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Association of the 5-HTTLPR genotype and unipolar depression: a meta-analysis

  • H. Clarke (a1), J. Flint (a2), A. S. Attwood (a1) and M. R. Munafò (a1)

We sought to ascertain the strength of evidence for association between the 5-HTTLPR polymorphism and unipolar depression.


We applied meta-analytic techniques to data from relevant published studies, and obtained an estimate of the likely magnitude of effect of any association. We also tested for possible publication bias, and explored the impact of various study design characteristics on the magnitude of the observed effect size.


Meta-analysis indicated evidence of a small but statistically significant association between the 5-HTTLPR polymorphism and unipolar depression [odds ratio (OR) 1.08, 95% confidence interval (CI) 1.03–1.12]. This remained significant when data from samples of European and East Asian ancestry were analyzed separately. In all cases there was evidence of significant between-study heterogeneity, although the observed associations were robust to the application of a random-effects framework.


Our results support the presence of a small effect of a polymorphism in the serotonin transporter promoter on susceptibility to depression. However, we caution that it is possible that the effect has an artifactual basis, rather than a biological origin.

Corresponding author
*Address for correspondence: M. R. Munafò, Ph.D., Department of Experimental Psychology, University of Bristol, 12a Priory Road, Bristol BS8 1TU, UK. (Email:
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Bellivier, F, Henry, C, Szoke, A, Schurhoff, F, Nosten-Bertrand, M, Feingold, J, Launay, JM, Leboyer, M, Laplanche, JL (1998). Serotonin transporter gene polymorphisms in patients with unipolar or bipolar depression. Neuroscience Letters 255, 143146.
Belmaker, RH, Agam, G (2008). Major depressive disorder. New England Journal of Medicine 358, 5568.
Borenstein, M, Borenstein, H (1999). Comprehensive Meta-Analysis. Biostat Inc.: Englewood, NJ.
Bozina, N, Mihaljevic-Peles, A, Sagud, M, Jakovljevic, M, Sertic, J (2006). Serotonin transporter polymorphism in Croatian patients with major depressive disorder. Psychiatricka Danubia 18, 8389.
Caspi, A, Sugden, K, Moffitt, TE, Taylor, A, Craig, IW, Harrington, H, McClay, J, Mill, J, Martin, J, Braithwaite, A, Poulton, R (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386389.
Cervilla, JA, Rivera, M, Molina, E, Torres-Gonzalez, F, Bellon, JA, Moreno, B, de Dios Luna, J, Lorente, JA, de Diego-Otero, Y, King, M, Nazareth, I, Gutierrez, B (2006). The 5-HTTLPR s/s genotype at the serotonin transporter gene (SLC6A4) increases the risk for depression in a large cohort of primary care attendees: the PREDICT-gene study. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 141B, 912917.
Chipman, P, Jorm, AF, Prior, M, Sanson, A, Smart, D, Tan, X, Easteal, S (2007). No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 144B, 561565.
Chorbov, VM, Lobos, EA, Todorov, AA, Heath, AC, Botteron, KN, Todd, RD (2007). Relationship of 5-HTTLPR genotypes and depression risk in the presence of trauma in a female twin sample. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 144B, 830833.
Collier, DA, Stober, G, Li, T, Heils, A, Catalano, M, Di Bella, D, Arranz, MJ, Murray, RM, Vallada, HP, Bengel, D, Muller, CR, Roberts, GW, Smeraldi, E, Kirov, G, Sham, P, Lesch, KP (1996). A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Molecular Psychiatry 1, 453460.
Dorado, P, Penas-Lledo, EM, Gonzalez, AP, Caceres, MC, Cobaleda, J, Llerena, A (2007). Increased risk for major depression associated with the short allele of the serotonin transporter promoter region (5-HTTLPR-S) and the CYP2C9*3 allele. Fundamentals of Clinical Pharmacology 21, 451453.
Egger, M, Davey Smith, G, Schneider, M, Minder, C (1997). Bias in meta-analysis detected by a simple, graphical test. British Medical Journal 315, 629634.
Faul, F, Erdfelder, E, Lang, A-G, Buchner, A (2007). G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavioral Research Methods 39, 175191.
Frisch, A, Postilnick, D, Rockah, R, Michaelovsky, E, Postilnick, S, Birman, E, Laor, N, Rauchverger, B, Kreinin, A, Poyurovsky, M, Schneidman, M, Modai, I, Weizman, R (1999). Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways. Molecular Psychiatry 4, 389392.
Furlong, RA, Ho, L, Walsh, C, Rubinsztein, JS, Jain, S, Paykel, ES, Easton, DF, Rubinsztein, DC (1998). Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders. American Journal of Medical Genetics 81, 5863.
Gillespie, NA, Whitfield, JB, Williams, B, Heath, AC, Martin, NG (2005). The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression. Psychological Medicine 35, 101111.
Grunblatt, E, Loffler, C, Zehetmayer, S, Jungwirth, S, Tragl, KH, Riederer, P, Fischer, P (2006). Association study of the 5-HTTLPR polymorphism and depression in 75-year-old nondemented subjects from the Vienna Transdanube Aging (VITA) study. Journal of Clinical Psychiatry 67, 13731378.
Hauser, J, Leszczynska, A, Samochowiec, J, Czerski, PM, Ostapowicz, A, Chlopocka, M, Horodnicki, J, Rybakowski, JK (2003). Association analysis of the insertion/deletion polymorphism in serotonin transporter gene in patients with affective disorder. European Psychiatry 18, 129132.
Heils, A, Teufel, A, Petri, S, Stober, G, Riederer, P, Bengel, D, Lesch, KP (1996). Allelic variation of human serotonin transporter gene expression. Journal of Neurochemistry 66, 26212624.
Higgins, JP, Thompson, SG, Deeks, JJ, Altman, DG (2003). Measuring inconsistency in meta-analyses. British Medical Journal 327, 557560.
Hoefgen, B, Schulze, TG, Ohlraun, S, von Widdern, O, Hofels, S, Gross, M, Heidmann, V, Kovalenko, S, Eckermann, A, Kolsch, H, Metten, M, Zobel, A, Becker, T, Nothen, MM, Propping, P, Heun, R, Maier, W, Rietschel, M (2005). The power of sample size and homogenous sampling: association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder. Biological Psychiatry 57, 247251.
Hoehe, MR, Wendel, B, Grunewald, I, Chiaroni, P, Levy, N, Morris-Rosendahl, D, Macher, JP, Sander, T, Crocq, MA (1998). Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorders. American Journal of Medical Genetics 81, 13.
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. American Journal of Human Genetics 78, 815826.
Ioannidis, JP, Ntzani, EE, Trikalinos, TA, Contopoulos-Ioannidis, DG (2001). Replication validity of genetic association studies. Nature Genetics 29, 306309.
Kendler, KS, Kuhn, JW, Vittum, J, Prescott, CA, Riley, B (2005). The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Archives of General Psychiatry 62, 529535.
Kim, DK, Lim, SW, Lee, S, Sohn, SE, Kim, S, Hahn, CG, Carroll, BJ (2000). Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 11, 215219.
Kim, JM, Stewart, R, Kim, SW, Yang, SJ, Shin, IS, Kim, YH, Yoon, JS (2007). Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders. Biological Psychiatry 62, 423428.
Kunugi, H, Hattori, M, Kato, T, Tatsumi, M, Sakai, T, Sasaki, T, Hirose, T, Nanko, S (1997). Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Molecular Psychiatry 2, 457462.
Laucht, M, Treutlein, J, Blomeyer, D, Buchmann, AF, Schmid, B, Becker, K, Zimmermann, US, Schmidt, MH, Esser, G, Rietschel, M, Banaschewski, T (2009). Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults. International Journal of Neuropsychopharmacology 12, 737747.
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, 15271531.
Little, KY, McLaughlin, DP, Zhang, L, Livermore, CS, Dalack, GW, McFinton, PR, DelProposto, ZS, Hill, E, Cassin, BJ, Watson, SJ, Cook, EH (1998). Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. American Journal of Psychiatry 155, 207213.
Lopez-Leon, S, Janssens, AC, Gonzalez-Zuloeta Ladd, AM, Del-Favero, J, Claes, SJ, Oostra, BA, van Duijn, CM (2008). Meta-analyses of genetic studies on major depressive disorder. Molecular Psychiatry 13, 772785.
Martin, J, Cleak, J, Willis-Owen, SA, Flint, J, Shifman, S (2007). Mapping regulatory variants for the serotonin transporter gene based on allelic expression imbalance. Molecular Psychiatry 12, 421422.
Mellerup, E, Bennike, B, Bolwig, T, Dam, H, Hasholt, L, Jorgensen, MB, Plenge, P, Sorensen, SA (2001). Platelet serotonin transporters and the transporter gene in control subjects, unipolar patients and bipolar patients. Acta Psychiatrica Scandinavica 103, 229233.
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 (2004). Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study. European Journal of Human Genetics 12, 377382.
Middeldorp, CM, de Geus, EJ, Beem, AL, Lakenberg, N, Hottenga, JJ, Slagboom, PE, Boomsma, DI (2007). Family based association analyses between the serotonin transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression. Behavior Genetics 37, 294301.
Minov, C, Baghai, TC, Schule, C, Zwanzger, P, Schwarz, MJ, Zill, P, Rupprecht, R, Bondy, B (2001). Serotonin-2A-receptor and -transporter polymorphisms: lack of association in patients with major depression. Neuroscience Letters 303, 119122.
Munafò, MR, Attwood, AS, Flint, J (2008). Bias in genetic association studies: effects of research location and resources. Psychological Medicine 38, 12131214.
Munafò, MR, Clark, TG, Roberts, KH, Johnstone, EC (2006). Neuroticism mediates the association of the serotonin transporter gene with lifetime major depression. Neuropsychobiology 53, 18.
Munafò, MR, Durrant, C, Lewis, G, Flint, J (2009 a). Gene×environment interactions at the serotonin transporter locus. Biological Psychiatry 65, 211219.
Munafò, MR, Flint, J (2004). Meta-analysis of genetic association studies. Trends in Genetics 20, 439444.
Munafò, MR, Freimer, NB, Ng, W, Ophoff, R, Veijola, J, Miettunen, J, Jarvelin, MR, Taanila, A, Flint, J (2009 b). 5-HTTLPR genotype and anxiety-related personality traits: a meta-analysis and new data. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 150B, 271281.
Munafò, MR, Stothart, G, Flint, J (2009 c). Bias in genetic association studies and impact factor. Molecular Psychiatry 14, 119120.
Nakamura, M, Ueno, S, Sano, A, Tanabe, H (2000). The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Molecular Psychiatry 5, 3238.
Ohara, K, Nagai, M, Tsukamoto, T, Tani, K, Suzuki, Y, Ohara, K (1998). Functional polymorphism in the serotonin transporter promoter at the SLC6A4 locus and mood disorders. Biological Psychiatry 44, 550554.
Oliveira, JR, Gallindo, RM, Maia, LG, Brito-Marques, PR, Otto, PA, Passos-Bueno, MR, Jr.Morais, MA, Zatz, M (1998). The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer's disease. Molecular Psychiatry 3, 438441.
Otte, C, McCaffery, J, Ali, S, Whooley, MA (2007). Association of a serotonin transporter polymorphism (5-HTTLPR) with depression, perceived stress, and norepinephrine in patients with coronary disease: the Heart and Soul Study. American Journal of Psychiatry 164, 13791384.
Philibert, RA, Sandhu, H, Hollenbeck, N, Gunter, T, Adams, W, Madan, A (2008). The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 147B, 543549.
Power, T, Stewart, R, Ancelin, ML, Jaussent, I, Malafosse, A, Ritchie, K (2010). 5-HTTLPR genotype, stressful life events and late-life depression: no evidence of interaction in a French population. Neurobiology of Aging 31, 886887.
Rees, M, Norton, N, Jones, I, McCandless, F, Scourfield, J, Holmans, P, Moorhead, S, Feldman, E, Sadler, S, Cole, T, Redman, K, Farmer, A, McGuffin, P, Owen, MJ, Craddock, N (1997). Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT). Molecular Psychiatry 2, 398402.
Risch, N, Herrell, R, Lehner, T, Liang, KY, Eaves, L, Hoh, J, Griem, A, Kovacs, M, Ott, J, Merikangas, KR (2009). Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. Journal of the American Medical Association 301, 24622471.
Serretti, A, Lilli, R, Lorenzi, C, Lattuada, E, Cusin, C, Smeraldi, E (2002). Serotonin transporter gene (5-HTTLPR) and major psychoses. Molecular Psychiatry 7, 9599.
Shcherbatykh, TV, Golimbet, VE, Orlova, VA, Kaleda, VG (2000). Polymorphism in the human serotonin transporter gene in endogenous psychoses [in Russian]. Genetika 36, 17121715.
Shi, M, Hu, J, Dong, X, Gao, Y, An, G, Liu, W, Chen, L, Sun, X (2008). Association of unipolar depression with gene polymorphisms in the serotonergic pathways in Han Chinese. Acta Neuropsychiatrica 20, 139144.
Steffens, DC, Svenson, I, Marchuk, DA, Levy, RM, Hays, JC, Flint, EP, Krishnan, KR, Siegler, IC (2002). Allelic differences in the serotonin transporter-linked polymorphic region in geriatric depression. American Journal of Geriatric Psychiatry 10, 185191.
Sterne, JA, Davey Smith, G (2001). Sifting the evidence – what's wrong with significance tests? British Medical Journal 322, 226231.
Surtees, PG, Wainwright, NW, Willis-Owen, SA, Luben, R, Day, NE, Flint, J (2006). Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder. Biological Psychiatry 59, 224229.
Taylor, WD, Steffens, DC, Payne, ME, MacFall, JR, Marchuk, DA, Svenson, IK, Krishnan, KR (2005). Influence of serotonin transporter promoter region polymorphisms on hippocampal volumes in late-life depression. Archives of General Psychiatry 62, 537544.
Wilhelm, K, Mitchell, PB, Niven, H, Finch, A, Wedgwood, L, Scimone, A, Blair, IP, Parker, G, Schofield, PR (2006). Life events, first depression onset and the serotonin transporter gene. British Journal of Psychiatry 188, 210215.
Willis-Owen, SA, Turri, MG, Munafò, MR, Surtees, PG, Wainwright, NW, Brixey, RD, Flint, J (2005). The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association. Biological Psychiatry 58, 451456.
Wray, NR, James, MR, Gordon, SD, Dumenil, T, Ryan, L, Coventry, WL, Statham, DJ, Pergadia, ML, Madden, PA, Heath, AC, Montgomery, GW, Martin, NG (2009). Accurate, large-scale genotyping of 5HTTLPR and flanking single nucleotide polymorphisms in an association study of depression, anxiety, and personality measures. Biological Psychiatry 66, 468476.
Zaboli, G, Jonsson, EG, Gizatullin, R, De Franciscis, A, Asberg, M, Leopardi, R (2008). Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia but not with major depression. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 147, 301307.
Zalsman, G, Huang, YY, Oquendo, MA, Burke, AK, Hu, XZ, Brent, DA, Ellis, SP, Goldman, D, Mann, JJ (2006). Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression. American Journal of Psychiatry 163, 15881593.
Zhang, K, Xu, Q, Xu, Y, Yang, H, Luo, J, Sun, Y, Sun, N, Wang, S, Shen, Y (2009). The combined effects of the 5-HTTLPR and 5-HTR1A genes modulates the relationship between negative life events and major depressive disorder in a Chinese population. Journal of Affective Disorders 114, 224231.
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