Hostname: page-component-f554764f5-246sw Total loading time: 0 Render date: 2025-04-18T07:45:14.892Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  12 April 2010

H. Clarke ,
J. Flint ,
A. S. Attwood  and
M. R. Munafò
H. Clarke
Affiliation:
Department of Experimental Psychology, University of Bristol, UK
J. Flint
Affiliation:
Wellcome Trust Centre for Human Genetics, University of Oxford, UK
A. S. Attwood
Affiliation:
Department of Experimental Psychology, University of Bristol, UK
M. R. Munafò*
Affiliation:
Department of Experimental Psychology, University of Bristol, UK
*
*Address for correspondence: M. R. Munafò, Ph.D., Department of Experimental Psychology, University of Bristol, 12a Priory Road, Bristol BS8 1TU, UK. (Email: marcus.munafo@bristol.ac.uk)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

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

Method

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.

Results

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.

Conclusions

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.

Keywords

Depressiongenotype5-HTTLPRmeta-analysisunipolar
Type
Review Article
Information
Psychological Medicine , Volume 40 , Issue 11 , November 2010 , pp. 1767 - 1778
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

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, 143–146.CrossRefGoogle ScholarPubMed
Belmaker, RH, Agam, G (2008). Major depressive disorder. New England Journal of Medicine 358, 55–68.CrossRefGoogle ScholarPubMed
Borenstein, M, Borenstein, H (1999). Comprehensive Meta-Analysis. Biostat Inc.: Englewood, NJ.Google Scholar
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, 83–89.Google ScholarPubMed
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, 386–389.CrossRefGoogle ScholarPubMed
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, 912–917.CrossRefGoogle Scholar
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, 561–565.CrossRefGoogle ScholarPubMed
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, 830–833.CrossRefGoogle Scholar
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, 453–460.Google ScholarPubMed
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, 451–453.CrossRefGoogle ScholarPubMed
Egger, M, Davey Smith, G, Schneider, M, Minder, C (1997). Bias in meta-analysis detected by a simple, graphical test. British Medical Journal 315, 629–634.CrossRefGoogle ScholarPubMed
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, 175–191.CrossRefGoogle ScholarPubMed
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, 389–392.CrossRefGoogle ScholarPubMed
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, 58–63.3.0.CO;2-V>CrossRefGoogle ScholarPubMed
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, 101–111.CrossRefGoogle ScholarPubMed
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, 1373–1378.CrossRefGoogle ScholarPubMed
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, 129–132.CrossRefGoogle ScholarPubMed
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, 2621–2624.CrossRefGoogle ScholarPubMed
Higgins, JP, Thompson, SG, Deeks, JJ, Altman, DG (2003). Measuring inconsistency in meta-analyses. British Medical Journal 327, 557–560.CrossRefGoogle ScholarPubMed
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, 247–251.CrossRefGoogle ScholarPubMed
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, 1–3.3.0.CO;2-2>CrossRefGoogle Scholar
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, 815–826.CrossRefGoogle ScholarPubMed
Ioannidis, JP, Ntzani, EE, Trikalinos, TA, Contopoulos-Ioannidis, DG (2001). Replication validity of genetic association studies. Nature Genetics 29, 306–309.CrossRefGoogle ScholarPubMed
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, 529–535.CrossRefGoogle Scholar
Kim, DK, Lim, SW, Lee, S, Sohn, SE, Kim, S, Hahn, CG, Carroll, BJ (2000). Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 11, 215–219.CrossRefGoogle ScholarPubMed
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, 423–428.CrossRefGoogle ScholarPubMed
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, 457–462.CrossRefGoogle ScholarPubMed
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, 737–747.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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, 207–213.CrossRefGoogle ScholarPubMed
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, 772–785.CrossRefGoogle ScholarPubMed
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, 421–422.CrossRefGoogle ScholarPubMed
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, 229–233.CrossRefGoogle ScholarPubMed
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, 377–382.CrossRefGoogle Scholar
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, 294–301.CrossRefGoogle ScholarPubMed
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, 119–122.CrossRefGoogle ScholarPubMed
Munafò, MR, Attwood, AS, Flint, J (2008). Bias in genetic association studies: effects of research location and resources. Psychological Medicine 38, 1213–1214.CrossRefGoogle ScholarPubMed
Munafò, MR, Clark, TG, Roberts, KH, Johnstone, EC (2006). Neuroticism mediates the association of the serotonin transporter gene with lifetime major depression. Neuropsychobiology 53, 1–8.CrossRefGoogle ScholarPubMed
Munafò, MR, Durrant, C, Lewis, G, Flint, J (2009 a). Gene×environment interactions at the serotonin transporter locus. Biological Psychiatry 65, 211–219.CrossRefGoogle Scholar
Munafò, MR, Flint, J (2004). Meta-analysis of genetic association studies. Trends in Genetics 20, 439–444.CrossRefGoogle ScholarPubMed
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, 271–281.CrossRefGoogle ScholarPubMed
Munafò, MR, Stothart, G, Flint, J (2009 c). Bias in genetic association studies and impact factor. Molecular Psychiatry 14, 119–120.CrossRefGoogle ScholarPubMed
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, 32–38.CrossRefGoogle ScholarPubMed
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, 550–554.CrossRefGoogle ScholarPubMed
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, 438–441.CrossRefGoogle ScholarPubMed
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, 1379–1384.CrossRefGoogle ScholarPubMed
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, 543–549.CrossRefGoogle ScholarPubMed
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, 886–887.CrossRefGoogle Scholar
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, 398–402.CrossRefGoogle ScholarPubMed
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, 2462–2471.CrossRefGoogle ScholarPubMed
Serretti, A, Lilli, R, Lorenzi, C, Lattuada, E, Cusin, C, Smeraldi, E (2002). Serotonin transporter gene (5-HTTLPR) and major psychoses. Molecular Psychiatry 7, 95–99.CrossRefGoogle ScholarPubMed
Shcherbatykh, TV, Golimbet, VE, Orlova, VA, Kaleda, VG (2000). Polymorphism in the human serotonin transporter gene in endogenous psychoses [in Russian]. Genetika 36, 1712–1715.Google ScholarPubMed
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, 139–144.CrossRefGoogle ScholarPubMed
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, 185–191.CrossRefGoogle ScholarPubMed
Sterne, JA, Davey Smith, G (2001). Sifting the evidence – what's wrong with significance tests? British Medical Journal 322, 226–231.CrossRefGoogle ScholarPubMed
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, 224–229.CrossRefGoogle ScholarPubMed
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, 537–544.CrossRefGoogle ScholarPubMed
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, 210–215.CrossRefGoogle ScholarPubMed
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, 451–456.CrossRefGoogle ScholarPubMed
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, 468–476.CrossRefGoogle Scholar
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, 301–307.CrossRefGoogle Scholar
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, 1588–1593.CrossRefGoogle ScholarPubMed
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, 224–231.CrossRefGoogle ScholarPubMed