Association of the 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism with psychiatric disorders: Review of psychopathology and pharmacotherapy

Pharmacogenomics and Personalized Medicine

Volumn 5, Issue 1, 2012, Pages 19-35

  Kenna, George A ^a   Roder Hanna, Nick ^b   Leggio, Lorenzo ^a   Zywiak, William H ^c   Clifford, James ^d   Edwards, Steven ^a   Kenna, John A ^b   Shoaff, Jessica ^a   Swift, Robert M ^a  

^a BROWN UNIVERSITY   (United States)

^b UNIVERSITY OF RHODE ISLAND   (United States)

^c BUTLER HOSPITAL   (United States)

^d VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

Author keywords

5 HT; 5 HTTLPR; Alleles; Genetics; Pharmacotherapy; Polymorphisms; Psychiatric; Psychopathology; SCC6A4; Serotonin; Triallele

Indexed keywords

CITALOPRAM; CORTICOTROPIN RELEASING FACTOR; ESCITALOPRAM; FLUOXETINE; METHYLPHENIDATE; NICOTINE; NICOTINE PATCH; NORTRIPTYLINE; ONDANSETRON; PAROXETINE; PLACEBO; REBOXETINE; SEROTONIN; SEROTONIN TRANSPORTER; SEROTONIN UPTAKE INHIBITOR; SERTRALINE; TRYPTOPHAN HYDROXYLASE;

5 HTT GENE; ALCOHOLISM; ALLELE; AMYGDALOID NUCLEUS; ANXIETY DISORDER; ATTENTION DEFICIT DISORDER; BIPOLAR DISORDER; COGNITIVE THERAPY; CONTROLLED CLINICAL TRIAL (TOPIC); EFFECT SIZE; GENE; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC TRANSCRIPTION; HEREDITY; HUMAN; MAJOR DEPRESSION; MEDICAL RESEARCH; MENTAL DISEASE; PATHOGENESIS; POSTTRAUMATIC STRESS DISORDER; PROMOTER REGION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SUICIDAL BEHAVIOR; SUICIDE ATTEMPT; TOBACCO DEPENDENCE; TREATMENT OUTCOME; TREATMENT RESPONSE;

EID: 84856782266     PISSN: None     EISSN: 11787066     Source Type: Journal    
DOI: 10.2147/PGPM.S23462     Document Type: Review

References (94)

1. Mohammad-Zadeh LF, Moses L, Gwalzney-Brant SM. Serotonin: a review. J Vet Pharmacol Ther. 2008;31:187-199.
2. Sanders-Bush E, Mayer SE. 5-Hydroxytryptamine (serotonin): receptor agonists and antagonists. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. New York: McGraw-Hill; 2006.
3. Kenna GA. Medications acting on the serotonergic system for the treatment of alcohol dependent patients. Curr Pharm Des. 2010;16:2126-2135.
4. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274:1527-1531.
5. Caspi A, Hariri AR, Holmes A, Uher R, Moffitt TE. Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry. 2010;167:509-527.
6. Hariri AR, Mattay VS, Tessitore A, et al. Serotonin transporter genetic variation and the response of the human amygdala. Science. 2002;297:400-403.
7. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386-389.
8. Matsushita S, Yoshino A, Murayama M, Kimura M, Muramatsu T, Higuchi S. Association study of serotonin transporter gene regulatory region polymorphism and alcoholism. Am J Med Genet. 2001;105: 446-450.
9. Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA. An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res. 2005;29:8-16.
10. Lipsky RH, Hu XZ, Goldman D. Additional functional variation at the SLC6 A4 gene. Am J Med Genet B Neuropsychiatr Genet. 2009;150:153.
11. Kuzelova H, Ptacek R, Macek M. The serotonin transporter gene (5-HTT) variant and psychiatric disorders: review of current literature. Neuro Endocrinol Lett. 2010;31:4-10.
12. Risch N, Herrell R, Lehner T, et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA. 2009;301:2462-2471.
13. Heils A, Teufel A, Petri S, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996;66:2621-2624.
14. Heils A, Teufel A, Petri S, et al. Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J Neural Transm Gen Sect. 1995;102:247-254.
15. Gonzalez-Angulo AM, Hennessy BT, Mills GB. Future of personalized medicine in oncology: a systems biology approach. J Clin Oncol. 2010;28: 2777-2783.
16. Roerig JL. Diagnosis and management of generalized anxiety disorder. J Am Pharm Assoc. 1999;39:811-821.
17. Heinz A, Braus DF, Smolka MN, et al. Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci. 2005;8:20-21.
18. Surguladze SA, Elkin A, Ecker C, et al. Genetic variation in the serotonin transporter modulates neural system-wide response to fearful faces. Genes Brain Behav. 2008;7:543-551.
19. Munafò MR, Brown SM, Hariri AR. Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biol Psychiatry. 2008;63:852-857.
20. Munafò MR, Freimer NB, Ng W, et al. 5-HTTLPR genotype and anxiety-related personality traits: a meta-analysis and new data. Am J Med Genet B Neuropsychiatr Genet. 2009;150:271-281.
21. Willis-Owen SA, Turri MG, Munafò MR, et al. The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association. Biol Psychiatry. 2005;58:451-456.
22. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Fourth Text Revision. Washington, DC: American Psychiatric Association; 2000.
23. Kendler KS, Gatz M, Gardner CO, Pedersen NL. A Swedish national twin study of lifetime major depression. Am J Psychiatry. 2006;163:109-114.
24. Vergne DE, Nemeroff CB. The interaction of serotonin transporter gene polymorphisms and early adverse life events on vulnerability for major depression. Curr Psychiatry Rep. 2006;8:452-457.
25. Munafò MR, Durrant C, Lewis G, Flint J. Gene x environment interactions at the serotonin transporter locus. Biol Psychiatry. 2009;65:211-219.
26. Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatry. 2011;68:444-454.
27. Coplan JD, Abdallah CG, Kaufman J, et al. Early-life stress, corticotropin- releasing factor, and serotonin transporter gene: A pilot study. Psychoneuroendocrinology. 2011;36:289-293.
28. Ressler KJ, Bradley B, Mercer KB, et al. Polymorphisms in CRHR1 and the serotonin transporter loci: gene × gene × environment interactions on depressive symptoms. Am J Med Genet B Neuropsychiatr Genet. 2010;153: 812-824.
29. Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ. Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry. 2002;7:1115-1119.
30. Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry. 1998;3:508-511.
31. Yoshida K, Ito K, Sato K, et al. Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:383-386.
32. Kim DK, Lim SW, Lee S, et al. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport. 2000;11:215-219.
33. Zanardi R, Benedetti F, Di Bella D, Catalano M, Smeraldi E. Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol. 2000;20:105-107.
34. Pollock BG, Ferrell RE, Mulsant BH, et al. Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology. 2000;23:587-590.
35. Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB. The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology. 2004;174: 525-529.
36. Lewis G, Mulligan J, Wiles N et al. Polymorphism of the 5-HT transporter and response to antidepressants: randomised controlled trial. Br J Psychiatry. 2011;198:464-471.
37. Huezo-Diaz P, Uher R, Smith R, et al. Moderation of antidepressant response by the serotonin transporter gene. Br J Psychiatry. 2009;195:30-38.
38. Keers R, Uher R, Huezo-Diaz R, et al. Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project. Pharmacogenomics. 2011;11:138-145.
39. Serretti A, Kato M, De Ronchi D, Kinoshita T. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry. 2007;12:247-257.
40. Taylor MJ, Sen S, Bhagwagar Z. Antidepressant response and the serotonin transporter gene-linked polymorphic region. Biol Psychiatry. 2010;68:536-543.
41. White KJ, Walline CC, Barker EL. Serotonin transporters: implications for antidepressant drug development. AAPS J. 2005;7:421-433.
42. Malone KM, Haas GL, Sweeney JA, Mann JJ. Major depression and the risk of attempted suicide. J Affect Disord. 1995;34:173-185.
43. Du L, Faludi G, Palkovits M, et al. Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims. Biol Psychiatry. 1999;46:196-201.
44. Du L, Faludi G, Palkovits M, Bakish D, Hrdina PD. Serotonergic genes and suicidality. Crisis. 2001;22:54-60.
45. Russ MJ, Lachman HM, Kashdan T, Saito T, Bajmakovic-Kacila S. Analysis of catechol-O-methyltransferase and 5-hydroxytryptamine transporter polymorphisms in patients at risk for suicide. Psychiatry Res. 2000;93:73-78.
46. Anguelova M, Benkelfat C, Turecki G. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior. Mol Psychiatry. 2003;8:646-653.
47. Craddock N, Jones I. Genetics of bipolar disorder. J Med Genet. 1999;36:585-594.
48. Cho HJ, Meira-Lima I, Cordeiro Q, et al. Population-based and family- based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis. Mol Psychiatry. 2005;10:771-781.
49. 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.
50. Rotondo A, Mazzanti C, Dell'Osso L, et al. Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. Am J Psychiatry. 2002;159:23-29.
51. Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord. 2003;5:407-420.
52. Mundo E, Walker M, Cate T, Macciardi F, Kennedy JL. The role of serotonin transporter protein gene in antidepressant-induced mania in bipolar disorder: preliminary findings. Arch Gen Psychiatry. 2001;58:539-544.
53. Rousseva A, Henry C, van den Bulke D, et al. Antidepressant-induced mania, rapid cycling and the serotonin transporter gene polymorphism. Pharmacogenomics J. 2003;3:101-104.
54. Serretti A, Artioli P, Zanardi R, et al. Genetic features of antidepressant induced mania and hypo-mania in bipolar disorder. Psychopharmacology. 2004;174:504-511.
55. Lee HJ, Lee MS, Kang RH, et al. Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder. Depress Anxiety. 2005;21:135-139.
56. Wang Z, Baker DG, Harrer J, Hamner M, Price M, Amstadter A. The relationship between combat-related posttraumatic stress disorder and the 5-HTTLPR/rs25531 polymorphism. Depress Anxiety. 2011;28:1067-1073.
57. Xie P, Kranzler HR, Poling J, et al. Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on posttraumatic stress disorder diagnosis in 2 independent populations. Arch Gen Psychiatry. 2009;66:1201-1209.
58. Aas M, Djurovic S, Athanasiu L, et al. Serotonin transporter gene polymorphism, childhood trauma, and cognition in patients with psychotic disorders. Schizophr Bull. September 9, 2011. [Epub ahead of print.]
59. Mushtaq D, Ali A, Margoob MA, Murtaza I, Andrade C. Association between serotonin transporter gene promoter-region polymorphism and 4- and 12-week treatment response to sertraline in posttraumatic stress disorder. J Affect Disord. 2011. [Epub ahead of print.]
60. Grabe HJ, Spitzer C, Schwahn C, et al. Serotonin transporter gene (SLC6A4) promoter polymorphisms and the susceptibility to posttraumatic stress disorder in the general population. Am J Psychiatry. 2009;166:926-933.
61. Kilpatrick DG, Koenen KC, Ruggiero KJ, et al. The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. Am J Psychiatry. 2007;164:1693-1699.
62. Enoch MA, Goldman D. Genetics of alcoholism and substance abuse. Psychiatr Clin North Am. 1999;2:289-299.
63. Prescott CA, Kendler KS. Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry. 1999;156:34-40.
64. Kweon YS, Lee HK, Lee CT, Lee KU, Pae CU. Association of the serotonin transporter gene polymorphism with Korean male alcoholics. J Psychiatr Res. 2005;39:371-376.
65. Johnson BA, Javors MA, Roache JD, et al. Can serotonin transporter genotype predict serotonergic function, chronicity, and severity of drinking? Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:209-216.
66. McHugh RK, Hofmann SG, Asnaani A, Sawyer AT, Otto MW. The serotonin transporter gene and risk for alcohol dependence: a metaanalytic review. Drug Alcohol Depend. 2010;108:1-6.
67. Ait-Daoud N, Roache JD, Dawes MA, et al. Can serotonin transporter genotype predict craving in alcoholism? Alcohol Clin Exp Res. 2009;33:1329-1335.
68. Tartter MA, Ray LA. The serotonin transporter polymorphism (5-HTTLPR) and alcohol problems in heavy drinkers: moderation by depressive symptoms. Front Psychiatry. 2011;2:49.
69. Feinn R, Nellissery M, Kranzler HR, Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence. Am J Med Genet B Neuropsychiatr Genet. 2005;133:79-84.
70. Enoch MA, Gorodetsky E, Hodgkinson C, Roy A, Goldman D. Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence. Mol Psychiatry. 2011;16:1139-1146.
71. Herman AI, Kaiss KM, Ma R, et al. Serotonin transporter promoter polymorphism and monoamine oxidase type A VNTR allelic variants together influence alcohol binge drinking in young women. Am J Med Genet B Neuropsychiatr Genet. 2005;133:74-78.
72. Kenna GA, Zywiak WH, McGeary JE, et al. A within-group design of nontreatment seeking 5-HTTLPR genotyped alcohol-dependent subjects receiving ondansetron and sertraline. Alcohol Clin Exp Res. 2009;33:315-323.
73. Kenna GA, McGeary JE, Swift RM. Pharmacotherapy, pharmacogenomics, and the future of alcohol dependence treatment, Part 2. Am J Health Syst Pharm. 2004;61:2380-2388.
74. Kenna GA. Pharmacotherapy of alcohol dependence: Targeting a complex disorder. Drug Disc Today: Therapeutic Strategies. 2005;2:71-78.
75. Kranzler HR, Burleson JA, Korner P, et al. Placebo-controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. Am J Psychiatry. 1995;152:391-397.
76. Pettinati HM, Volpicelli JR, Kranzler HR, Luck G, Rukstalis MR, Cnaan A. Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype. Alcohol Clin Exp Res. 2000;24:1041-1049.
77. Kranzler HR, Armeli S, Tennen H, et al. Double-blind, randomized trial of sertraline for alcohol dependence: moderation by age of onset and 5-HTTLPR genotype. J Clin Psychopharmacol. 2011;31:22-30.
78. Johnson BA. Serotonergic agents and alcoholism treatment: rebirth of the subtype concept - an hypothesis. Alcohol Clin Exp Res. 2000;24:1597-1601.
79. Hammoumi S, Payen A, Favre JD, et al. Does the short variant of the serotonin transporter linked polymorphic region constitute a marker of alcohol dependence? Alcohol. 1999;17:107-112.
80. Bleich S, Bönsch D, Rauh J, et al. Association of the long allele of the 5-HTTLPR polymorphism with compulsive craving in alcohol dependence. Alcohol Alcohol. 2007;42:509-512.
81. Johnson BA, Roache JD, Javors MA, et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: A randomized controlled trial. JAMA. 2000;284:963-971.
82. Johnson BA, Ait-Daoud N, Seneviratne C, et al. Pharmacogenetic approach at the serotonin transporter gene as a method to reduce severe alcohol consumption. Am J Psychiatry. 2011;168:265-275.
83. Kendler KS, Neale MC, Sullivan P, Corey LA, Gardner CO, Prescott CA. A population-based twin study in women of smoking initiation and nicotine dependence. Psychol Med. 1999;29:299-308.
84. Heath AC, Madden PA, Slutske WS, Martin NG. Personality and the inheritance of smoking behavior: a genetic perspective. Behav Genet. 1995;25:103-117.
85. Arinami T, Ishiguro H, Onaivi ES. Polymorphisms in genes involved in neurotransmission in relation to smoking. Eur J Pharmacol. 2000;410:215-226.
86. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2007;(1):CD000031.
87. Kremer I, Bachner-Melman R, Reshef A, et al. Association of the serotonin transporter gene with smoking behavior. Am J Psychiatry. 2005;162:924-930.
88. Munafò MR, Johnstone EC, Wileyto EP, Shields PG, Elliot KM, Lerman C. Lack of association of 5-HTTLPR genotype with smoking cessation in a nicotine replacement therapy randomized trial. Cancer Epidemiol Biomarkers Prev. 2006;15:398-400.
89. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet. 2005;366:237-248.
90. Thakur GA, Grizenko N, Sengupta SM, Schmitz N, Joober R. The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD. BMC Psychiatry. 2010;10:50.
91. Seeger G, Schloss P, Schmidt MH. Functional polymorphism within the promotor of the serotonin transporter gene is associated with severe hyperkinetic disorders. Mol Psychiatry. 2001;6:235-238.
92. Faraone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attentiondeficit/ hyperactivity disorder. Biol Psychiatry. 2005;57:1313-1323.
93. Retz W, Thome J, Blocher D, Baader M, Rösler M. Association of attention deficit hyperactivity disorder-related psychopathology and personality traits with the serotonin transporter promoter region polymorphism. Neurosci Lett. 2002;319:133-136.
94. Zoroǧlu SS, Erdal ME, Alaşehirli B, et al. Significance of serotonin transporter gene 5-HTTLPR and variable number of tandem repeat polymorphism in attention deficit hyperactivity disorder. Neuropsychobiol. 2002;45:176-181.