Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking

Twin and adoption studies suggest that 30 to 60% of the variance in many personality traits is due to inherited factors. However, there is little knowledge of the number or identity of the responsible genes, how they differ between individuals, or how their gene products interact with the developing brain and with environmental and experiential factors to generate the complex blend of attitudes and actions that comprise human temperament1. In the accompanying paper, Ebstein et al.2 have found a population association between a long allele of polymorphic exon III repeat sequence of the D4 dopamine receptor gene (DADR) and the normal personality trait of Novelty Seeking. The possibility of a causal relationship between DADR and Novelty Seeking is further supported by studies showing that the number of exon III repeats can affect the binding of ligands to the receptor3,4; that DADR is expressed in lim-bic areas involved in cognition and emotion5,6; that dopamine mediates exploratory behaviour in experimental animals7–12; that the rewarding effects of amphetamines and cocaine are related to dopamine release13; and that Novelty Seeking is low in dopamine-deficient patients with Parkinson's disease14. We investigated the relationship between DADR exon III sequence variants and personality test scores in a population of 315 mostly male siblings, other family members and individuals from the United States. The association between long alleles of exon III and personality traits related to Novelty Seeking was confirmed. Moreover, family studies showed that this association is the result of genetic transmission rather than of population stratification.

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  1. 1

    Bouchard, T.J.J., Genes, environment, and personality. Science 264, 1700–1701 (1994).

  2. 2

    Ebstein, R.R. et al. Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nature Genet. 12, 78–80 (1996).

  3. 3

    Van Tol, H.H.M. et al. Multiple dopamine D4 receptor variants in the human population. Nature 358, 149–152 (1992).

  4. 4

    Asghari, V. et al. Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes. Mol. Pharmacol. 46, 364–373 (1994).

  5. 5

    Van Tol, H.H.M. et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350, 610–614 (1991).

  6. 6

    Meador-Woodruff, J.H. et al. Dopamine receptor gene expression in the human medial temporal lobe. Neuropsychopharmacology. 10, 239–248 (1994).

  7. 7

    Stellar, J.R. & Stellar, E. in The Neurobiology of Motivation and Reward (Springer-Verlag, New York, 1985).

  8. 8

    Kalivas, R.W. & Nemeroff, C.B. in The Mesocorticolimbic Dopamine System 537(Annals of the New York Academy of Sciences, New York, 1988).

  9. 9

    Hooks, M.S. & Kalivas, R.W. Involvement of dopamine and excitatory amino acid transmission in novelty-induced motor activity. J. Pharmacol. Exp. Ther. 269, 976–988 (1994).

  10. 10

    Fink, J.S. & Reis, D.J. Genetic variations in midbrain dopamine cell number: parallel with differences in responses to dopaminergic agonists and in naturalistic behaviors mediated by central dopaminergic systems. Brain Res. 222, 335–349 (1981).

  11. 11

    Fink, J.S. & Smith, G.P. Mesolimbic and mesocortical dopaminergic neurons are necessary for normal exploratory behavior in rats. Neurosci. Lett. 17, 61–65 (1980).

  12. 12

    Cloninger, C.R., Przybeck, T.R. & Svrakic, D.M. The Tridimensional Personality Questionnaire: U.S. normative data. Psychol. Rep. 69, 1047–1057 (1991).

  13. 13

    Ritz, M.C. & Kuhar, M.J. Psychostimulant drugs and a dopamine hypothesis regarding addiction: update on recent research. Biochem. Soc. Symp. 59, 51–64 (1993).

  14. 14

    Menza, M.A., Golbe, L.I., Cody, R.A. & Forman, N.E. Dopamine-related personality traits in Parkinsons disease. Neurology 43, 505–508 (1993).

  15. 15

    Cloninger, C.R. A systematic method for clinical description and classification of personality variants. A proposal. Arch. Gen. Psych. 44, 573–588 (1987).

  16. 16

    Costa, R.T.J. & McCrae, R.R. . in Revised NEO Personality Inventory (NEO PI-R) and NEO Five Inventory (NEO-FFI) professional manual (Psychological Assessment Resources, Odessa, FL, 1992).

  17. 17

    McCrae, R.R. & Costa, P.T.J. in Personality in Adulthood (Guilford, New York, 1990).

  18. 18

    Costa, P.T.J. & McCrae, R.R. in The Revised NEO Personality Inventory (NEO PI-R) (eds Cheek, J. & Donahue, E.M.) (Plenum, New York, In press).

  19. 19

    Lichter, J.B. et al. A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. Hum. Mol. Genet. 2, 767–773 (1993).

  20. 20

    George, V.T. & Elston, R.C. Testing the association between polymorphic markers and quantitative traits in pedigrees. Genet. Epidemiol. 4, 193–201 (1987).

  21. 21

    Nick, T.G., George, V., Elston, R.C. & Wilson, A.F. Statistical validity for testing associations between genetic markers and quantitative traits in family data. Genet. Epidemiol. 12, 145–146 (1995).

  22. 22

    Elston, R.C., George, V.T. & Sorant, A.J.M. in Trait-marker association program (ASSOC). In S.A.G.E. Users Guide, Release 2.2 (Department of Biometry and Genetics (LSU Medical Center, New Orleans, 1994).

  23. 23

    Spielman, R.S., McGinnis, R.E. & Ewens, W.J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516 (1993).

  24. 24

    Cohen, J. in Statistical Power Analysis for the Behavioral Sciences (Erlbaum,Hillsdale,NJ, 1988).

  25. 25

    Heath, A.C., Cloninger, C.R. & Martin, N.G. Testing a model for thegenetic structure of personality: a comparison of the personality systems of Cloninger and Eysenck. J. Pers. Soc. Psychol. 66, 762–775 (1994).

  26. 26

    Plomin, R., Owen, M.J. & McGuffin, P. The genetic basis of complex human behaviors. Science 264, 1733–1739 (1994).

  27. 27

    Lander, E.S. & Schork, N.J. Genetic dissection of complex traits. Science 265, 2037–2048 (1994).

  28. 28

    Hamer, D.H. & Copeland, P. in The Science of Desire (Simon & Schuester, New York, 1994).

  29. 29

    Costa, P.T.J. & McCrae, R.R. in The Developing Structure of Temperament and Personality from Infancy to Adulthood (eds. Halverson, C.F., Kohnstamm, G.A. & Martin, R.R) 139–150 (Lawrence Erlbaum Associates, Hillsdale, NJ, in the press).

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Benjamin, J., Li, L., Patterson, C. et al. Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. Nat Genet 12, 81–84 (1996). https://doi.org/10.1038/ng0196-81

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