Association between suicidal behavior and genes of serotonergic system confirmed in men with affective disorders

  • Joanna Pawlak Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poland
  • Monika Dmitrzak-Węglarz Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poland
  • Maria Skibinska Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poland
  • Aleksandra Szczepankiewicz Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poland Laboratory of Molecular and Cell Biology, Poznan University of Medical Sciences, Poland
  • Anna Leszczynska-Rodziewicz Laboratory of Molecular and Cell Biology, Poznan University of Medical Sciences, Poland
  • Piotr Czerski Laboratory of Molecular and Cell Biology, Poznan University of Medical Sciences, Poland
  • Dorota Zaremba Laboratory of Molecular and Cell Biology, Poznan University of Medical Sciences, Poland
  • Joanna Hauser Laboratory of Molecular and Cell Biology, Poznan University of Medical Sciences, Poland
  • Małgorzata Maciukiewicz Laboratory of Molecular and Cell Biology, Poznan University of Medical Sciences, Poland
Keywords: suicide, affective disorder, serotonergic system genes


Introduction. Suicidal behavior is a crucial clinical problem in many groups of psychiatric patients. It occurs most often in affective disorders, psychotic disorders, substance abuse/dependence and personality disorders. Although not all patients with these diagnoses present suicidal behavior, it is very important to find the most vulnerable subgroups. The extensive number of studies shows that suicidal behavior (completed and attempted suicide) is associated with changes in functioning of serotonergic system. Tryptophan hydroxylase (TPH) is rate-limiting enzyme in biosynthesis of serotonin. Serotonin transporter (5-HTT) is the main factor removing serotonin from the synaptic space. Genetic studies confirm that suicide behavior has a genetic component independently of major psychiatric disorders. Aim. The aim of this study is to look for association between selected candidate genes and suicidal behavior in affective disorders.Material and methods. In the study we included 597 patients meeting DSM-IV criteria for bipolar disorder or unipolar disorder and 563 healthy controls. Polymorphism of serotonin transporter gene 5-HTTLPR and single nucleotide polymorphisms – SNPs (rs1799913 and rs1800532) in tryptophan hydroxylase 1 (TPH1) gene were analyzed. We used in computation Statistica 8.0 package (STATSOFT, Poland) (tests: The two-tailed Pearson's chi-square (?2) test and Fisher's exact test).Results. Main positive findings are an association between TPH1 polymorphisms and bipolar disease type I (BPI) diagnosis in men and an association between TPH1 polymorphisms and suicidal attempts in male patients. In all group we did not find nor allelic neither genotypic associations of selected polymorphisms and diagnosis or suicide attempts. Conclusions. Our findings partially confirm that serotonergic system plays a role in affective disorder and suicidal behavior, but the association needs further investigation.


Turecki G. Suicidal behavior: Is there a genetic predisposition? Bipolar Disord. 2001;3:335–349.

Valtonen H, Suominen K, Mantere O, Leppamaki S, Arvilommi P, Isometsa ET. Suicidal ideation and attempts in bipolar i and ii disorders. J Clin Psychiatry. 2005;66: 1456–1462.

Malafosse A. Genetics of suicidal behavior. Am J Med Genet C Semin Med Genet. 2005;133C:1–2.

Brent DA, Bridge J, Johnson BA, Connolly J. Suicidal behavior runs in families. A controlled family study of adolescent suicide victims. Arch Gen Psychiatry. 1996;53: 1145–1152.

Brent DA, Mann JJ. Family genetic studies, suicide, and suicidal behavior. Am J Med Genet C Semin Med Genet. 2005;133C:13–24.

Mann JJ. Neurobiology of suicidal behaviour. Nat Rev Neurosci. 2003;4:819–828.

Arango V, Underwood MD, Gubbi AV, Mann JJ. Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res. 1995;688:121–133.

Mann JJ, Huang YY, Underwood MD, Kassir SA, Oppenheim S, Kelly TM, Dwork AJ, Arango V. A serotonin transporter gene promoter polymorphism (5-httlpr) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry. 2000;57:729–738.

Stanley M, Mann JJ. Increased serotonin-2 binding sites in frontal cortex of suicide victims. Lancet. 1983;1: 214–216.

Asberg M, Nordstrom P, Traskman-Bendz L. Cerebrospinal fluid studies in suicide. An overview. Ann N Y Acad Sci. 1986;487:243–255.

Cooper SJ, Kelly CB, King DJ: 5-hydroxyindoleacetic acid in cerebrospinal fluid and prediction of suicidal behaviour in schizophrenia. Lancet. 1992;340:940–941.

Coccaro EF, Siever LJ, Klar HM, Maurer G, Cochrane K, Cooper TB, Mohs RC, Davis KL. Serotonergic studies in patients with affective and personality disorders. Correlates with suicidal and impulsive aggressive behavior. Arch Gen Psychiatry. 1989;46:587–599.

Bellivier F, Chaste P, Malafosse A. Association between the tph gene a218c polymorphism and suicidal behavior: A meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2004;124B:87–91.

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. Suicide attempts and the tryptophan hydroxylase gene. Mol Psychiatry. 2001;6:268–273.

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

Courtet P, Baud P, Abbar M, Boulenger JP, Castelnau D, Mouthon D, Malafosse A, Buresi C. Association between violent suicidal behavior and the low activity allele of the serotonin transporter gene. Mol Psychiatry. 2001;6: 338–341.

Bellivier F, Szoke A, Henry C, Lacoste J, Bottos C, Nosten-Bertrand M, Hardy P, Rouillon F, Launay JM, Laplanche JL, Leboyer M. Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders. Biol Psychiatry. 2000;48:319–322.

Gorwood P, Bellivier F, Ades J, Leboyer M. The drd2 gene and the risk for alcohol dependence in bipolar patients. Eur Psychiatry. 2000;15:103–108.

Du L, Faludi G, Palkovits M, Demeter E, Bakish D, Lapierre YD, Sotonyi P, Hrdina PD. Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims. Biol Psychiatry. 1999;46:196–201.

Asberg M, Traskman L, Thoren P: 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? Arch Gen Psychiatry. 1976;33:1193–1197.

Beautrais AL. Suicides and serious suicide attempts: Two populations or one? Psychol Med. 2001;31:837–845.

Stoltenberg SF, Twitchell GR, Hanna GL, Cook EH, Fitzgerald HE, Zucker RA, Little KY. Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism. Am J Med Genet. 2002;114:230–234.

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. 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. 2010;153B:387–396.

Chen C, Glatt SJ, Tsuang MT. The tryptophan hydroxylase gene influences risk for bipolar disorder but not major depressive disorder: Results of meta-analyses. Bipolar Disord. 2008;10:816–821.

Choi KY, Yoon HK, Kim YK. Association between serotonin-related polymorphisms in 5HT2A, TPH1, TPH2 genes and bipolar disorder in korean population. Psychiatry Investig. 2010;7:60–67.

Mendlewicz J, Massat I, Souery D, Del-Favero J, Oruc L, Nothen MM, Blackwood D, Muir W, Battersby S, Lerer B, Segman RH, Kaneva R, Serretti A, Lilli R, Lorenzi C, Jakovljevic M, Ivezic S, Rietschel M, Milanova V, Van Broeckhoven C. Serotonin transporter 5-HTTLPR polymorphism and affective disorders: No evidence of association in a large european multicenter study. Eur J Hum Genet. 2004;12:377–382.

Craddock N, Jones I. Molecular genetics of bipolar disorder. Br J Psychiatry Suppl. 2001;41:s128–133.

Seretti A, Cusin C, Lattuada E, Di Bella D, Catalano M, Smeraldi E. Serotonin transporter gene (5-httlpr) is not associated with depressive symptomatology in mood disorders. Mol Psychiatry. 1999;4:280–283.

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

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

Clayden RC, Zaruk A, Meyre D, Thabane L, Samaan Z. 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. 2012;2:e166.

Stefulj J, Kubat M, Balija M, Jernej B. Tph gene polymorphism and aging: Indication of combined effect on the predisposition to violent suicide. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:139–141.

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

Tsai SJ, Hong CJ, Wang YC. Tryptophan hydroxylase gene polymorphism (a218c) and suicidal behaviors. Neuroreport. 1999;10:3773–3775.

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

Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J. Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients. Am J Psychiatry. 1997;154: 1451–1453.

Faludi G, Du L, Palkovits M, Antal B, Sotonyi P, Hrdina PD. Serotonin transporter, serotonin-2a receptor and tryptophan hydroxilase gene polymorphisms in depressed suicide victims. Neurobiology (Bp) 2000;8:269–271.

Bennett PJ, McMahon WM, Watabe J, Achilles J, Bacon M, Coon H, Grey T, Keller T, Tate D, Tcaciuc I, Workman J, Gray D. Tryptophan hydroxylase polymorphisms in suicide victims. Psychiatr Genet. 2000;10:13–17.

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. Tph and suicidal behavior: A study in suicide completers. Mol Psychiatry. 2001;6: 98–102.

Ohtani M, Shindo S, Yoshioka N. Polymorphisms of the tryptophan hydroxylase gene and serotonin 1a receptor gene in suicide victims among japanese. Tohoku J Exp Med. 2004;202:123–133.

Furlong RA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC. 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. 1998;81:245–247.

Bellivier F, Leboyer M, Courtet P, Buresi C, Beaufils B, Samolyk D, Allilaire JF, Feingold J, Mallet J, Malafosse A. Association between the tryptophan hydroxylase gene and manic-depressive illness. Arch Gen Psychiatry. 1998;55:33–37.

Kunugi H, Ishida S, Kato T, Sakai T, Tatsumi M, Hirose T, Nanko S. No evidence for an association of polymorphisms of the tryptophan hydroxylase gene with affective disorders or attempted suicide among japanese patients. Am J Psychiatry. 1999;156:774–776.

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. Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: A multicenter association study. Biol Psychiatry. 2001;49:405–409.

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

Rujescu D, Giegling I, Bondy B, Gietl A, Zill P, Moller HJ. Association of anger-related traits with snps in the tph gene. Mol Psychiatry. 2002;7:1023–1029.

Rujescu D, Giegling I, Sato T, Hartmann AM, Moller HJ. Genetic variations in tryptophan hydroxylase in suicidal behavior: Analysis and meta-analysis. Biol Psychiatry. 2003;54:465–473.

De Luca V, Strauss J, Kennedy JL. Power based association analysis (pbat) of serotonergic and noradrenergic polymorphisms in bipolar patients with suicidal behaviour. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:197–203.

De Luca V, Tharmalingam S, King N, Strauss J, Bulgin N, Kennedy JL. Association study of a novel functional polymorphism of the serotonin transporter gene in bipolar disorder and suicidal behaviour. Psychopharmacology (Berl) 2005;182:128–131.

Zalsman G, Huang YY, Oquendo MA, Burke AK, Hu XZ, Brent DA, Ellis SP, Goldman D, Mann JJ. Association of a triallelic serotonin transporter gene promoter region (5-httlpr) polymorphism with stressful life events and severity of depression. Am J Psychiatry. 2006;163: 1588–1593.

Ho LW, Furlong RA, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC. Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder. Am J Med Genet. 2000;96:36–42.

Ohara K, Nagai M, Tsukamoto T, Tani K, Suzuki Y. Functional polymorphism in the serotonin transporter promoter at the slc6a4 locus and mood disorders. Biol Psychiatry. 1998;44:550–554.

Bondy B, Erfurth A, de Jonge S, Kruger M, Meyer H. Possible association of the short allele of the serotonin transporter promoter gene polymorphism (5-httlpr) with violent suicide. Mol Psychiatry. 2000;5:193–195.

Gorwood P, Batel P, Ades J, Hamon M, Boni C. Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior. Biol Psychiatry. 2000;48:259–264.

Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: Moderation by a polymorphism in the 5-htt gene. Science. 2003;301:386–389.

Coventry WL, James MR, Eaves LJ, Gordon SD, Gillespie NA, Ryan L, Heath AC, Montgomery GW, Martin NG, Wray NR. Do 5-HTTLPR and stress interact in risk for depression and suicidality? Item response analyses of a large sample. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:757–765.

Neves FS, Silveira G, Romano-Silva MA, Malloy-Diniz L, Ferreira AA, De Marco L, Correa H. Is the 5-httlpr polymorphism associated with bipolar disorder or with suicidal behavior of bipolar disorder patients? Am J Med Genet B Neuropsychiatr Genet. 2008;147B:114–116.

Neves FS, Malloy-Diniz LF, Romano-Silva MA, Aguiar GC, de Matos LO, Correa H. Is the serotonin transporter polymorphism (5-httlpr) a potential marker for suicidal behavior in bipolar disorder patients? J Affect Disord. 2010;125:98–102.

Li D, He L. Meta-analysis supports association between serotonin transporter (5-htt) and suicidal behavior. Mol Psychiatry. 2007;12:47–54.

Perroud N, Neidhart E, Petit B, Vessaz M, Laforge T, Relecom C, La Harpe R, Malafosse A, Guipponi M. 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. 2010;153B:909–918.

Turecki G. Dissecting the suicide phenotype: The role of impulsive-aggressive behaviours. J Psychiatry Neurosci. 2005;30:398–408.

Savitz JB, Ramesar RS. Personality: Is it a viable endophenotype for genetic studies of bipolar affective disorder? Bipolar Disord. 2006;8:322–337

How to Cite
Pawlak, J., Dmitrzak-Węglarz, M., Skibinska, M., Szczepankiewicz, A., Leszczynska-Rodziewicz, A., Czerski, P., Zaremba, D., Hauser, J., & Maciukiewicz, M. (2016). Association between suicidal behavior and genes of serotonergic system confirmed in men with affective disorders. Journal of Medical Science, 83(1), 7-16. Retrieved from
Original Papers