Skip to main content

Advertisement

SpringerLink
Log in

A functional dopamine-β-hydroxylase gene promoter polymorphism is associated with impulsive personality styles, but not with affective disorders

  • Basic Neurosciences, Genetics and Immunology - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Dopamine-β-hydroxylase (DβH) catalyzes the conversion of dopamine to norepinephrine in central noradrenergic and adrenergic neurons and thus is critically involved in the biosynthesis of catecholamines. There are equivocal findings concerning the question whether or not DßH activity levels are altered in affective disorders or in subtypes of affective disorders. Moreover, information about the role of dopamine beta-hydroxylase (DBH) genotype, which explains a large part of the variance of enzymatic activity, in affective disorders and personality dimensions is limited. To resolve these inconsistencies, association tests were performed using four independent samples, healthy volunteers (N = 387), patients with affective disorders (N = 182), adult attention deficit hyperactivity disorder (ADHD) patients (N = 407), and patients with personality disorders (N = 637). In the latter two samples, the revised NEO personality inventory (NEO-PI-R) was administered. All participants were genotyped for a putatively functional single nucleotide polymorphism (C-1021T, rs1611115). No differences in DBH C-1021T genotype distribution were observed between patients with affective disorders and healthy control subjects. Also when the patient sample was divided into uni- and bipolar patients versus controls, no significant differences emerged. Furthermore, no clear-cut association was detected between the TT genotype and personality disorder clusters while there was a significant association with adult ADHD. However, personality disorder patients carrying the DBH TT genotype exhibited higher neuroticism and novelty seeking scores as compared to individuals with the CC or CT genotype. Analyses on the level of the neuroticism and novelty seeking subscales revealed that the DBH TT genotype was primarily associated with personality features related to impulsiveness and aggressive hostility. Also adult ADHD patients carrying the homozygous TT genotypes displayed by significantly increased neuroticism scores; when both personality disorder and adult ADHD patient were analyzed together, TT carriers also displayed by significantly lower conscientiousness levels. Our results thus do not implicate the DBH C-1021T polymorphism in the pathophysiology of depressive disorders or personality disorders, yet homozygosity at this locus appears to increase the risk towards personality traits related to impulsiveness, aggression and related disease states, namely adult ADHD. These data argue for a dimensional rather than categorical effect of genetic variance in DBH activity; accordingly, the inconsistency of previous findings concerning DβH levels in affective disorders might be caused by the underlying association of the TT genotype at DBH-1021 with impulsive personality traits.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie (2000) Das AMDP-System. Manual zur Dokumentation psychiatrischer Befunde, 7th edn. Hogrefe, Goettingen

  • Arnsten AF, Li BM (2005) Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 57:1377–1384

    Article  PubMed  CAS  Google Scholar 

  • Bhaduri N, Mukhopadhyay K (2006) Lack of significant association between -1021C → T polymorphism in the dopamine beta hydroxylase gene and attention deficit hyperactivity disorder. Neurosci Lett 402:12–16

    Article  PubMed  CAS  Google Scholar 

  • Brozoski TJ, Brown RM, Rosvold HE, Goldman PS (1979) Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205:929–932

    Article  PubMed  CAS  Google Scholar 

  • Cloninger CR, Przybeck TR, Svrakic DM (1991) The Tridimensional Personality Questionnaire: U.S. normative data. Psychol Rep 69:1047–1057

    Article  PubMed  CAS  Google Scholar 

  • Coccaro EF, Lee R, McCloskey M (2003) Norepinephrine function in personality disorder: plasma free MHPG correlates inversely with life history of aggression. CNS Spectr 8:731–736

    PubMed  Google Scholar 

  • Collier DA, Stöber G, Li T, Heils A, Catalano M, Di Bella D et al (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1:453–460

    PubMed  CAS  Google Scholar 

  • Cohen J (1988) Statistical power analysis for the behavioral sciences, 2nd edn. Lawrence Erlbaum Associates, Hillsdale

  • Costa PT Jr, McCrae RR (1995) Domains and facets: hierarchical personality assessment using the revised NEO personality inventory. J Pers Assess 64:21–50

    Article  PubMed  Google Scholar 

  • Craig SP, Buckle VJ, Lamouroux A, Mallet J, Craig IW (1988) Localization of the human dopamine beta hydroxylase (DBH) gene to chromosome 9q34. Cytogenet Cell Genet 48:48–50

    Article  PubMed  CAS  Google Scholar 

  • Cubells JF, Zabetian CP (2004) Human genetics of plasma dopamine beta-hydroxylase activity: applications to research in psychiatry and neurology. Psychopharmacology (Berl) 174:463–476

    Article  CAS  Google Scholar 

  • Cubells JF, Price LH, Meyers BS, Anderson GM, Zabetian CP, Alexopoulos GS, Nelson JC, Sanacora G, Kirwin P, Carpenter L, Malison RT, Gelernter J (2002) Genotype-controlled analysis of plasma dopamine beta-hydroxylase activity in psychotic unipolar major depression. Biol Psychiatry 51:358–364

    Article  PubMed  CAS  Google Scholar 

  • D’Amato T, Leboyer M, Malafosse A, Samolyk D, Lamouroux A, Junien C, Mallet J (1989) Two TaqI dimorphic sites at the human beta-hydroxylase locus. Nucleic Acids Res 17:5871

    Article  PubMed  CAS  Google Scholar 

  • Dunnette J, Weinshilboum R (1976) Human serum dopamine beta-hydroxylase: correlation of enzymatic activity with immunoreactive protein in genetically defined samples. Am J Hum Genet 28:155–166

    PubMed  CAS  Google Scholar 

  • Ehlis AC, Reif A, Herrmann MJ, Lesch KP, Fallgatter AJ (2007) Impact of catechol-O-methyltransferase on prefrontal brain functioning in schizophrenia spectrum disorders. Neuropsychopharmacology 32:162–170

    Article  PubMed  CAS  Google Scholar 

  • Eisemann M, Ericsson U, Von Knorring L, Perris C, Perris H, Ross S (1983) Serum dopamine-beta-hydroxylase in diagnostic subgroups of depressed patients and in relation to their personality characteristics. Neuropsychobiology 9:193–196

    Article  PubMed  CAS  Google Scholar 

  • Erdfelder E, Faul F, Buchner A (1996) GPOWER: a general power analysis program. Behav Res Methods Instrum Comput 28:1–11

    Google Scholar 

  • Fahndrich E, Muller-Oerlinghausen B, Coper H (1982) Longitudinal assessment of MAO-, COMT-, and DBH- activity in patients with bipolar depression. Int Pharmacopsychiatry 17:8–17

    PubMed  CAS  Google Scholar 

  • Fichter MM, Narrow WE, Roper MT, Rehm J, Elton M, Rae DS, Locke BZ, Regier DA (1996) Prevalence of mental illness in Germany and the United States. Comparison of the Upper Bavarian Study and the Epidemiologic Catchment Area Program. J Nerv Ment Dis 184:598–606

    Article  PubMed  CAS  Google Scholar 

  • Freire MT, Hutz MH, Bau CH (2005) The DBH–1021 C/T polymorphism is not associated with alcoholism but possibly with patients’ exposure to life events. J Neural Transm 112:1269–1274

    Article  PubMed  CAS  Google Scholar 

  • Gabel S, Stadler J, Bjorn J, Shindledecker R (1995) Homovanillic acid and dopamine-beta-hydroxylase in male youth: relationships with paternal substance abuse and antisocial behavior. Am J Drug Alcohol Abuse 21:363–378

    Article  PubMed  CAS  Google Scholar 

  • Galvin M, Shekhar A, Simon J, Stilwell B, Ten Eyck R, Laite G, Karwisch G, Blix S (1991) Low dopamine-beta-hydroxylase: a biological sequela of abuse and neglect? Psychiatry Res 39:1–11

    Article  PubMed  CAS  Google Scholar 

  • Jacob CP, Strobel A, Hohenberger K, Ringel T, Gutknecht L, Reif A, Brocke B, Lesch KP (2004) Association between allelic variation of serotonin transporter function and neuroticism in anxious cluster C personality disorders. Am J Psychiatry 161:569–572

    Article  PubMed  Google Scholar 

  • Jacob CP, Muller J, Schmidt M, Hohenberger K, Gutknecht L, Reif A, Schmidtke A, Mossner R, Lesch KP (2005) Cluster B personality disorders are associated with allelic variation of monoamine oxidase A activity. Neuropsychopharmacology 30:1711–1718

    Article  PubMed  CAS  Google Scholar 

  • Jacob CP, Romanos J, Dempfle A, Heine M, Windemuth-Kieselbach C, Kruse A, Reif A, Walitza S, Romanos M, Strobel A, Brocke B, Schafer H, Schmidtke A, Boning J, Lesch KP (2007) Co-morbidity of adult attention-deficit/hyperactivity disorder with focus on personality traits and related disorders in a tertiary referral center. Eur Arch Psychiatry Clin Neurosci 257:309–317

    Article  PubMed  Google Scholar 

  • Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, Faraone SV, Greenhill LL, Howes MJ, Secnik K, Spencer T, Ustun TB, Walters EE, Zaslavsky AM (2006) The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 163:716–723

    Article  PubMed  Google Scholar 

  • Kobayashi K, Kurosawa Y, Fujita K, Nagatsu T (1989) Human dopamine beta-hydroxylase gene: two mRNA types having different 3′-terminal regions are produced through alternative polyadenylation. Nucleic Acids Res 17:1089–1102

    Article  PubMed  CAS  Google Scholar 

  • Kohnke MD, Zabetian CP, Anderson GM, Kolb W, Gaertner I, Buchkremer G, Vonthein R, Schick S, Lutz U, Kohnke AM, Cubells JF (2002) A genotype-controlled analysis of plasma dopamine beta-hydroxylase in healthy and alcoholic subjects: evidence for alcohol-related differences in noradrenergic function. Biol Psychiatry 52:1151–1158

    Article  PubMed  CAS  Google Scholar 

  • Kuperman S, Kramer J, Loney J (1988) Enzyme activity and behavior in hyperactive children grown up. Biol Psychiatry 24:375–383

    Article  PubMed  CAS  Google Scholar 

  • Lenzenweger MF, Lane MC, Loranger AW, Kessler RC (2007) DSM-IV personality disorders in the National Comorbidity Survey Replication. Biol Psychiatry 62:553–564

    Article  PubMed  Google Scholar 

  • Levitt M, Dunner DL, Mendlewicz J, Frewin DB, Lawlor W, Fleiss JL, Stallone F, Fieve RR (1976) Plasma dopamine beta hydroxylase activity in affective disorders. Psychopharmacologia 46:205–210

    Article  PubMed  CAS  Google Scholar 

  • Marino MD, Bourdelat-Parks BN, Cameron Liles L, Weinshenker D (2005) Genetic reduction of noradrenergic function alters social memory and reduces aggression in mice. Behav Brain Res 161:197–203

    Article  PubMed  CAS  Google Scholar 

  • Major LF, Lerner P, Goodwin FK, Ballenger JC, Brown GL, Lovenberg W (1980) Dopamine beta-hydroxylase in CSF. Relationship to personality measures. Arch Gen Psychiatry 37:308–310

    PubMed  CAS  Google Scholar 

  • Markianos ES, Nystrom I, Reichel H, Matussek N (1976) Serum dopamine-beta-hydroxylase in psychiatric patients and normals. Effect of d-amphetamine and haloperidol. Psychopharmacology (Berl) 50:259–267

    Article  CAS  Google Scholar 

  • Mathew RJ, Ho BT, Davis C, Taylor D, Reck J (1981) Depression, antidepressants, and plasma DBH. Psychiatry Res 5:331–334

    Article  PubMed  CAS  Google Scholar 

  • Matuzas W, Meltzer HY, Uhlenhuth EH, Glass RM, Tong C (1982) Plasma dopamine-beta-hydroxylase in depressed patients. Biol Psychiatry 17:1415–1424

    PubMed  CAS  Google Scholar 

  • Meltzer HY, Cho HW, Carroll BJ, Russo P (1976) Serum dopamine-beta-hydroxylase activity in the affective psychoses and schizophrenia. Decreased activity in unipolar psychotically depressed patients. Arch Gen Psychiatry 33:585–591

    PubMed  CAS  Google Scholar 

  • Meyers BS, Alexopoulos GS, Kakuma T, Tirumalasetti F, Gabriele M, Alpert S et al (1999) Decreased dopamine beta-hydroxylase activity in unipolar geriatric delusional depression. Biol Psychiatry 45:448–452

    Article  PubMed  CAS  Google Scholar 

  • Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  PubMed  CAS  Google Scholar 

  • Mod L, Rihmer Z, Magyar I, Arato M, Alfoldi A, Bagdy G (1986) Serum DBH activity in psychotic vs. nonpsychotic unipolar and bipolar depression. Psychiatry Res 19:331–333

    Article  PubMed  CAS  Google Scholar 

  • O’Connor DT, Levine GL, Frigon RP (1983) Homologous radio-immunoassay of human plasma dopamine-beta-hydroxylase: analysis of homospecific activity, circulating plasma pool and intergroup differences based on race, blood pressure and cardiac function. J Hypertens 1:227–233

    Article  PubMed  CAS  Google Scholar 

  • O’Connor DT, Cervenka JH, Stone RA, Levine GL, Parmer RJ, Franco-Bourland RE, Madrazo I, Langlais PJ, Robertson D, Biaggioni I (1994) Dopamine beta-hydroxylase immunoreactivity in human cerebrospinal fluid: properties, relationship to central noradrenergic neuronal activity and variation in Parkinson’s disease and congenital dopamine beta-hydroxylase deficiency. Clin Sci (Lond) 86:149–158

    CAS  Google Scholar 

  • Oxenstierna G, Edman G, Iselius L, Oreland L, Ross SB, Sedvall G (1986) Concentrations of monoamine metabolites in the cerebrospinal fluid of twins and unrelated individuals—a genetic study. J Psychiatr Res 20:19–29

    Article  PubMed  CAS  Google Scholar 

  • Puzynski S, Rode A, Zaluska M (1983) Studies on biogenic amine metabolizing enzymes (DBH, COMT, MAO) and pathogenesis of affective illness. I. Plasma dopamine-beta-hydroxylase activity in endogenous depression. Acta Psychiatr Scand 67:89–95

    Article  PubMed  CAS  Google Scholar 

  • Reif A, Lesch KP (2003) Toward a molecular architecture of personality. Behav Brain Res 139:1–20

    Article  PubMed  CAS  Google Scholar 

  • Rogeness GA, Hernandez JM, Macedo CA, Mitchell EL (1982) Biochemical differences in children with conduct disorder socialized and undersocialized. Am J Psychiatry 139:307–311

    PubMed  CAS  Google Scholar 

  • Roy A, Brockington K (1987) Plasma dopamine-beta-hydroxylase in depressed patients and controls. Neuropsychobiology 18:57–59

    Article  PubMed  CAS  Google Scholar 

  • Sapru MK, Rao BS, Channabasavanna SM (1989) Serum dopamine-beta-hydroxylase activity in clinical subtypes of depression. Acta Psychiatr Scand 80:474–478

    Article  PubMed  CAS  Google Scholar 

  • Sofuoglu S, Dogan P, Kose K, Esel E, Basturk M, Oguz H, Gonul AS (1995) Changes in platelet monoamine oxidase and plasma dopamine-beta-hydroxylase activities in lithium-treated bipolar patients. Psychiatry Res 59:165–170

    Article  PubMed  CAS  Google Scholar 

  • Strandman E, Wetterberg L, Perris C, Ross SB (1978) Serum dopamine-beta-hydroxylase in affective disorders. Neuropsychobiology 4:248–255

    Article  PubMed  CAS  Google Scholar 

  • Tang Y, Anderson GM, Zabetian CP, Kohnke MD, Cubells JF (2005) Haplotype-controlled analysis of the association of a non-synonymous single nucleotide polymorphism at DBH (+1603C → T) with plasma dopamine beta-hydroxylase activity. Am J Med Genet B Neuropsychiatr Genet 139:88–90

    Google Scholar 

  • Tang Y, Buxbaum SG, Waldman I, Anderson GM, Zabetian CP, Kohnke MD, Cubells JF (2006) A single nucleotide polymorphism at DBH, possibly associated with attention-deficit/hyperactivity disorder, associates with lower plasma dopamine beta-hydroxylase activity and is in linkage disequilibrium with two putative functional single nucleotide polymorphisms. Biol Psychiatry 60(10):1034–1038

    Article  PubMed  CAS  Google Scholar 

  • Thomas SA, Palmiter RD (1997) Disruption of the dopamine beta-hydroxylase gene in mice suggests roles for norepinephrine in motor function, learning, and memory. Behav Neurosci 111:579–589

    Article  PubMed  CAS  Google Scholar 

  • Zabetian CP, Anderson GM, Buxbaum SG, Elston RC, Ichinose H, Nagatsu T, Kim KS, Kim CH, Malison RT, Gelernter J, Cubells JF (2001) A quantitative-trait analysis of human plasma-dopamine beta-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus. Am J Hum Genet 68:515–522

    Article  PubMed  CAS  Google Scholar 

  • Zabetian CP, Buxbaum SG, Elston RC, Kohnke MD, Anderson GM, Gelernter J, Cubells JF (2003) The structure of linkage disequilibrium at the DBH locus strongly influences the magnitude of association between diallelic markers and plasma dopamine beta-hydroxylase activity. Am J Hum Genet 72:1389–1400

    Article  PubMed  CAS  Google Scholar 

  • Zhang HB, Wang YF, Li J, Wang B, Yang L (2005) Association between dopamine beta hydroxylase gene and attention deficit hyperactivity disorder complicated with disruptive behavior disorder. Zhonghua Er Ke Za Zhi 43:26–30

    PubMed  Google Scholar 

  • Zuckerman M (1993) P-impulsive sensation seeking and its behavioral, psychophysiological and biochemical correlates. Neuropsychobiology 28:30–36

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are indebted to T. Töpner for excellent technical assistance. This study was supported by the Deutsche Forschungsgemeinschaft (Grant RE1632/1-1 and 1-3 to A.R., KFO 125/1-1 to A.R., K.P.L. and C.P.J., and SFB581 to K.-P.L.), Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (IZKF Wuerzburg, 01KS9603 to K.P.L and N-4(1) to A.R.) and the European Commission (NEWMOOD LSHM-CT-2003-503474 to K.P.L.).

Author information

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Clinical and Molecular Psychobiology, University of Wuerzburg, Fuechsleinstrasse 15, 97080, Wuerzburg, Germany

    C. Hess, A. Reif, A. Boreatti-Hümmer, M. Heine, K.-P. Lesch & C. P. Jacob

  2. Interdiciplinary Center for Clinical Research (IZKF), University of Wuerzburg, Wuerzburg, Germany

    A. Reif & K.-P. Lesch

  3. Department of Psychology, Johann Wolfgang Goethe University Frankfurt/Main, Frankfurt/Main, Germany

    A. Strobel

Authors
  1. C. Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Reif
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Strobel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Boreatti-Hümmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Heine
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K.-P. Lesch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. P. Jacob
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. P. Jacob.

Additional information

C. Hess and A. Reif contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hess, C., Reif, A., Strobel, A. et al. A functional dopamine-β-hydroxylase gene promoter polymorphism is associated with impulsive personality styles, but not with affective disorders. J Neural Transm 116, 121–130 (2009). https://doi.org/10.1007/s00702-008-0138-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-008-0138-0

Keywords

Search

Navigation