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Behavioral and Brain Functions

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Open Access 01-12-2010 | Research

Association between dopaminergic polymorphisms and borderline personality traits among at-risk young adults and psychiatric inpatients

Authors: Zsofia Nemoda, Karlen Lyons-Ruth, Anna Szekely, Eszter Bertha, Gabor Faludi, Maria Sasvari-Szekely

Published in: Behavioral and Brain Functions | Issue 1/2010

Abstract

Background

In the development of borderline personality disorder (BPD) both genetic and environmental factors have important roles. The characteristic affective disturbance and impulsive aggression are linked to imbalances in the central serotonin system, and most of the genetic association studies focused on serotonergic candidate genes. However, the efficacy of dopamine D2 receptor (DRD2) blocking antipsychotic drugs in BPD treatment also suggests involvement of the dopamine system in the neurobiology of BPD.

Methods

In the present study we tested the dopamine dysfunction hypothesis of impulsive self- and other-damaging behaviors: borderline and antisocial traits were assessed by Structured Clinical Interview for Diagnosis (SCID) for DSM-IV in a community-based US sample of 99 young adults from low-to-moderate income families. For the BPD trait analyses a second, independent group was used consisting of 136 Hungarian patients with bipolar or major depressive disorder filling out self-report SCID-II Screen questionnaire. In the genetic association analyses the previously indicated polymorphisms of the catechol-O-methyl-transferase (COMT Val158Met) and dopamine transporter (DAT1 40 bp VNTR) were studied. In addition, candidate polymorphisms of the DRD2 and DRD4 dopamine receptor genes were selected from the impulsive behavior literature.

Results

The DRD2 TaqI B1-allele and A1-allele were associated with borderline traits in the young adult sample (p = 0.001, and p = 0.005, respectively). Also, the DRD4 -616 CC genotype appeared as a risk factor (p = 0.02). With severity of abuse accounted for in the model, genetic effects of the DRD2 and DRD4 polymorphisms were still significant (DRD2 TaqIB: p = 0.001, DRD2 TaqIA: p = 0.008, DRD4 -616 C/G: p = 0.002). Only the DRD4 promoter finding was replicated in the independent sample of psychiatric inpatients (p = 0.007). No association was found with the COMT and DAT1 polymorphisms.

Conclusions

Our results of the two independent samples suggest a possible involvement of the DRD4 -616 C/G promoter variant in the development of BPD traits. In addition, an association of the DRD2 genetic polymorphisms with impulsive self-damaging behaviors was also demonstrated.

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Lieb K, Zanarini MC, Schmahl C, Linehan MM, Bohus M: Borderline personality disorder. Lancet. 2004, 364: 453-461. 10.1016/S0140-6736(04)16770-6.CrossRefPubMed

Nigg JT, Goldsmith HH: Genetics of personality disorders: perspectives from personality and psychopathology research. Psychol Bull. 1994, 115: 346-380. 10.1037/0033-2909.115.3.346.CrossRefPubMed

Torgersen S, Lygren S, Oien PA, Skre I, Onstad S, Edvardsen J, Tambs K, Kringlen E: A twin study of personality disorders. Compr Psychiatry. 2000, 41: 416-425. 10.1053/comp.2000.16560.CrossRefPubMed

Distel MA, Trull TJ, Derom CA, Thiery EW, Grimmer MA, Martin NG, Willemsen G, Boomsma DI: Heritability of borderline personality disorder features is similar across three countries. Psychol Med. 2008, 38: 1219-1229. 10.1017/S0033291707002024.CrossRefPubMed

Oquendo MA, Mann JJ: The biology of impulsivity and suicidality. Psychiatr Clin North Am. 2000, 23: 11-25. 10.1016/S0193-953X(05)70140-4.CrossRefPubMed

Friedel RO: Dopamine dysfunction in borderline personality disorder: A hypothesis. Neuropsychopharmacology. 2004, 29: 1029-1039. 10.1038/sj.npp.1300424.CrossRefPubMed

Joyce PR, McHugh PC, McKenzie JM, Sullivan PF, Mulder RT, Luty SE, Carter JD, Frampton CM, Robert Cloninger C, Miller AM, Kennedy MA: A dopamine transporter polymorphism is a risk factor for borderline personality disorder in depressed patients. Psychol Med. 2006, 36: 807-813. 10.1017/S0033291706007288.CrossRefPubMed

Tadić A, Victor A, Başkaya O, von Cube R, Hoch J, Kouti I, Anicker NJ, Höppner W, Lieb K, Dahmen N: Interaction between gene variants of the serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT) in borderline personality disorder. Am J Med Genet B. 2009, 150: 487-495.

Oak JN, Oldenhof J, Van Tol HH: The dopamine D(4) receptor: one decade of research. Eur J Pharmacol. 2000, 405: 303-327. 10.1016/S0014-2999(00)00562-8.CrossRefPubMed

10.

Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P: Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005, 57: 1313-1323. 10.1016/j.biopsych.2004.11.024.CrossRefPubMed

11.

Munafò MR, Yalcin B, Willis-Owen SA, Flint J: Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data. Biol Psychiatry. 2008, 63: 197-206. 10.1016/j.biopsych.2007.04.006.CrossRefPubMed

12.

Posner MI, Rothbart MK, Vizueta N, Thomas KM, Levy KN, Fossella J, Silbersweig D, Stern E, Clarkin J, Kernberg O: An approach to the psychobiology of personality disorders. Dev Psychopathol. 2003, 15: 1093-1106. 10.1017/S0954579403000506.CrossRefPubMed

13.

Lyons-Ruth K, Holmes BM, Sasvari-Szekely M, Ronai Z, Nemoda Z, Pauls D: Serotonin transporter polymorphism and borderline or antisocial traits among low-income young adults. Psychiatr Genet. 2007, 17: 339-343. 10.1097/YPG.0b013e3281ac237e.PubMedCentralCrossRefPubMed

14.

Cohen P, Chen H, Gordon K, Johnson J, Brook J, Kasen S: Socioeconomic background and the developmental course of schizotypal and borderline personality disorder symptoms. Dev Psychopathol. 2008, 20 (2): 633-50. 10.1017/S095457940800031X.CrossRefPubMed

15.

Page A, Taylor R, Hall W, Carter G: Mental disorders and socioeconomic status: impact on population risk of attempted suicide in Australia. Suicide Life Threat Behav. 2009, 39: 471-81. 10.1521/suli.2009.39.5.471.CrossRefPubMed

16.

Widiger TA, Weissman MM: Epidemiology of borderline personality disorder. Hosp Community Psychiatry. 1991, 42: 1015-1021.PubMed

17.

Moran P: The epidemiology of antisocial personality disorder. Soc Psychiatry Psychiatr Epidemiol. 1999, 34: 231-242. 10.1007/s001270050138.CrossRefPubMed

18.

Neville MJ, Johnstone EC, Walton RT: Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat. 2004, 23: 540-545. 10.1002/humu.20039.CrossRefPubMed

19.

Thompson J, Thomas N, Singleton A, Piggott M, Lloyd S, Perry EK, Morris CM, Perry RH, Ferrier IN, Court JA: D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics. 1997, 7 (6): 479-484. 10.1097/00008571-199712000-00006.CrossRefPubMed

20.

Pohjalainen T, Rinne JO, Någren K, Lehikoinen P, Anttila K, Syvälahti EK, Hietala J: The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry. 1998, 3: 256-260. 10.1038/sj.mp.4000350.CrossRefPubMed

21.

Jönsson EG, Nöthen MM, Grünhage F, Farde L, Nakashima Y, Propping P, Sedvall GC: Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry. 1999, 4: 290-296. 10.1038/sj.mp.4000532.CrossRefPubMed

22.

Ritchie T, Noble EP: Association of seven polymorphisms of the D2 dopamine receptor gene with brain receptor-binding characteristics. Neurochem Res. 2003, 28: 73-82. 10.1023/A:1021648128758.CrossRefPubMed

23.

Laruelle M, Gelernter J, Innis RB: D2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene. Mol Psychiatry. 1998, 3: 261-265. 10.1038/sj.mp.4000343.CrossRefPubMed

24.

Noble EP: D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am J Med Genet B. 2003, 116: 103-125.CrossRef

25.

Eisenberg DT, Mackillop J, Modi M, Beauchemin J, Dang D, Lisman SA, Lum JK, Wilson DS: Examining impulsivity as an endophenotype using a behavioral approach: a DRD2 TaqI A and DRD4 48-bp VNTR association study. Behav Brain Funct. 2007, 3: 2-10.1186/1744-9081-3-2.PubMedCentralCrossRefPubMed

26.

White MJ, Morris CP, Lawford BR, Young RM: Behavioral phenotypes of impulsivity related to the ANKK1 gene are independent of an acute stressor. Behav Brain Funct. 2008, 4: 54-10.1186/1744-9081-4-54.PubMedCentralCrossRefPubMed

27.

Schoots O, Van Tol HH: The human dopamine D4 receptor repeat sequences modulate expression. Pharmacogenomics J. 2003, 3: 343-348. 10.1038/sj.tpj.6500208.CrossRefPubMed

28.

Eisenberg DT, Campbell B, Mackillop J, Lum JK, Wilson DS: Season of birth and dopamine receptor gene associations with impulsivity, sensation seeking and reproductive behaviors. PLoS One. 2007, 2: e1216-10.1371/journal.pone.0001216.PubMedCentralCrossRefPubMed

29.

Beaver KM, Wright JP, DeLisi M, Walsh A, Vaughn MG, Boisvert D, Vaske J: A gene × gene interaction between DRD2 and DRD4 is associated with conduct disorder and antisocial behavior in males. Behav Brain Funct. 2007, 3: 30-10.1186/1744-9081-3-30.PubMedCentralCrossRefPubMed

30.

Congdon E, Lesch KP, Canli T: Analysis of DRD4 and DAT polymorphisms and behavioral inhibition in healthy adults: implications for impulsivity. Am J Med Genet B. 2008, 147: 27-32. 10.1002/ajmg.b.30557.CrossRef

31.

Bakermans-Kranenburg MJ, van Ijzendoorn MH: Gene-environment interaction of the dopamine D4 receptor (DRD4) and observed maternal insensitivity predicting externalizing behavior in preschoolers. Dev Psychobiol. 2006, 48: 406-409. 10.1002/dev.20152.CrossRefPubMed

32.

Bakermans-Kranenburg MJ, Van IJzendoorn MH, Pijlman FT, Mesman J, Juffer F: Experimental evidence for differential susceptibility: dopamine D4 receptor polymorphism (DRD4 VNTR) moderates intervention effects on toddlers' externalizing behavior in a randomized controlled trial. Dev Psychol. 2008, 44: 293-300. 10.1037/0012-1649.44.1.293.CrossRefPubMed

33.

First MB, Gibbon M, Spitzer RL, Williams JBW, Benjamin LS: User's guide for the structured clinical interview for DSM-IV Axis II personality disorders [SCID-II]. 1997, Washington, DC: American Psychiatric Press

34.

First MB, Spitzer RL, Gibbon M, Williams JBW: Structured clinical interview for DSM-IV Axis I disorders - Clinical version (SCID-CV). 1997, Washington D.C.: American Psychiatric Press

35.

Straus MA, Hamby SL, Boney-McCoy S, Sugarman DB: The revised Conflict Tactics Scales (CTS2): Development and preliminary psychometric data. Journal of Family Issues. 1996, 17: 283-316. 10.1177/019251396017003001.CrossRef

36.

Norris FH: Epidemiology of trauma: frequency and impact of different potentially traumatic events on different demographic groups. J Consult Clin Psychol. 1992, 60: 409-418. 10.1037/0022-006X.60.3.409.CrossRefPubMed

37.

Dutra L, Bureau JF, Holmes B, Lyubchik A, Lyons-Ruth K: Quality of early care and childhood trauma: a prospective study of developmental pathways to dissociation. J Nerv Ment Dis. 2009, 197: 383-390. 10.1097/NMD.0b013e3181a653b7.PubMedCentralCrossRefPubMed

38.

Hejjas K, Szekely A, Domotor E, Halmai Z, Balogh G, Schilling B, Sarosi A, Faludi G, Sasvari-Szekely M, Nemoda Z: Association between depression and the Gln460Arg polymorphism of P2RX7 gene: a dimensional approach. Am J Med Genet B. 2009, 150: 295-299. 10.1002/ajmg.b.30799.CrossRef

39.

American Psychiatric Association: Diagnostic and statistical manual of mental disorders. 1994, Washington, DC: American Psychiatric Press, 4

40.

Ekselius L, Lindström E, von Knorring L, Bodlund O, Kullgren G: SCID II interviews and the SCID Screen questionnaire as diagnostic tools for personality disorders in DSM-III-R. Acta Psychiatr Scand. 1994, 90: 120-123. 10.1111/j.1600-0447.1994.tb01566.x.CrossRefPubMed

41.

Grandy DK, Zhang Y, Civelli O: PCR detection of the TaqA RFLP at the DRD2 locus. Hum Mol Genet. 1993, 2: 2197-10.1093/hmg/2.12.2197-a.CrossRefPubMed

42.

Castiglione CM, Deinard AS, Speed WC, Sirugo G, Rosenbaum HC, Zhang Y, Grandy DK, Grigorenko EL, Bonne-Tamir B, Pakstis AJ, Kidd JR, Kidd KK: Evolution of haplotypes at the DRD2 locus. Am J Hum Genet. 1995, 57: 1445-56.PubMedCentralPubMed

43.

Kidd KK, Pakstis AJ, Castiglione CM, Kidd JR, Speed WC, Goldman D, Knowler WC, Lu RB, Bonne-Tamir B: DRD2 haplotypes containing the TaqI A1 allele: implications for alcoholism research. Alcohol Clin Exp Res. 1996, 20: 697-705. 10.1111/j.1530-0277.1996.tb01674.x.CrossRefPubMed

44.

Vandenbergh DJ, Persico AM, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR: Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics. 1992, 14: 1104-1106. 10.1016/S0888-7543(05)80138-7.CrossRefPubMed

45.

Ronai Z, Guttman A, Nemoda Z, Staub M, Kalasz H, Sasvari-Szekely M: Rapid and sensitive genotyping of dopamine D4 receptor tandem repeats by automated ultrathin-layer gel electrophoresis. Electrophoresis. 2000, 21 (10): 2058-2061. 10.1002/1522-2683(20000601)21:10<2058::AID-ELPS2058>3.0.CO;2-1.CrossRefPubMed

46.

Szantai E, Kiraly O, Nemoda Z, Kereszturi E, Csapo Z, Sasvari-Szekely M, Gervai J, Ronai Z: Linkage analysis and molecular haplotyping of the dopamine D4 receptor gene promoter region. Psychiatr Genet. 2005, 15: 259-270. 10.1097/00041444-200512000-00008.CrossRefPubMed

47.

Tarnok Z, Ronai Z, Gervai J, Kereszturi E, Gadoros J, Sasvari-Szekely M, Nemoda Z: Dopaminergic candidate genes in Tourette syndrome: Association between tic severity and 3' UTR polymorphism of the dopamine transporter gene. Am J Med Genet. 2007, 144: 900-905. 10.1002/ajmg.b.30517.CrossRef

48.

Christensen K: Calculation of Chi-square test for deviation from Hardy-Weinberg equilibrium. http://www.husdyr.kvl.dk/htm/kc/popgen/genetik/applets/kitest.htm

49.

Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I: Controlling the false discovery rate in behavior genetics research. Behav Brain Res. 2001, 125: 279-284. 10.1016/S0166-4328(01)00297-2.CrossRefPubMed

50.

Dudbridge F: Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Human Heredity. 2008, 66: 87-98. 10.1159/000119108.PubMedCentralCrossRefPubMed

51.

Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005, 21: 263-5. 10.1093/bioinformatics/bth457.CrossRefPubMed

52.

Young LJ, Wang Z: The neurobiology of pair bonding. Nat Neurosci. 2004, 7: 1048-1054. 10.1038/nn1327.CrossRefPubMed

53.

Curtis JT, Liu Y, Aragona BJ, Wang Z: Dopamine and monogamy. Brain Res. 2006, 1126: 76-90. 10.1016/j.brainres.2006.07.126.CrossRefPubMed

54.

Forbes EE, Brown SM, Kimak M, Ferrell RE, Manuck SB, Hariri AR: Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity. Mol Psychiatry. 2009, 14: 60-70. 10.1038/sj.mp.4002086.PubMedCentralCrossRefPubMed

55.

Arinami T, Gao M, Hamaguchi H, Toru M: A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet. 1997, 6: 577-582. 10.1093/hmg/6.4.577.CrossRefPubMed

56.

Mill J, Asherson P, Craig I, D'Souza UM: Transient expression analysis of allelic variants of a VNTR in the dopamine transporter gene (DAT1). BMC Genet. 2005, 6: 3-10.1186/1471-2156-6-3.PubMedCentralCrossRefPubMed

57.

Wonodi I, Hong LE, Stine OC, Mitchell BD, Elliott A, Roberts RC, Conley RR, McMahon RP, Thaker GK: Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia. Am J Med Genet. 2009, 150: 282-289. 10.1002/ajmg.b.30811.CrossRef

58.

Heinz A, Goldman D, Jones DW, Palmour R, Hommer D, Gorey JG, Lee KS, Linnoila M, Weinberger DR: Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology. 2000, 22: 133-139. 10.1016/S0893-133X(99)00099-8.CrossRefPubMed

59.

van Dyck CH, Malison RT, Jacobsen LK, Seibyl JP, Staley JK, Laruelle M, Baldwin RM, Innis RB, Gelernter J: Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene. J Nucl Med. 2005, 46: 745-751.PubMed

60.

Giessen van de EM, de Win MM, Tanck MW, Brink van den W, Baas F, Booij J: Striatal dopamine transporter availability associated with polymorphisms in the dopamine transporter gene SLC6A3. J Nucl Med. 2009, 50: 45-52. 10.2967/jnumed.108.053652.CrossRefPubMed

61.

White MJ, Lawford BR, Morris CP, Young RM: Interaction between DRD2 C957T polymorphism and an acute psychosocial stressor on reward-related behavioral impulsivity. Behav Genet. 2009, 39: 285-95. 10.1007/s10519-008-9255-7.CrossRefPubMed

62.

Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV: Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet. 2003, 12: 205-16. 10.1093/hmg/ddg055.CrossRefPubMed

63.

Hirvonen M, Laakso A, Någren K, Rinne JO, Pohjalainen T, Hietala J: C957T polymorphism of the dopamine D2 receptor (DRD2) gene affects striatal DRD2 availability in vivo. Mol Psychiatry. 2004, 9: 1060-1. 10.1038/sj.mp.4001561. Erratum in: Mol Psychiatry 2005, 10:889CrossRefPubMed

64.

Hirvonen MM, Laakso A, Någren K, Rinne JO, Pohjalainen T, Hietala J: C957T polymorphism of dopamine D2 receptor gene affects striatal DRD2 in vivo availability by changing the receptor affinity. Synapse. 2009, 63: 907-12. 10.1002/syn.20672.CrossRefPubMed

65.

Yang BZ, Kranzler HR, Zhao H, Gruen JR, Luo X, Gelernter J: Association of haplotypic variants in DRD2, ANKK1, TTC12 and NCAM1 to alcohol dependence in independent case control and family samples. Hum Mol Genet. 2007, 16: 2844-2853. 10.1093/hmg/ddm240.CrossRefPubMed

66.

Huang W, Payne TJ, Ma JZ, Beuten J, Dupont RT, Inohara N, Li MD: Significant association of ANKK1 and detection of a functional polymorphism with nicotine dependence in an African-American sample. Neuropsychopharmacology. 2009, 34: 319-330. 10.1038/npp.2008.37.CrossRefPubMed

67.

Young RM, Lawford BR, Nutting A, Noble EP: Advances in molecular genetics and the prevention and treatment of substance misuse: Implications of association studies of the A1 allele of the D2 dopamine receptor gene. Addict Behav. 2004, 29: 1275-1294. 10.1016/j.addbeh.2004.06.012.CrossRefPubMed

68.

Smith L, Watson M, Gates S, Ball D, Foxcroft D: Meta-analysis of the association of the Taq1A polymorphism with the risk of alcohol dependency: a HuGE gene-disease association review. Am J Epidemiol. 2008, 167: 125-138. 10.1093/aje/kwm281.CrossRefPubMed

Title: Association between dopaminergic polymorphisms and borderline personality traits among at-risk young adults and psychiatric inpatients
Authors: Zsofia Nemoda
Karlen Lyons-Ruth
Anna Szekely
Eszter Bertha
Gabor Faludi
Maria Sasvari-Szekely
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: Behavioral and Brain Functions / Issue 1/2010
Electronic ISSN: 1744-9081
DOI: https://doi.org/10.1186/1744-9081-6-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Association between dopaminergic polymorphisms and borderline personality traits among at-risk young adults and psychiatric inpatients

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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