) Genetic variations in tryptophan hydroxylase in suicidal behavior: analysis and meta-analysis. Biol Psychiatry 54:465–473PubMedCrossRefGoogle Scholar
  38. Souery D, Oswald P, Linkowski P, Mendlewicz J (2003) Molecular genetics in the analysis of suicide. Ann Med 35:191–196PubMedCrossRefGoogle Scholar
  39. Souery D, Van Gestel S, Massat I, Blairy S, Adolfsson R, Blackwood D, Del-Favero J, Dikeos D, Jakovljevic M, Kaneva R, Lattuada E, Lerer B, Lilli R, Milanova V, Muir W, Nothen M, Oruc L, Papadimitriou G, Propping P, Schulze T, Serretti A, Shapira B, Smeraldi E, Stefanis C, Thomson M, Van Broeckhoven C, Mendlewicz J (2001) Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study. Biol Psychiatry 49:405–409PubMedCrossRefGoogle Scholar
  40. Staner L, Uyanik G, Correa H, Tremeau F, Monreal J, Crocq MA, Stefos G, Morris-Rosendahl DJ, Macher JP (2002) A dimensional impulsive-aggressive phenotype is associated with the A218C polymorphism of the tryptophan hydroxylase gene: a pilot study in well-characterized impulsive inpatients. Am J Med Genet 114:553–557PubMedCrossRefGoogle Scholar
  41. Tsai SJ, Hong CJ, Wang YC (1999) Tryptophan hydroxylase gene polymorphism (A218C) and suicidal behaviors. Neuroreport 10:3773–3775PubMedCrossRefGoogle Scholar
  42. Turecki G, Zhu Z, Tzenova J, Lesage A, Seguin M, Tousignant M, Chawky N, Vanier C, Lipp O, Alda M, Joober R, Benkelfat C, Rouleau GA (2001) TPH and suicidal behavior: a study in suicide completers. Mol Psychiatry 6:98–102PubMedCrossRefGoogle Scholar
  43. Underwood MD, Mann JJ, Arango V (2004) Serotonergic and noradrenergic neurobiology of alcoholic suicide. Alcohol Clin Exp Res 28:57S–69SPubMedCrossRefGoogle Scholar
  44. van Heeringen K (2003) The neurobiology of suicide and suicidality. Can J Psychiatry 48:292–300PubMedGoogle Scholar
  45. Zalsman G, Frisch A, King RA, Pauls DL, Grice DE, Gelernter J, Alsobrook J, Michaelovsky E, Apter A, Tyano S, Weizman A, Leckman JF (2001) Case control and family-based studies of tryptophan hydroxylase gene A218C polymorphism and suicidality in adolescents. Am J Med Genet 105:451–457PubMedCrossRefGoogle Scholar
  46. Zill P, Buttner A, Eisenmenger W, Moller HJ, Bondy B, Ackenheil M (2004) Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol Psychiatry 56:581–586PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Shanghai Jiaotong University, Bio-X CenterShanghaiPeople’s Republic of China
  2. 2.Institute for Nutritional SciencesSIBS, Chinese Academy of SciencesShanghaiChina
  3. 3.NHGG Bio-X CenterShanghai Jiaotong UniversityShanghaiChina

Personalised recommendations