Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1997 Nov;61(5):1144–1152. doi: 10.1086/301595

D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance-dependent, personality-disorder, and control subjects.

J Gelernter 1, H Kranzler 1, E Coccaro 1, L Siever 1, A New 1, C L Mulgrew 1
PMCID: PMC1716050  PMID: 9345090

Abstract

Two reports have been published suggesting an association between the personality trait of novelty seeking and the DRD4*7R allele at the D4 dopamine-receptor locus (with heterozygotes or homozygotes for DRD4*7R having higher novelty seeking). We studied novelty seeking and four coding-sequence polymorphisms affecting protein structure in the D4 dopamine-receptor gene (DRD4) in a sample of 341 American subjects, of whom 224 are of primarily European ancestry and 117 are of primarily African ancestry. These subjects had diagnoses of substance dependence or personality disorder (PD) or were screened to exclude major psychiatric diagnosis. We found that, although the substance-dependent subjects had significantly higher novelty seeking than the control and PD subjects, they did not differ in DRD4*7R allele frequency. There was no association between any DRD4 polymorphism and novelty seeking in any population or diagnostic group, except for a significant association between the DRD4*7R allele and lower novelty seeking among European American females and African American substance abusers. The novelty seeking of subjects heterozygous for a null mutation did not differ from that of subjects with two functional alleles. We conclude that the most likely explanation of these results is that the DRD4 VNTR does not influence directly the trait of novelty seeking, in these samples.

Full text

PDF
1144

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adamson M. D., Kennedy J., Petronis A., Dean M., Virkkunen M., Linnoila M., Goldman D. DRD4 dopamine receptor genotype and CSF monoamine metabolites in Finnish alcoholics and controls. Am J Med Genet. 1995 Jun 19;60(3):199–205. doi: 10.1002/ajmg.1320600306. [DOI] [PubMed] [Google Scholar]
  2. Asghari V., Sanyal S., Buchwaldt S., Paterson A., Jovanovic V., Van Tol H. H. Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem. 1995 Sep;65(3):1157–1165. doi: 10.1046/j.1471-4159.1995.65031157.x. [DOI] [PubMed] [Google Scholar]
  3. Asghari V., Schoots O., van Kats S., Ohara K., Jovanovic V., Guan H. C., Bunzow J. R., Petronis A., Van Tol H. H. Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes. Mol Pharmacol. 1994 Aug;46(2):364–373. [PubMed] [Google Scholar]
  4. Benjamin J., Li L., Patterson C., Greenberg B. D., Murphy D. L., Hamer D. H. Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. Nat Genet. 1996 Jan;12(1):81–84. doi: 10.1038/ng0196-81. [DOI] [PubMed] [Google Scholar]
  5. Catalano M., Nobile M., Novelli E., Nöthen M. M., Smeraldi E. Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients. Biol Psychiatry. 1993 Oct 1;34(7):459–464. doi: 10.1016/0006-3223(93)90236-7. [DOI] [PubMed] [Google Scholar]
  6. Chang F. M., Kidd K. K. Rapid molecular haplotyping of the first exon of the human dopamine D4 receptor gene by heteroduplex analysis. Am J Med Genet. 1997 Feb 21;74(1):91–94. doi: 10.1002/(sici)1096-8628(19970221)74:1<91::aid-ajmg18>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  7. Cloninger C. R. Neurogenetic adaptive mechanisms in alcoholism. Science. 1987 Apr 24;236(4800):410–416. doi: 10.1126/science.2882604. [DOI] [PubMed] [Google Scholar]
  8. Cloninger C. R., Przybeck T. R., Svrakic D. M. The Tridimensional Personality Questionnaire: U.S. normative data. Psychol Rep. 1991 Dec;69(3 Pt 1):1047–1057. doi: 10.2466/pr0.1991.69.3.1047. [DOI] [PubMed] [Google Scholar]
  9. Coccaro E. F., Kavoussi R. J., Sheline Y. I., Lish J. D., Csernansky J. G. Impulsive aggression in personality disorder correlates with tritiated paroxetine binding in the platelet. Arch Gen Psychiatry. 1996 Jun;53(6):531–536. doi: 10.1001/archpsyc.1996.01830060075010. [DOI] [PubMed] [Google Scholar]
  10. Cubells J. F., Kobayashi K., Nagatsu T., Kidd K. K., Kidd J. R., Calafell F., Kranzler H. R., Ichinose H., Gelernter J. Population genetics of a functional variant of the dopamine beta-hydroxylase gene (DBH). Am J Med Genet. 1997 Jul 25;74(4):374–379. doi: 10.1002/(sici)1096-8628(19970725)74:4<374::aid-ajmg7>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  11. Ebstein R. P., Novick O., Umansky R., Priel B., Osher Y., Blaine D., Bennett E. R., Nemanov L., Katz M., Belmaker R. H. Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nat Genet. 1996 Jan;12(1):78–80. doi: 10.1038/ng0196-78. [DOI] [PubMed] [Google Scholar]
  12. Feng D., Baker L. Spouse similarity in attitudes, personality, and psychological well-being. Behav Genet. 1994 Jul;24(4):357–364. doi: 10.1007/BF01067537. [DOI] [PubMed] [Google Scholar]
  13. Gelernter J., Kennedy J. L., van Tol H. H., Civelli O., Kidd K. K. The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS. Genomics. 1992 May;13(1):208–210. doi: 10.1016/0888-7543(92)90222-e. [DOI] [PubMed] [Google Scholar]
  14. George S. R., Cheng R., Nguyen T., Israel Y., O'Dowd B. F. Polymorphisms of the D4 dopamine receptor alleles in chronic alcoholism. Biochem Biophys Res Commun. 1993 Oct 15;196(1):107–114. doi: 10.1006/bbrc.1993.2222. [DOI] [PubMed] [Google Scholar]
  15. Grice D. E., Leckman J. F., Pauls D. L., Kurlan R., Kidd K. K., Pakstis A. J., Chang F. M., Buxbaum J. D., Cohen D. J., Gelernter J. Linkage disequilibrium between an allele at the dopamine D4 receptor locus and Tourette syndrome, by the transmission-disequilibrium test. Am J Hum Genet. 1996 Sep;59(3):644–652. [PMC free article] [PubMed] [Google Scholar]
  16. Jönsson E. G., Nöthen M. M., Gustavsson J. P., Neidt H., Brené S., Tylec A., Propping P., Sedvall G. C. Lack of evidence for allelic association between personality traits and the dopamine D4 receptor gene polymorphisms. Am J Psychiatry. 1997 May;154(5):697–699. doi: 10.1176/ajp.154.5.697. [DOI] [PubMed] [Google Scholar]
  17. Lichter J. B., Barr C. L., Kennedy J. L., Van Tol H. H., Kidd K. K., Livak K. J. A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. Hum Mol Genet. 1993 Jun;2(6):767–773. doi: 10.1093/hmg/2.6.767. [DOI] [PubMed] [Google Scholar]
  18. Liu I. S., Seeman P., Sanyal S., Ulpian C., Rodgers-Johnson P. E., Serjeant G. R., Van Tol H. H. Dopamine D4 receptor variant in Africans, D4valine194glycine, is insensitive to dopamine and clozapine: report of a homozygous individual. Am J Med Genet. 1996 Jan 22;61(3):277–282. doi: 10.1002/(SICI)1096-8628(19960122)61:3<277::AID-AJMG14>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  19. Malhotra A. K., Virkkunen M., Rooney W., Eggert M., Linnoila M., Goldman D. The association between the dopamine D4 receptor (D4DR) 16 amino acid repeat polymorphism and novelty seeking. Mol Psychiatry. 1996 Nov;1(5):388–391. [PubMed] [Google Scholar]
  20. Meador-Woodruff J. H., Grandy D. K., Van Tol H. H., Damask S. P., Little K. Y., Civelli O., Watson S. J., Jr Dopamine receptor gene expression in the human medial temporal lobe. Neuropsychopharmacology. 1994 Jul;10(4):239–248. doi: 10.1038/npp.1994.27. [DOI] [PubMed] [Google Scholar]
  21. Muramatsu T., Higuchi S., Murayama M., Matsushita S., Hayashida M. Association between alcoholism and the dopamine D4 receptor gene. J Med Genet. 1996 Feb;33(2):113–115. doi: 10.1136/jmg.33.2.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nöthen M. M., Cichon S., Hemmer S., Hebebrand J., Remschmidt H., Lehmkuhl G., Poustka F., Schmidt M., Catalano M., Fimmers R. Human dopamine D4 receptor gene: frequent occurrence of a null allele and observation of homozygosity. Hum Mol Genet. 1994 Dec;3(12):2207–2212. doi: 10.1093/hmg/3.12.2207. [DOI] [PubMed] [Google Scholar]
  23. Petronis A., Van Tol H. H., Lichter J. B., Livak K. J., Kennedy J. L. The D4 dopamine receptor gene maps on 11p proximal to HRAS. Genomics. 1993 Oct;18(1):161–163. doi: 10.1006/geno.1993.1445. [DOI] [PubMed] [Google Scholar]
  24. Spitzer R. L., Williams J. B., Gibbon M., First M. B. The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. Arch Gen Psychiatry. 1992 Aug;49(8):624–629. doi: 10.1001/archpsyc.1992.01820080032005. [DOI] [PubMed] [Google Scholar]
  25. Van Tol H. H., Bunzow J. R., Guan H. C., Sunahara R. K., Seeman P., Niznik H. B., Civelli O. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature. 1991 Apr 18;350(6319):610–614. doi: 10.1038/350610a0. [DOI] [PubMed] [Google Scholar]
  26. Van Tol H. H., Wu C. M., Guan H. C., Ohara K., Bunzow J. R., Civelli O., Kennedy J., Seeman P., Niznik H. B., Jovanovic V. Multiple dopamine D4 receptor variants in the human population. Nature. 1992 Jul 9;358(6382):149–152. doi: 10.1038/358149a0. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES