Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

A Meta-analysis of the Association Between SLC6A3 Gene Polymorphisms and Schizophrenia

  • 91 Accesses


The dopamine transporter is coded by the SLC6A3 gene and plays an important role in regulation of the neurotransmitter dopamine. To detect the association between the SLC6A3 gene and the risk of schizophrenia, 31 case-control articles were included in this meta-analysis. There were 23 studies with 40 bp VNTR (3246 cases and 3639 controls), 4 studies with rs40184 (2020 cases and 1674 controls), rs6347 (1317 cases and 1917 controls), rs403636 (2045 cases and 1704 controls), and rs2975226 (849 cases and 904 controls); and 3 studies with rs12516948 (1920 cases and 1569 controls), rs27072 (984 cases and 1015 controls), rs6869645 (1142 cases and 1082 controls), rs37022 (1168 cases and 1091 controls), rs464049 (1169cases and 1096 controls), rs2652511 (707 cases and 714 controls), and rs3756450 (1176 cases and 1096 controls). Pooled, subgroup, and sensitivity analyses were performed, and the results were visualized by forest and funnel plots. In the dominant genetic model, the genotype AA+AT of rs2975226 in the Indian population (Pz = 0, odds ratio [OR] = 3.245, 95% confidence interval [CI] = 1.806–5.831), TT of rs464049 (Pz = 0.002, OR = 1.389, 95% CI = 1.129–1.708), and TT of rs3756450 (Pz = 0.014, OR = 1.251, 95% CI = 1.047–1.495) might be risk factors for schizophrenia. Additionally, no other single nucleotide polymorphisms were observed. These results indicate that more functional studies are warranted.

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

Fig. 1


  1. Alvarez S, Mas S, Gasso P, Bernardo M, Parellada E, Lafuente A (2010) Lack of association between schizophrenia and polymorphisms in dopamine metabolism and transport genes. Fundam Clin Pharmacol 24(6):741–747.

  2. Arj-Ong S, Thakkinstian A, McEvoy M, Attia J (2010) A systematic review and meta-analysis of tumor necrosis factor alpha-308 polymorphism and Kawasaki disease. Pediatr Int 52(4):527–532.

  3. Bahi A, Dreyer JL (2019) Dopamine transporter (DAT) knockdown in the nucleus accumbens improves anxiety- and depression-related behaviors in adult mice. Behav Brain Res 359:104–115.

  4. Bamne MN, Talkowski ME, Chowdari KV, Nimgaonkar VL (2010) Functional analysis of upstream common polymorphisms of the dopamine transporter gene. Schizophr Bull 36(5):977–982.

  5. Barendregt JJ, Doi SA, Lee YY, Norman RE, Vos T (2013) Meta-analysis of prevalence. J Epidemiol Community Health 67(11):974–978.

  6. Bodeau-Pean S, Laurent C, Campion D, Jay M, Thibaut F, Dollfus S et al (1995) No evidence for linkage or association between the dopamine transporter gene and schizophrenia in a French population. Psychiatry Res 59(1–2):1–6

  7. Cardno AG, Gottesman II (2000) Twin studies of schizophrenia: from bow-and-arrow concordances to star wars mx and functional genomics. Am J Med Genet 97(1):12–17

  8. Carvelli L, Blakely RD, DeFelice LJ (2008) Dopamine transporter/syntaxin 1A interactions regulate transporter channel activity and dopaminergic synaptic transmission. Proc Natl Acad Sci U S A 105(37):14192–14197.

  9. Cordeiro Q, Siqueira-Roberto J, Vallada H (2010) Association between the SLC6A3 A1343G polymorphism and schizophrenia. Arq Neuropsiquiatr 68(5):716–719

  10. Cordeiro Q, Talkowski M, Wood J, Ikenaga E, Vallada H (2004) Lack of association between VNTR polymorphism of dopamine transporter gene (SLC6A3) and schizophrenia in a Brazilian sample. Arq Neuropsiquiatr 62(4):973–976

  11. Costa A, Riedel M, Muller U, Moller HJ, Ettinger U (2011) Relationship between SLC6A3 genotype and striatal dopamine transporter availability: a meta-analysis of human single photon emission computed tomography studies. Synapse 65(10):998–1005.

  12. Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192(4238):481–483

  13. Daniels J, Williams J, Asherson P, McGuffin P, Owen M (1995) No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT). Am J Med Genet 60(1):85–87.

  14. Fan Miao, W. B. (2014). The forensic significance and the correlaction to paranoid schizophrenia of four SNP polymorphism in DTA gene

  15. Frey S (2014) The economic burden of schizophrenia in Germany: a population-based retrospective cohort study using genetic matching. Eur Psychiatry 29(8):479–489.

  16. Fujiwara Y, Yamaguchi K, Tanaka Y, Tomita H, Shiro Y, Kashihara K, Sato K, Kuroda S (1997) Polymorphism of dopamine receptors and transporter genes in neuropsychiatric diseases. Eur Neurol 38(Suppl 1):6–10.

  17. Fusar-Poli P, Meyer-Lindenberg A (2013) Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies. Schizophr Bull 39(1):33–42.

  18. Galehdari H, Hosseini S, Foroughmand AM, Musaviun M, Khatami S, Pooryasin A, Ajam T, Haidari M (2009) Lack of association between the -839C/T polymorphism in the SLC6A3 gene promoter and schizophrenia in the Iranian population. J Genet 88(3):321–323

  19. Gamma F, Faraone SV, Glatt SJ, Yeh YC, Tsuang MT (2005) Meta-analysis shows schizophrenia is not associated with the 40-base-pair repeat polymorphism of the dopamine transporter gene. Schizophr Res 73(1):55–58.

  20. Georgieva L, Dimitrova A, Nikolov I, Koleva S, Tsvetkova R, Owen MJ, Toncheva D, Kirov G (2002) Dopamine transporter gene (DAT1) VNTR polymorphism in major psychiatric disorders: family-based association study in the Bulgarian population. Acta Psychiatr Scand 105(5):396–399

  21. Greenwood TA, Lazzeroni LC, Calkins ME, Freedman R, Green MF, Gur RE, Gur RC, Light GA, Nuechterlein KH, Olincy A, Radant AD, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Sugar CA, Swerdlow NR, Tsuang DW, Tsuang MT, Turetsky BI, Braff DL (2016) Genetic assessment of additional endophenotypes from the consortium on the genetics of schizophrenia family study. Schizophr Res 170(1):30–40.

  22. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560.

  23. Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S (2012) The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 69(8):776–786.

  24. Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III--the final common pathway. Schizophr Bull 35(3):549–562.

  25. Huang CC, Lu RB, Yen CH, Yeh YW, Chou HW, Kuo SC, Chen CY, Chang CC, Chang HA, Ho PS, Liang CS, Cheng S, Shih MC, Huang SY (2015) Dopamine transporter gene may be associated with bipolar disorder and its personality traits. Eur Arch Psychiatry Clin Neurosci 265(4):281–290.

  26. Huang SY, Chen HK, Ma KH, Shy MJ, Chen JH, Lin WC, Lu RB (2010) Association of promoter variants of human dopamine transporter gene with schizophrenia in Han Chinese. Schizophr Res 116(1):68–74.

  27. Inada T, Sugita T, Dobashi I, Inagaki A, Kitao Y, Matsuda G, Kato S, Takano T, Yagi G, Asai M (1996) Dopamine transporter gene polymorphism and psychiatric symptoms seen in schizophrenic patients at their first episode. Am J Med Genet 67(4):406–408.<406::AID-AJMG15>3.0.CO;2-N

  28. Jeong SH, Joo EJ, Ahn YM, Kim YS (2004) Association study of dopamine transporter gene and schizophrenia in Korean population using multiple single nucleotide polymorphism markers. Prog Neuro-Psychopharmacol Biol Psychiatry 28(6):975–983.

  29. Joober R, Toulouse A, Benkelfat C, Lal S, Bloom D, Labelle A, Lalonde P, Turecki G, Rouleau GA (2000) DRD3 and DAT1 genes in schizophrenia: an association study. J Psychiatr Res 34(4–5):285–291

  30. Khodayari N, Garshasbi M, Fadai F, Rahimi A, Hafizi L, Ebrahimi A, Najmabadi H, Ohadi M (2004) Association of the dopamine transporter gene (DAT1) core promoter polymorphism -67T variant with schizophrenia. Am J Med Genet B Neuropsychiatr Genet 129B(1):10–12.

  31. King N, Bassett AS, Honer WG, Masellis M, Kennedy JL (1997) Absence of linkage for schizophrenia on the short arm of chromosome 5 in multiplex Canadian families. Am J Med Genet 74(5):472–474

  32. Krelling R, Cordeiro Q, Miracca E, Gutt EK, Petresco S, Moreno RA, Vallada H (2008) Molecular genetic case-control women investigation from the first Brazilian high-risk study on functional psychosis. Rev Bras Psiquiatr 30(4):341–345

  33. Kukshal P, Kodavali VC, Srivastava V, Wood J, McClain L, Bhatia T, Bhagwat AM, Deshpande SN, Nimgaonkar VL, Thelma BK (2013) Dopaminergic gene polymorphisms and cognitive function in a north Indian schizophrenia cohort. J Psychiatr Res 47(11):1615–1622.

  34. Lafuente, A., Bernardo, M., Mas, S., Crescenti, A., Aparici, M., Gasso, P., ..., Parellada, E. (2007). Dopamine transporter (DAT) genotype (VNTR) and phenotype in extrapyramidal symptoms induced by antipsychotics. Schizophr Res, 90(1–3), 115–122. doi:

  35. Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R (1999) Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 46(1):56–72

  36. Lewis DA, Lieberman JA (2000) Catching up on schizophrenia: natural history and neurobiology. Neuron 28(2):325–334

  37. Li T, Yang L, Wiese C, Xu CT, Zeng Z, Giros B, Caron MG, Moises HW, Liu X (1994) No association between alleles or genotypes at the dopamine transporter gene and schizophrenia. Psychiatry Res 52(1):17–23

  38. Lin Sicui JS, Xiaolong H, Liansheng Z, Meiti C (2000) Dopamine transporter gene and schizophrenia. Sichuan mental health 13(2):3

  39. Liu HC, Lin SK, Liu SK, Chen SL, Hu CJ, Chang JG, Leu SJ (2004) DAT polymorphism and diverse clinical manifestations in methamphetamine abusers. Psychiatr Genet 14(1):33–37

  40. Maier W, Minges J, Eckstein N, Brodski C, Albus M, Lerer B, Hallmayer J, Fimmers R, Ackenheil M, Ebstein RE, Borrmann M, Lichtermann D, Wildenauer DB (1996) Genetic relationship between dopamine transporter gene and schizophrenia: linkage and association. Schizophr Res 20(1–2):175–180

  41. Martinez D, Gelernter J, Abi-Dargham A, van Dyck CH, Kegeles L, Innis RB, Laruelle M (2001) The variable number of tandem repeats polymorphism of the dopamine transporter gene is not associated with significant change in dopamine transporter phenotype in humans. Neuropsychopharmacology 24(5):553–560.

  42. Mas S, Bernardo M, Parellada E, Garcia-Rizo C, Gasso P, Alvarez S, Lafuente A (2009) ARVCF single marker and haplotypic association with schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 33(6):1064–1069.

  43. Meda SA, Jagannathan K, Gelernter J, Calhoun VD, Liu J, Stevens MC, Pearlson GD (2010) A pilot multivariate parallel ICA study to investigate differential linkage between neural networks and genetic profiles in schizophrenia. Neuroimage 53(3):1007–1015.

  44. Mick E, Kim JW, Biederman J, Wozniak J, Wilens T, Spencer T, Smoller JW, Faraone SV (2008) Family based association study of pediatric bipolar disorder and the dopamine transporter gene (SLC6A3). Am J Med Genet B Neuropsychiatr Genet 147B(7):1182–1185.

  45. Miller GM, Madras BK (2002) Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression. Mol Psychiatry 7(1):44–55.

  46. Munafo MR, Flint J (2004) Meta-analysis of genetic association studies. Trends Genet 20(9):439–444.

  47. Myung SK, Park JY (2018) Efficacy of pharmacotherapy for smoking cessation in adolescent smokers: a meta-analysis of randomized controlled trials. Nicotine Tob Res.

  48. Naing C, Reid SA, Aung K (2017) Comparing antibiotic treatment for leptospirosis using network meta-analysis: a tutorial. BMC Infect Dis 17(1):29.

  49. Pal, P., Mihanovic, M., Molnar, S., Xi, H., Sun, G., Guha, S., ..., Rudan, P. (2009). Association of tagging single nucleotide polymorphisms on 8 candidate genes in dopaminergic pathway with schizophrenia in Croatian population. Croat Med J, 50(4), 361–369

  50. Pan Y, Yao J, Wang B (2014) Association of dopamine D1 receptor gene polymorphism with schizophrenia: a meta-analysis. Neuropsychiatr Dis Treat 10:1133–1139.

  51. Pattarachotanant N, Sritharathikhun T, Suttirat S, Tencomnao T (2010) Association of C/T polymorphism in intron 14 of the dopamine transporter gene (rs40184) with major depression in a northeastern Thai population. Genet Mol Res 9(1):565–572.

  52. Peitl V, Stefanovic M, Karlovic D (2017) Depressive symptoms in schizophrenia and dopamine and serotonin gene polymorphisms. Prog Neuro-Psychopharmacol Biol Psychiatry 77:209–215.

  53. Persico AM, Macciardi F (1997) Genotypic association between dopamine transporter gene polymorphisms and schizophrenia. Am J Med Genet 74(1):53–57

  54. Prata DP, Mechelli A, Picchioni MM, Fu CH, Toulopoulou T, Bramon E et al (2009) Altered effect of dopamine transporter 3'UTR VNTR genotype on prefrontal and striatal function in schizophrenia. Arch Gen Psychiatry 66(11):1162–1172.

  55. Purves-Tyson TD, Owens SJ, Rothmond DA, Halliday GM, Double KL, Stevens J, McCrossin T, Shannon Weickert C (2017) Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain. Transl Psychiatry 7(1):e1003.

  56. Rybakowski JK, Borkowska A, Czerski PM, Dmitrzak-Weglarz M, Skibinska M, Kapelski P, Hauser J (2006) Performance on the Wisconsin card sorting test in schizophrenia and genes of dopaminergic inactivation (COMT, DAT, NET). Psychiatry Res 143(1):13–19.

  57. Saiz, P. A., Garcia-Portilla, M. P., Arango, C., Morales, B., Arias, B., Corcoran, P., ..., Bobes, J. (2010). Genetic polymorphisms in the dopamine-2 receptor (DRD2), dopamine-3 receptor (DRD3), and dopamine transporter (SLC6A3) genes in schizophrenia: data from an association study. Prog Neuro-Psychopharmacol Biol Psychiatry, 34(1), 26–31. doi:

  58. Sedgwick P, Marston L (2015) How to read a funnel plot in a meta-analysis. BMJ 351:h4718.

  59. Semwal P, Prasad S, Varma PG, Bhagwat AM, Deshpande SN, Thelma BK (2002) Candidate gene polymorphisms among north Indians and their association with schizophrenia in a case-control study. J Genet 81(2):65–71

  60. Simons CJ, van Winkel R, Group (2013) Intermediate phenotype analysis of patients, unaffected siblings, and healthy controls identifies VMAT2 as a candidate gene for psychotic disorder and neurocognition. Schizophr Bull 39(4):848–856.

  61. Srivastava, V., Varma, P. G., Prasad, S., Semwal, P., Nimgaonkar, V. L., Lerer, B., ... Bk, T. (2006). Genetic susceptibility to tardive dyskinesia among schizophrenia subjects: IV. Role of dopaminergic pathway gene polymorphisms. Pharmacogenet Genomics, 16(2), 111–117

  62. Sullivan PF (2005) The genetics of schizophrenia. PLoS Med 2(7):e212.

  63. Szekeres G, Keri S, Juhasz A, Rimanoczy A, Szendi I, Czimmer C, Janka Z (2004) Role of dopamine D3 receptor (DRD3) and dopamine transporter (DAT) polymorphism in cognitive dysfunctions and therapeutic response to atypical antipsychotics in patients with schizophrenia. Am J Med Genet B Neuropsychiatr Genet 124B(1):1–5.

  64. Talkowski ME, Kirov G, Bamne M, Georgieva L, Torres G, Mansour H, Chowdari KV, Milanova V, Wood J, McClain L, Prasad K, Shirts B, Zhang J, O’Donovan MC, Owen MJ, Devlin B, Nimgaonkar VL (2008) A network of dopaminergic gene variations implicated as risk factors for schizophrenia. Hum Mol Genet 17(5):747–758.

  65. Thakkinstian A, McElduff P, D'Este C, Duffy D, Attia J (2005) A method for meta-analysis of molecular association studies. Stat Med 24(9):1291–1306.

  66. Thal LB, Tomlinson ID, Quinlan MA, Kovtun O, Blakely RD, Rosenthal SJ (2019) Single quantum dot imaging reveals PKCbeta-dependent alterations in membrane diffusion and clustering of an attention-deficit hyperactivity disorder/autism/bipolar disorder-associated dopamine transporter variant. ACS Chem Neurosci 10(1):460–471.

  67. Todt, U., Netzer, C., Toliat, M., Heinze, A., Goebel, I., Nurnberg, P., ... Kubisch, C. (2009). New genetic evidence for involvement of the dopamine system in migraine with aura. Hum Genet, 125(3), 265–279. doi:

  68. Treble-Barna A, Wade SL, Martin LJ, Pilipenko V, Yeates KO, Taylor HG, Kurowski BG (2017) Influence of dopamine-related genes on neurobehavioral recovery after traumatic brain injury during early childhood. J Neurotrauma 34(11):1919–1931.

  69. Tybura P, Grzywacz A, Samochowiec A, Samochowiec J (2011) Associations between candidate genes with schizophrenia susceptibility and the treatment efficiency. Psychiatr Pol 45(6):811–823

  70. VanNess SH, Owens MJ, Kilts CD (2005) The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density. BMC Genet 6:55.

  71. Walton E, Liu J, Hass J, White T, Scholz M, Roessner V, Gollub R, Calhoun VD, Ehrlich S (2014) MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls. Epigenetics 9(8):1101–1107.

  72. Wiers CE, Shumay E, Volkow ND, Frieling H, Kotsiari A, Lindenmeyer J, Walter H, Bermpohl F (2015) Effects of depressive symptoms and peripheral DAT methylation on neural reactivity to alcohol cues in alcoholism. Transl Psychiatry 5:e648.

  73. Wonodi I, Hong LE, Stine OC, Mitchell BD, Elliott A, Roberts RC, Conley RR, McMahon RP, Thaker GK (2009) Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 150B(2):282–289.

  74. Wray NR, Visscher PM (2010) Narrowing the boundaries of the genetic architecture of schizophrenia. Schizophr Bull 36(1):14–23.

  75. Xu FL, Wu X, Zhang JJ, Wang BJ, Yao J (2018) A meta-analysis of data associating DRD4 gene polymorphisms with schizophrenia. Neuropsychiatr Dis Treat 14:153–164.

  76. Yang B, Huang X, Ruan L, Yu T, Li X, Jesse FF, Cao Y, Li X, Liu B, Yang F, Lee YS, He L, Li W, He G (2014) No association of SLC6A3 and SLC6A4 gene polymorphisms with schizophrenia in the Han Chinese population. Neurosci Lett 579:114–118.

  77. Yao J, Pan YQ, Ding M, Pang H, Wang BJ (2015) Association between DRD2 (rs1799732 and rs1801028) and ANKK1 (rs1800497) polymorphisms and schizophrenia: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 168B(1):1–13.

  78. Zhang, M. L., Yuan, G. Z., Yao, J. J., Qian, Y. C., Zhang, X., Huang, Y. P., ... Jiang, S. D. (2003). [Associations between six functional genes and schizophrenia]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 20(1), 69–71

  79. Zilles D, Meyer J, Schneider-Axmann T, Ekawardhani S, Gruber E, Falkai P, Gruber O (2012) Genetic polymorphisms of 5-HTT and DAT but not COMT differentially affect verbal and visuospatial working memory functioning. Eur Arch Psychiatry Clin Neurosci 262(8):667–676.

  80. Zintzaras E, Ioannidis JP (2005) Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol 28(2):123–137.

Download references


This study was supported by the National Natural Science Foundation of China (No. 81671872).

Author information

Bao-jie Wang and Mei Ding designed the study and wrote the protocol. Feng-ling Xu managed the literature search, and Xue Wu, Yong-ping Liu, and Xi Xia checked the literature. Feng-ling Xu performed the analyses. The first draft of the manuscript was written by Feng-ling Xu and revised by Jun Yao.

Correspondence to Jun Yao or Bao-jie Wang.

Ethics declarations

Competing Interests

The authors declare that they have no competing interests.

Ethical Standards

This study complied with ethical standards.

Consent for Publication

Consent for publication is not applicable in this article.

Ethics Approval and Consent to Participate

Ethics approval and consent to participate is not applicable in this article.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material


(DOCX 14886 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xu, F., Ding, M., Wu, X. et al. A Meta-analysis of the Association Between SLC6A3 Gene Polymorphisms and Schizophrenia. J Mol Neurosci 70, 155–166 (2020).

Download citation


  • SLC6A3
  • Schizophrenia
  • Meta-analysis
  • Pooled analysis