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

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Abstract

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.

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References

  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 13:662–669

    Article  PubMed  Google Scholar 

  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 38:400–405

    Article  CAS  PubMed  Google Scholar 

  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 11:449–455

    Article  CAS  PubMed  Google Scholar 

  4. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of Ld and haplotype maps. Bioinformatics 21:263–265

    Article  CAS  PubMed  Google Scholar 

  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):41–49

  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 88:522–526

    Article  CAS  PubMed  Google Scholar 

  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 12:102–106

    Article  PubMed  Google Scholar 

  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 43:158–166

    Article  PubMed  Google Scholar 

  9. Cousins DA, Butts K, Young AH (2009) The role of dopamine in bipolar disorder. Bipolar Disord 11:787–806

    Article  CAS  PubMed  Google Scholar 

  10. Cryan JF, Hoyer D, Markou A (2003) Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biol Psychiatry 54:49–58

    Article  CAS  PubMed  Google Scholar 

  11. Cummings JL (1992) Depression and Parkinson’s disease: a review. Am J Psychiatry 149:443–454

    Article  CAS  PubMed  Google Scholar 

  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 264:401–408

    Article  PubMed  Google Scholar 

  13. Endicott J, Spitzer RL (1978) A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 35:837–844

    Article  CAS  PubMed  Google Scholar 

  14. Engstrom C, Brandstrom S, Sigvardsson S, Cloninger R, Nylander PO (2004) Bipolar disorder: I. Temperament and character. J Affect Disord 82:131–134

    Article  PubMed  Google Scholar 

  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 12:923–933

    Article  CAS  PubMed  Google Scholar 

  16. Gainetdinov RR, Jones SR, Caron MG (1999) Functional hyperdopaminergia in dopamine transporter knock-out mice. Biol Psychiatry 46:303–311

    Article  CAS  PubMed  Google Scholar 

  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:1568–1575

    Article  CAS  PubMed  Google Scholar 

  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 379:606–612

    Article  CAS  PubMed  Google Scholar 

  19. Gizer IR, Ficks C, Waldman ID (2009) Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 126:51–90

    Article  CAS  PubMed  Google Scholar 

  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 105:145–151

    Article  CAS  PubMed  Google Scholar 

  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 7:165–173

    Article  CAS  PubMed  Google Scholar 

  22. Greenwood TA, Kelsoe JR (2003) Promoter and intronic variants affect the transcriptional regulation of the human dopamine transporter gene. Genomics 82:511–520

    Article  CAS  PubMed  Google Scholar 

  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):115

    Article  CAS  Google Scholar 

  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 116:68–74

    Article  PubMed  Google Scholar 

  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 28:374–384

    Article  CAS  PubMed  Google Scholar 

  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 73:19–32

    Article  PubMed  Google Scholar 

  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 41:1579–1591

    Article  CAS  PubMed  Google Scholar 

  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:47–49

    Article  CAS  PubMed  Google Scholar 

  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 15:659–668

    Article  CAS  PubMed  Google Scholar 

  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 161:1814–1821

    Article  PubMed  Google Scholar 

  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 4:558–565

    Article  CAS  PubMed  Google Scholar 

  32. Latalova K, Prasko J, Kamaradova D, Sedlackova J, Ociskova M (2013) Comorbidity bipolar disorder and personality disorders. Neuro Endocrinol Lett 34:1–8

    CAS  PubMed  Google Scholar 

  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 60:497–502

    Article  PubMed  Google Scholar 

  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 28:773–788

    Article  CAS  PubMed  Google Scholar 

  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:1182–1185

    Article  CAS  PubMed  Google Scholar 

  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 9:565–572

    Article  CAS  PubMed  Google Scholar 

  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 36:1644–1655

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 158:139–147

    Article  PubMed  Google Scholar 

  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 53:1096–1102

    Article  PubMed  Google Scholar 

  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 7:869–876

    Article  CAS  PubMed  Google Scholar 

  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 53:9–16

    Article  CAS  PubMed  Google Scholar 

  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 67:551–555

    Article  CAS  PubMed  Google Scholar 

  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 8:490–495

    Article  PubMed  Google Scholar 

  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 70:44–51

    Article  CAS  PubMed  Google Scholar 

  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 125:265–279

    Article  CAS  PubMed  Google Scholar 

  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 50:45–52

    Article  PubMed  Google Scholar 

  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 50:45–52

    Article  PubMed  Google Scholar 

  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 6:55

    Article  PubMed Central  PubMed  Google Scholar 

  49. Yatham LN (2005) Atypical antipsychotics for bipolar disorder. Psychiatr Clin North Am 28:325–347

    Article  PubMed  Google Scholar 

  50. Ying SY, Lin SL (2009) Intron-mediated RNA interference and microRNA biogenesis. Methods Mol Biol 487:387–413

    CAS  PubMed  Google Scholar 

  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 564:99–104

    Article  CAS  PubMed  Google Scholar 

  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:1481–1487

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

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.

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Authors and Affiliations

  1. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, People’s Republic of China

    Chang-Chih Huang, Che-Hung Yen, Yi-Wei Yeh, Shin-Chang Kuo, Chun-Yen Chen, Chuan-Chia Chang & San-Yuan Huang

  2. Department of Psychiatry, Taipei Buddhist Tzu Chi General Hospital, New Taipei City, People’s Republic of China

    Chang-Chih Huang

  3. Department of Psychiatry, Institute of Behavior Medicine, College of Medicine, National Cheng Kung University, Tainan, People’s Republic of China

    Ru-Band Lu

  4. Department of Neurology, Tri-Service General Hospital, Taipei, Taiwan, People’s Republic of China

    Che-Hung Yen

  5. Department of Psychiatry, Tri-Service General Hospital, No. 325, Cheng-Kung Road, Sec. 2, Nei-Hu District, Taipei, 114, Taiwan, People’s Republic of China

    Yi-Wei Yeh, Shin-Chang Kuo, Chun-Yen Chen, Chuan-Chia Chang, Hsin-An Chang, Mei-Chen Shih & San-Yuan Huang

  6. Department of Psychiatry, Taoyuan Armed Forces General Hospital, Taoyuan, People’s Republic of China

    Han-Wei Chou

  7. Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, Taipei, Taiwan, People’s Republic of China

    Pei-Shen Ho & Chih-Sung Liang

  8. College of Arts and Sciences, Cornell University, Ithaca, NY, USA

    Serena Cheng

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  1. Chang-Chih Huang
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Huang, CC., Lu, RB., Yen, CH. et al. Dopamine transporter gene may be associated with bipolar disorder and its personality traits. Eur Arch Psychiatry Clin Neurosci 265, 281–290 (2015). https://doi.org/10.1007/s00406-014-0570-0

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