Dopamine transporter gene may be associated with bipolar disorder and its personality traits

  • Chang-Chih Huang
  • Ru-Band Lu
  • Che-Hung Yen
  • Yi-Wei Yeh
  • Han-Wei Chou
  • Shin-Chang Kuo
  • Chun-Yen Chen
  • Chuan-Chia Chang
  • Hsin-An Chang
  • Pei-Shen Ho
  • Chih-Sung Liang
  • Serena Cheng
  • Mei-Chen Shih
  • San-Yuan HuangEmail author
Original Paper


Dopamine transporter and its genetic factors have been suggested to play a critical role in the development of bipolar disorder (BPD). However, the importance of the dopamine transporter gene (DAT1) in the pathogenesis of BPD remains unclear. The aims of this study were to assess 18 polymorphisms of the DAT1 gene to determine whether this gene is associated with BPD and whether it influences personality traits of patients with BPD. DAT1 polymorphisms were analyzed in 492 BPD (374 BPDI and 118 BPDII) patients and 436 controls. All participants were screened using the same assessment tool, and all met the criteria for BPD. The Tridimensional Personality Questionnaire was used to assess personality traits in both patients and controls. Several polymorphisms had a weak association with BPD, including rs2550948, rs2652511, and rs2975226 in allele distribution analysis (P < 0.05). Furthermore, the promoter G-A-C-G haplotype (rs6350-rs2975226-rs2652511-rs6413429) was over-represented in the BPD patients compared to the controls (P = 0.007). In personality assessment, the BPDII patients had the highest harm avoidance score, followed by the BPDI patients and controls (P = 3.7 × 10−32). In addition, a significant association between rs40184 and harm avoidance was found in the patients with BPD. The DAT1 promoter may be associated with vulnerabilities in BPD. The BPD patients had a higher rate of harm avoidance personality traits than the controls, and DAT1 variants may influence personality traits in patients with BPD.


DAT1 polymorphisms Bipolar disorder Personality traits Han Chinese 



This study was supported by grants from National Science Council NSC101-2325-B-016-003 (SYH), the Tri-Service General Hospital TSGH-C100-009-008, TSGH-C101-009-008, TSGH-C102-069-023, TSGH-C104-129 (SYH), and the Medical Affairs Bureau, Ministry of National Defense, Taiwan, DOD100-C09-01, DOD102-114 (SYH). Further support was provided by the National Cheng Kung University Project of Promoting Academic Excellence and Developing World Class Research Centers, Taiwan, Republic of China. We thank to Ms. Yun-Hsin Lin, Mr. Cheng-Chang Huang, and Ms. Fang-Yi Lin for their assistance in preparing this manuscript.

Conflict of interest

All authors do not have a financial interest/arrangement or affiliation with any organization that could be perceived as real or apparent conflict of interest in the context of the subject of our article.


  1. 1.
    Almeida KM, Nery FG, Moreno RA, Gorenstein C, Lafer B (2011) Personality traits in bipolar disorder type 1: a sib-pair analysis. Bipolar Disord 13:662–669CrossRefPubMedGoogle Scholar
  2. 2.
    Andreasen NC, Grove WM, Shapiro RW, Keller MB, Hirschfeld RM, McDonald-Scott P (1981) Reliability of lifetime diagnosis. A multicenter collaborative perspective. Arch Gen Psychiatry 38:400–405CrossRefPubMedGoogle Scholar
  3. 3.
    Bannon MJ, Michelhaugh SK, Wang J, Sacchetti P (2001) The human dopamine transporter gene: gene organization, transcriptional regulation, and potential involvement in neuropsychiatric disorders. Eur Neuropsychopharmacol 11:449–455CrossRefPubMedGoogle Scholar
  4. 4.
    Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of Ld and haplotype maps. Bioinformatics 21:263–265CrossRefPubMedGoogle Scholar
  5. 5.
    Berk M, Dodd S, Kauer-Sant’anna M, Malhi GS, Bourin M, Kapczinski F, Norman T (2007) Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatr Scand Suppl (434):41–49Google Scholar
  6. 6.
    Bocchetta A, Piccardi MP, Palmas MA, Chillotti C, Oi A, Del Zompo M (1999) Family-based association study between bipolar disorder and DRD2, DRD4, DAT, and SERT in Sardinia. Am J Med Genet 88:522–526CrossRefPubMedGoogle Scholar
  7. 7.
    Chang TT, Yeh TL, Chiu NT, Chen PS, Huang HY, Yang YK, Lee IH, Lu RB (2010) Higher striatal dopamine transporters in euthymic patients with bipolar disorder: a SPECT study with [tc] TRODAT-1. Bipolar Disord 12:102–106CrossRefPubMedGoogle Scholar
  8. 8.
    Chen WJ, Chen HM, Chen CC, Yu WY, Cheng AT (2002) Cloninger’s tridimensional personality questionnaire: psychometric properties and construct validity in Taiwanese adults. Compr Psychiatry 43:158–166CrossRefPubMedGoogle Scholar
  9. 9.
    Cousins DA, Butts K, Young AH (2009) The role of dopamine in bipolar disorder. Bipolar Disord 11:787–806CrossRefPubMedGoogle Scholar
  10. 10.
    Cryan JF, Hoyer D, Markou A (2003) Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biol Psychiatry 54:49–58CrossRefPubMedGoogle Scholar
  11. 11.
    Cummings JL (1992) Depression and Parkinson’s disease: a review. Am J Psychiatry 149:443–454CrossRefPubMedGoogle Scholar
  12. 12.
    de Azeredo LA, Rovaris DL, Mota NR, Polina ER, Marques FZ, Contini V, Vitola ES, Belmonte-de-Abreu P, Rohde LA, Grevet EH, Bau CH (2014) Further evidence for the association between a polymorphism in the promoter region of SLC6A3/DAT1 and adhd: Findings from a sample of adults. Eur Arch Psychiatry Clin Neurosci 264:401–408CrossRefPubMedGoogle Scholar
  13. 13.
    Endicott J, Spitzer RL (1978) A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 35:837–844CrossRefPubMedGoogle Scholar
  14. 14.
    Engstrom C, Brandstrom S, Sigvardsson S, Cloninger R, Nylander PO (2004) Bipolar disorder: I. Temperament and character. J Affect Disord 82:131–134CrossRefPubMedGoogle Scholar
  15. 15.
    Friedel S, Saar K, Sauer S, Dempfle A, Walitza S, Renner T, Romanos M, Freitag C, Seitz C, Palmason H, Scherag A, Windemuth-Kieselbach C, Schimmelmann BG, Wewetzer C, Meyer J, Warnke A, Lesch KP, Reinhardt R, Herpertz-Dahlmann B, Linder M, Hinney A, Remschmidt H, Schafer H, Konrad K, Hubner N, Hebebrand J (2007) Association and linkage of allelic variants of the dopamine transporter gene in ADHD. Mol Psychiatry 12:923–933CrossRefPubMedGoogle Scholar
  16. 16.
    Gainetdinov RR, Jones SR, Caron MG (1999) Functional hyperdopaminergia in dopamine transporter knock-out mice. Biol Psychiatry 46:303–311CrossRefPubMedGoogle Scholar
  17. 17.
    Genro JP, Polanczyk GV, Zeni C, Oliveira AS, Roman T, Rohde LA, Hutz MH (2008) A common haplotype at the dopamine transporter gene 5′ region is associated with attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 147B:1568–1575CrossRefPubMedGoogle Scholar
  18. 18.
    Giros B, Jaber M, Jones SR, Wightman RM, Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612CrossRefPubMedGoogle Scholar
  19. 19.
    Gizer IR, Ficks C, Waldman ID (2009) Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 126:51–90CrossRefPubMedGoogle Scholar
  20. 20.
    Greenwood TA, Alexander M, Keck PE, McElroy S, Sadovnick AD, Remick RA, Kelsoe JR (2001) Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder. Am J Med Genet 105:145–151CrossRefPubMedGoogle Scholar
  21. 21.
    Greenwood TA, Alexander M, Keck PE, McElroy S, Sadovnick AD, Remick RA, Shaw SH, Kelsoe JR (2002) Segmental linkage disequilibrium within the dopamine transporter gene. Mol Psychiatry 7:165–173CrossRefPubMedGoogle Scholar
  22. 22.
    Greenwood TA, Kelsoe JR (2003) Promoter and intronic variants affect the transcriptional regulation of the human dopamine transporter gene. Genomics 82:511–520CrossRefPubMedGoogle Scholar
  23. 23.
    Greenwood TA, Schork NJ, Eskin E, Kelsoe JR (2006) Identification of additional variants within the human dopamine transporter gene provides further evidence for an association with bipolar disorder in two independent samples. Mol Psychiatry 11(125–133):115CrossRefGoogle Scholar
  24. 24.
    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 116:68–74CrossRefPubMedGoogle Scholar
  25. 25.
    Huang SY, Lin WW, Ko HC, Lee JF, Wang TJ, Chou YH, Yin SJ, Lu RB (2004) Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence. Alcohol Clin Exp Res 28:374–384CrossRefPubMedGoogle Scholar
  26. 26.
    Judd LL, Akiskal HS, Schettler PJ, Coryell W, Maser J, Rice JA, Solomon DA, Keller MB (2003) The comparative clinical phenotype and long term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct disorders? J Affect Disord 73:19–32CrossRefPubMedGoogle Scholar
  27. 27.
    Jylha P, Mantere O, Melartin T, Suominen K, Vuorilehto M, Arvilommi P, Holma I, Holma M, Leppamaki S, Valtonen H, Rytsala H, Isometsa E (2011) Differences in temperament and character dimensions in patients with bipolar I or II or major depressive disorder and general population subjects. Psychol Med 41:1579–1591CrossRefPubMedGoogle Scholar
  28. 28.
    Keikhaee MR, Fadai F, Sargolzaee MR, Javanbakht A, Najmabadi H, Ohadi M (2005) Association analysis of the dopamine transporter (DAT1)-67A/T polymorphism in bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 135B:47–49CrossRefPubMedGoogle Scholar
  29. 29.
    Kelada SN, Costa-Mallen P, Checkoway H, Carlson CS, Weller TS, Swanson PD, Franklin GM, Longstreth WT Jr, Afsharinejad Z, Costa LG (2005) Dopamine transporter (SLC6A3) 5′ region haplotypes significantly affect transcriptional activity in vitro but are not associated with Parkinson’s disease. Pharmacogenet Genomics 15:659–668CrossRefPubMedGoogle Scholar
  30. 30.
    Kieseppa T, Partonen T, Haukka J, Kaprio J, Lonnqvist J (2004) High concordance of bipolar I disorder in a nationwide sample of twins. Am J Psychiatry 161:1814–1821CrossRefPubMedGoogle Scholar
  31. 31.
    Kirov G, Jones I, McCandless F, Craddock N, Owen MJ (1999) Family-based association studies of bipolar disorder with candidate genes involved in dopamine neurotransmission: DBH, DAT1, COMT, DRD2, DRD3 and DRD5. Mol Psychiatry 4:558–565CrossRefPubMedGoogle Scholar
  32. 32.
    Latalova K, Prasko J, Kamaradova D, Sedlackova J, Ociskova M (2013) Comorbidity bipolar disorder and personality disorders. Neuro Endocrinol Lett 34:1–8PubMedGoogle Scholar
  33. 33.
    McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A (2003) The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 60:497–502CrossRefPubMedGoogle Scholar
  34. 34.
    Merikangas KR, Stevens DE, Fenton B, Stolar M, O’Malley S, Woods SW, Risch N (1998) Co-morbidity and familial aggregation of alcoholism and anxiety disorders. Psychol Med 28:773–788CrossRefPubMedGoogle Scholar
  35. 35.
    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:1182–1185CrossRefPubMedGoogle Scholar
  36. 36.
    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 9:565–572CrossRefPubMedGoogle Scholar
  37. 37.
    Pinsonneault JK, Han DD, Burdick KE, Kataki M, Bertolino A, Malhotra AK, Gu HH, Sadee W (2011) Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacology 36:1644–1655CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Rosenstrom T, Jylha P, Robert Cloninger C, Hintsanen M, Elovainio M, Mantere O, Pulkki-Raback L, Riihimaki K, Vuorilehto M, Keltikangas-Jarvinen L, Isometsa E (2014) Temperament and character traits predict future burden of depression. J Affect Disord 158:139–147CrossRefPubMedGoogle Scholar
  39. 39.
    Sarisoy G, Kacar OF, Pazvantoglu O, Ozturk A, Korkmaz IZ, Kocamanoglu B, Boke O, Sahin AR (2012) Temperament and character traits in patients with bipolar disorder and associations with attempted suicide. Compr Psychiatry 53:1096–1102CrossRefPubMedGoogle Scholar
  40. 40.
    Savitz J, van der Merwe L, Ramesar R (2008) Personality endophenotypes for bipolar affective disorder: a family-based genetic association analysis. Genes Brain Behav 7:869–876CrossRefPubMedGoogle Scholar
  41. 41.
    Serretti A, Mandelli L, Lorenzi C, Landoni S, Calati R, Insacco C, Cloninger CR (2006) Temperament and character in mood disorders: influence of DRD4, SERTPR, TPH and MAO-A polymorphisms. Neuropsychobiology 53:9–16CrossRefPubMedGoogle Scholar
  42. 42.
    Souery D, Lipp O, Mahieu B, Mendelbaum K, De Martelaer V, Van Broeckhoven C, Mendlewicz J (1996) Association study of bipolar disorder with candidate genes involved in catecholamine neurotransmission: DRD2, DRD3, DAT1, and TH genes. Am J Med Genet 67:551–555CrossRefPubMedGoogle Scholar
  43. 43.
    Stober G, Sprandel J, Schmidt F, Faul T, Jabs B, Knapp M (2006) Association study of 5′-UTR polymorphisms of the human dopamine transporter gene with manic depression. Bipolar Disord 8:490–495CrossRefPubMedGoogle Scholar
  44. 44.
    Stolf AR, Szobot CM, Halpern R, Akutagava-Martins GC, Muller D, Guimaraes LS, Kessler FH, Pechansky F, Roman T (2014) Crack cocaine users show differences in genotype frequencies of the 3′ UTR variable number of tandem repeats of the dopamine transporter gene (DAT1/SLC6A3). Neuropsychobiology 70:44–51CrossRefPubMedGoogle Scholar
  45. 45.
    Todt U, Netzer C, Toliat M, Heinze A, Goebel I, Nurnberg P, Gobel H, Freudenberg J, Kubisch C (2009) New genetic evidence for involvement of the dopamine system in migraine with aura. Hum Genet 125:265–279CrossRefPubMedGoogle Scholar
  46. 46.
    van de Giessen E, de Win MM, Tanck MW, van den Brink W, Baas F, Booij J (2009) Striatal dopamine transporter availability associated with polymorphisms in the dopamine transporter gene SLC6A3. J Nucl Med 50:45–52CrossRefPubMedGoogle Scholar
  47. 47.
    van de Giessen EM, de Win MM, Tanck MW, van den Brink W, Baas F, Booij J (2009) Striatal dopamine transporter availability associated with polymorphisms in the dopamine transporter gene SLC6A3. J Nucl Med 50:45–52CrossRefPubMedGoogle Scholar
  48. 48.
    VanNess SH, Owens MJ, Kilts CD (2005) The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density. BMC Genet 6:55CrossRefPubMedCentralPubMedGoogle Scholar
  49. 49.
    Yatham LN (2005) Atypical antipsychotics for bipolar disorder. Psychiatr Clin North Am 28:325–347CrossRefPubMedGoogle Scholar
  50. 50.
    Ying SY, Lin SL (2009) Intron-mediated RNA interference and microRNA biogenesis. Methods Mol Biol 487:387–413PubMedGoogle Scholar
  51. 51.
    Zhai D, Li S, Zhao Y, Lin Z (2014) SLC6A3 is a risk factor for Parkinson’s disease: a meta-analysis of sixteen years’ studies. Neurosci Lett 564:99–104CrossRefPubMedGoogle Scholar
  52. 52.
    Zhou K, Chen W, Buitelaar J, Banaschewski T, Oades RD, Franke B, Sonuga-Barke E, Ebstein R, Eisenberg J, Gill M, Manor I, Miranda A, Mulas F, Roeyers H, Rothenberger A, Sergeant J, Steinhausen HC, Lasky-Su J, Taylor E, Brookes KJ, Xu X, Neale BM, Rijsdijk F, Thompson M, Asherson P, Faraone SV (2008) Genetic heterogeneity in ADHD: DAT1 gene only affects probands without CD. Am J Med Genet B Neuropsychiatr Genet 147B:1481–1487CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Chang-Chih Huang
    • 1
    • 2
  • Ru-Band Lu
    • 3
  • Che-Hung Yen
    • 1
    • 4
  • Yi-Wei Yeh
    • 1
    • 5
  • Han-Wei Chou
    • 6
  • Shin-Chang Kuo
    • 1
    • 5
  • Chun-Yen Chen
    • 1
    • 5
  • Chuan-Chia Chang
    • 1
    • 5
  • Hsin-An Chang
    • 5
  • Pei-Shen Ho
    • 7
  • Chih-Sung Liang
    • 7
  • Serena Cheng
    • 8
  • Mei-Chen Shih
    • 5
  • San-Yuan Huang
    • 1
    • 5
    Email author
  1. 1.Graduate Institute of Medical SciencesNational Defense Medical CenterTaipeiPeople’s Republic of China
  2. 2.Department of PsychiatryTaipei Buddhist Tzu Chi General HospitalNew Taipei CityPeople’s Republic of China
  3. 3.Department of Psychiatry, Institute of Behavior Medicine, College of MedicineNational Cheng Kung UniversityTainanPeople’s Republic of China
  4. 4.Department of NeurologyTri-Service General HospitalTaipeiPeople’s Republic of China
  5. 5.Department of PsychiatryTri-Service General HospitalTaipeiPeople’s Republic of China
  6. 6.Department of PsychiatryTaoyuan Armed Forces General HospitalTaoyuanPeople’s Republic of China
  7. 7.Department of Psychiatry, Beitou BranchTri-Service General HospitalTaipeiPeople’s Republic of China
  8. 8.College of Arts and SciencesCornell UniversityIthacaUSA

Personalised recommendations