Association of TPH1 and serotonin transporter genotypes with treatment response for suicidal ideation: a preliminary study

Abstract

Variants in three genes coding for components of the serotonergic system, the tryptophan hydroxylase 1 (TPH1) rs1799913, serotonin transporter (SLC6A4) 5-HTTLPR, and serotonin receptor 2A (HTR2A) rs6311, were evaluated for association with suicidal ideation (SI) and with recovery from SI in a psychiatric inpatient population. Five hundred and eighty-two adult inpatients, including 390 patients who had SI, collected from December 2012 to April 2016 were assessed. SI recovery, calculated as change in SI between the first two-week period after admission and weeks 5 and 6, was appraised for association with the three variants. In this preliminary study, both TPH1 and 5-HTTLPR genotypes were associated with recovery (TPH1: recessive model, increased recovery with AC genotype, P = 0.026; additive model, increased recovery with AC genotype, P = 0.037; 5-HTTLPR: recessive model, increased recovery with AC, P = 0.043). When patients with comorbid alcohol use disorder (AUD) were removed, given that TPH1 has been associated with alcoholism, the associations of those recovered from SI with TPH1 rs1799913 remained significant for the additive (increased recovery with AC, P = 0.045) and recessive (increased recovery with C-carriers, P = 0.008) models, and with 5-HTTLPR using the dominant model (increased recovery with S′S′, P = 0.016). In females, an association of SI recovery with TPH1 rs1799913 was found using a recessive model (increased recovery with C-carriers, P = 0.031), with 5-HTTLPR using additive (increased recovery with L′S′, P = 0.048) and recessive (increased recovery with S′S′, P = 0.042) models. Additionally, an association of SI with TPH1 rs1799913 was found in females using both additive (increased risk in AC, P = 0.033) and recessive (increased risk in C-carriers, P = 0.043) models, and with 5-HTTLPR using a recessive model (increased risk in S′S′, P = 0.030). This study provides evidence that variation in the TPH1 and serotonin transporter genes play key roles in moderating recovery from SI during treatment in an inpatient psychiatric clinic.

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

References

  1. 1.

    Anguelova M, Benkelfat C, Turecki G (2003) A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol Psychiatry 8:574–591

    CAS  PubMed  Google Scholar 

  2. 2.

    Antypa N, Serretti A, Rujescu D (2013) Serotonergic genes and suicide: a systematic review. Eur Neuropsychopharmacol 23:1125–1142

    CAS  PubMed  Google Scholar 

  3. 3.

    Arango V, Huang YY, Underwood MD, Mann JJ (2003) Genetics of the serotonergic system in suicidal behavior. J Psychiatr Res 37:375–386

    PubMed  Google Scholar 

  4. 4.

    Bozina N, Peles AM, Sagud M, Bilusic H, Jakovljevic M (2008) Association study of paroxetine therapeutic response with sert gene polymorphisms in patients with major depressive disorder. World J Biol Psychiatry 9:190–197

    PubMed  Google Scholar 

  5. 5.

    Brezo J, Bureau A, Merette C, Jomphe V, Barker ED, Vitaro F, Hebert M, Carbonneau R, Tremblay RE, Turecki G (2010) Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study. Mol Psychiatry 15:831–843

    CAS  PubMed  Google Scholar 

  6. 6.

    Buttenschon HN, Flint TJ, Foldager L, Qin P, Christoffersen S, Hansen NF, Kristensen IB, Mortensen PB, Borglum AD, Mors O (2013) An association study of suicide and candidate genes in the serotonergic system. J Affect Disord 148:291–298

    PubMed  Google Scholar 

  7. 7.

    Chen D, Liu F, Yang C, Liang X, Shang Q, He W, Wang Z (2012) Association between the tph1 a218c polymorphism and risk of mood disorders and alcohol dependence: evidence from the current studies. J Affect Disord 138:27–33

    CAS  PubMed  Google Scholar 

  8. 8.

    Clayden RC, Zaruk A, Meyre D, Thabane L, Samaan Z (2012) The association of attempted suicide with genetic variants in the slc6a4 and tph genes depends on the definition of suicidal behavior: a systematic review and meta-analysis. Translational psychiatry 2:e166

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    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

    CAS  PubMed  Google Scholar 

  10. 10.

    Courtet P, Jollant F, Castelnau D, Astruc B, Buresi C, Malafosse A (2004) implication of genes of the serotonergic system on vulnerability to suicidal behavior. J Psychiatry Neurosci 29:350–359

    PubMed  Google Scholar 

  11. 11.

    Cusin C, Serretti A, Zanardi R, Lattuada E, Rossini D, Lilli R, Lorenzi C, Smeraldi E (2002) Influence of monoamine oxidase a and serotonin receptor 2a polymorphisms in ssri antidepressant activity. Int J Neuropsychopharmacol 5:27–35

    CAS  PubMed  Google Scholar 

  12. 12.

    Evaluation AWGoP (2016) The american psychiatric association practice guidelines for the psychiatric evaluation of adults. American Psychiatric Association, Arlington, VA

  13. 13.

    First MB, Spitzer RL, Gibbon M, Williams JBW (1998) Structured clinical interview for dsm-iv axis disorders—patient edition (scid-i/p, version 2.0, 8/98 revision). Biometrics Research Department, New York State Psychiatric Institute, New York

  14. 14.

    Fowler JC (2012) Suicide risk assessment in clinical practice: pragmatic guidelines for imperfect assessments. Psychotherapy (Chic) 49:81–90

    Google Scholar 

  15. 15.

    Fox E, Zougkou K, Ridgewell A, Garner K (2011) The serotonin transporter gene alters sensitivity to attention bias modification: evidence for a plasticity gene. Biol Psychiatry 70:1049–1054

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Galfalvy H, Huang YY, Oquendo MA, Currier D, Mann JJ (2009) Increased risk of suicide attempt in mood disorders and tph1 genotype. J Affect Disord 115:331–338

    PubMed  Google Scholar 

  17. 17.

    Gonzalez-Castro TB, Juarez-Rojop I, Lopez-Narvaez ML, Tovilla-Zarate CA (2014) Association of tph-1 and tph-2 gene polymorphisms with suicidal behavior: a systematic review and meta-analysis. BMC Psychiatry 14:196

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Graham DP, Helmer DA, Harding MJ, Kosten TR, Petersen NJ, Nielsen DA (2013) Serotonin transporter genotype and mild traumatic brain injury independently influence resilience and perception of limitations in veterans. J Psychiatr Res 47:835–842

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 78:815–826

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Ishiguro H, Saito T, Shibuya H, Toru M, Arinami T (1999) The 5′ region of the tryptophan hydroxylase gene: mutation search and association study with alcoholism. J Neural Transm 106:1017–1025

    CAS  PubMed  Google Scholar 

  21. 21.

    Johnson BA, Brent DA, Bridge J, Connolly J (1998) The familial aggregation of adolescent suicide attempts. Acta Psychiatr Scand 97:18–24

    CAS  PubMed  Google Scholar 

  22. 22.

    Jonsson EG, Goldman D, Spurlock G, Gustavsson JP, Nielsen DA, Linnoila M, Owen MJ, Sedvall GC (1997) Tryptophan hydroxylase and catechol-o-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in csf of healthy volunteers. Eur Arch Psychiatry Clin Neurosci 247:297–302

    CAS  PubMed  Google Scholar 

  23. 23.

    Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D (2002) The human genome browser at ucsc. Genome Res 12:996–1006

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Koller G, Engel RR, Preuss UW, Karakesisoglou A, Zill P, Bondy B, Soyka M (2005) Tryptophan hydroxylase gene 1 polymorphisms are not associated with suicide attempts in alcohol-dependent individuals. Addict Biol 10:269–273

    CAS  PubMed  Google Scholar 

  25. 25.

    Kosten TR, Domingo CB, Hamon SC, Nielsen DA (2013) Dbh gene as predictor of response in a cocaine vaccine clinical trial. Neurosci Lett 541:29–33

    CAS  PubMed  Google Scholar 

  26. 26.

    Lao O, van Duijn K, Kersbergen P, de Knijff P, Kayser M (2006) Proportioning whole-genome single-nucleotide-polymorphism diversity for the identification of geographic population structure and genetic ancestry. Am J Hum Genet 78:680–690

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayes M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C et al (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide snps. Nat Genet 45:984–994

    CAS  PubMed  Google Scholar 

  28. 28.

    Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531

    CAS  PubMed  Google Scholar 

  29. 29.

    Li D, He L (2006) Further clarification of the contribution of the tryptophan hydroxylase (tph) gene to suicidal behavior using systematic allelic and genotypic meta-analyses. Hum Genet 119:233–240

    PubMed  Google Scholar 

  30. 30.

    Limosin F, Loze JY, Boni C, Hamon M, Ades J, Rouillon F, Gorwood P (2005) Male-specific association between the 5-httlpr s allele and suicide attempts in alcohol-dependent subjects. J Psychiatr Res 39:179–182

    PubMed  Google Scholar 

  31. 31.

    Madan A, Frueh BC, Allen JG, Ellis TE, Rufino KA, Oldham JM, Fowler JC (2016) Psychometric reevaluation of the columbia-suicide severity rating scale: findings from a prospective, inpatient cohort of severely mentally ill adults. J Clin Psychiatry 77:e867–e873

    PubMed  Google Scholar 

  32. 32.

    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 154:1451–1453

    CAS  PubMed  Google Scholar 

  33. 33.

    McGuffin P, Marusic A, Farmer A (2001) What can psychiatric genetics offer suicidology? Crisis 22:61–65

    CAS  PubMed  Google Scholar 

  34. 34.

    McGuffin P, Perroud N, Uher R, Butler A, Aitchison KJ, Craig I, Lewis C, Farmer A (2010) The genetics of affective disorder and suicide. Eur Psychiatry 25:275–277

    CAS  PubMed  Google Scholar 

  35. 35.

    Io Medicine (2002) Reducing suicide: a national imperative. The National Academies Press, Washington, DC

    Google Scholar 

  36. 36.

    Mirkovic B, Laurent C, Podlipski MA, Frebourg T, Cohen D, Gerardin P (2016) Genetic association studies of suicidal behavior: a review of the past 10 years, progress, limitations, and future directions. Front Psychiatry 7:158

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Mokrovic G, Matosic A, Hranilovic D, Stefulj J, Novokmet M, Oreskovic D, Balija M, Marusic S, Cicin-Sain L (2008) Alcohol dependence and polymorphisms of serotonin-related genes: association studies. Coll Antropol 32(Suppl 1):127–131

    CAS  PubMed  Google Scholar 

  38. 38.

    Moscicki EK, O’Carroll P, Rae DS, Locke BZ, Roy A, Regier DA (1988) Suicide attempts in the epidemiologic catchment area study. Yale J Biol Med 61:259–268

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Mullins N, Perroud N, Uher R, Butler AW, Cohen-Woods S, Rivera M, Malki K, Euesden J, Power RA, Tansey KE, Jones L, Jones I, Craddock N, Owen MJ, Korszun A, Gill M, Mors O, Preisig M, Maier W, Rietschel M, Rice JP, Muller-Myhsok B, Binder EB, Lucae S, Ising M, Craig IW, Farmer AE, McGuffin P, Breen G, Lewis CM (2014) Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: a genome-wide association and polygenic scoring study. Am J Med Genet B Neuropsychiatr Genet 165B:428–437

    PubMed  Google Scholar 

  40. 40.

    Murphy DL, Lerner A, Rudnick G, Lesch KP (2004) Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Mol Interv 4:109–123

    CAS  PubMed  Google Scholar 

  41. 41.

    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

    CAS  PubMed  Google Scholar 

  42. 42.

    Nielsen DA, Harding MJ, Hamon SC, Huang W, Kosten TR (2012) Modifying the role of serotonergic 5-HTTLPR and TPH2 variants on disulfiram treatment of cocaine addiction: a preliminary study. Genes Brain Behav 11:1001–1008

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    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

    CAS  PubMed  Google Scholar 

  44. 44.

    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 202:123–133

    CAS  PubMed  Google Scholar 

  45. 45.

    Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, Meozzi PA, Myers L, Mora Z, Tagliaferro P, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Iwasaki S, Arinami T, Teasenfitz L, Uhl GR (2006) Discovery of the presence and functional expression of cannabinoid cb2 receptors in brain. Ann N Y Acad Sci 1074:514–536

    CAS  PubMed  Google Scholar 

  46. 46.

    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 96:861–863

    CAS  PubMed  Google Scholar 

  47. 47.

    Oquendo MA, Halberstam B, Mann JJ (2003) Risk factors for suicidal behavior: Utility and limitations of research instruments. In: First MB (ed) Standardized evaluation in clinical practice, pp 103–130

  48. 48.

    Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ (2011) The columbia-suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 168:1266–1277

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Praschak-Rieder N, Kennedy J, Wilson AA, Hussey D, Boovariwala A, Willeit M, Ginovart N, Tharmalingam S, Masellis M, Houle S, Meyer JH (2007) Novel 5-httlpr allele associates with higher serotonin transporter binding in putamen: a [(11)c] dasb positron emission tomography study. Biol Psychiatry 62:327–331

    CAS  PubMed  Google Scholar 

  50. 50.

    Pregelj P (2012) Single nucleotide polymorphisms and suicidal behaviour. Psychiatria Danubina 24(Suppl 1):S61–S64

    PubMed  Google Scholar 

  51. 51.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Roy A, Nielsen D, Rylander G, Sarchiapone M, Segal N (1999) Genetics of suicide in depression. J Clin Psychiatry 60(Suppl 2):12–17 (discussion 18-20, 113-116)

    PubMed  Google Scholar 

  53. 53.

    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 43:233–236

    CAS  PubMed  Google Scholar 

  54. 54.

    Saetre P, Lundmark P, Wang A, Hansen T, Rasmussen HB, Djurovic S, Melle I, Andreassen OA, Werge T, Agartz I, Hall H, Terenius L, Jonsson EG (2010) The tryptophan hydroxylase 1 (tph1) gene, schizophrenia susceptibility, and suicidal behavior: a multi-centre case-control study and meta-analysis. Am J Med Genet B Neuropsychiatr Genet 153B:387–396

    CAS  PubMed  Google Scholar 

  55. 55.

    Schild AH, Pietschnig J, Tran US, Voracek M (2013) Genetic association studies between snps and suicidal behavior: a meta-analytical field synopsis. Prog Neuropsychopharmacol Biol Psychiatry 46:36–42

    CAS  PubMed  Google Scholar 

  56. 56.

    Serretti A, Artioli P (2004) From molecular biology to pharmacogenetics: a review of the literature on antidepressant treatment and suggestions of possible candidate genes. Psychopharmacology 174:490–503

    CAS  PubMed  Google Scholar 

  57. 57.

    Souery D, Oswald P, Linkowski P, Mendlewicz J (2003) Molecular genetics in the analysis of suicide. Ann Med 35:191–196

    CAS  PubMed  Google Scholar 

  58. 58.

    Stefulj J, Kubat M, Balija M, Skavic J, Jernej B (2005) Variability of the tryptophan hydroxylase gene: study in victims of violent suicide. Psychiatry Res 134:67–73

    CAS  PubMed  Google Scholar 

  59. 59.

    Stein MB, Seedat S, Gelernter J (2006) Serotonin transporter gene promoter polymorphism predicts ssri response in generalized social anxiety disorder. Psychopharmacology 187:68–72

    CAS  PubMed  Google Scholar 

  60. 60.

    Tsuang MT (1983) Risk of suicide in the relatives of schizophrenics, manics, depressives, and controls. J Clin Psychiatry 44(396–397):398–400

    Google Scholar 

  61. 61.

    Viana MM, De Marco LA, Boson WL, Romano-Silva MA, Correa H (2006) Investigation of a218c tryptophan hydroxylase polymorphism: association with familial suicide behavior and proband’s suicide attempt characteristics. Genes Brain Behav 5:340–345

    CAS  PubMed  Google Scholar 

  62. 62.

    WHO (2017) Suicide data [www document]

  63. 63.

    WHO (2016) World health statistics 2016 data visualizations dashboard| suicide

  64. 64.

    Wrzosek M, Lukaszkiewicz J, Wrzosek M, Serafin P, Jakubczyk A, Klimkiewicz A, Matsumoto H, Brower KJ, Wojnar M (2011) Association of polymorphisms in htr2a, htr1a and tph2 genes with suicide attempts in alcohol dependence: a preliminary report. Psychiatry Res 190:149–151

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    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 105:451–457

    CAS  PubMed  Google Scholar 

  66. 66.

    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 41:168–173

    PubMed  Google Scholar 

  67. 67.

    Zupanc T, Pregelj P, Paska AV (2013) Tryptophan hydroxylase 2 (tph 2) single nucleotide polymorphisms, suicide, and alcohol-related suicide. Psychiatria Danubina 25(Suppl 2):S332–S336

    PubMed  Google Scholar 

  68. 68.

    Zupanc T, Pregelj P, Tomori M, Komel R, Paska AV (2011) Tph2 polymorphisms and alcohol-related suicide. Neurosci Lett 490:78–81

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Supported by the McNair Medical Institute (MP), the Veteran Health Administration (VHA5I01CX000994), American Foundation for Suicide Prevention (SRG-2-125-14), and the Toomim Family Fund. This material is the result of work supported with resources and the use of facilities at the Michael E. DeBakey VA Medical Center, Houston, TX.

Author information

Affiliations

Authors

Corresponding author

Correspondence to David A. Nielsen.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 45 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nielsen, D.A., Deng, H., Patriquin, M.A. et al. Association of TPH1 and serotonin transporter genotypes with treatment response for suicidal ideation: a preliminary study. Eur Arch Psychiatry Clin Neurosci 270, 633–642 (2020). https://doi.org/10.1007/s00406-019-01009-w

Download citation

Keywords

  • Polymorphism
  • Tryptophan
  • Serotonin
  • Gene
  • Suicide
  • Recovery