D 2 and D 4 Dopamine Receptor Polymorphisms and Personality Ernest P. Noble, 1,2 * Tulin Z. Ozkaragoz, 1 Terry L. Ritchie, 1 Xuxian Zhang, 1 Thomas R. Belin, 1 and Robert S. Sparkes 3 1 Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California 2 Brain Research Institute, University of California, Los Angeles, California 3 Department of Medicine, University of California, Los Angeles, California The relationship of various dimensions of temperament, measured by the Tridimen- sional Personality Questionnaire (TPQ), to polymorphisms of the D 2 dopamine receptor (DRD2) and D 4 dopamine receptor (DRD4) genes was determined in 119 healthy Cauca- sian boys who had not yet begun to consume alcohol and other drugs of abuse. Total Nov- elty Seeking score of the TPQ was signifi- cantly higher in boys having, in common, all three minor (A1,B1, and Intron 6 1) alleles of the DRD2 compared to boys without any of these alleles. Boys with the DRD4 7 repeat (7R) allele also had a significantly higher Novelty Seeking score than those without this allele. However, the greatest difference in Novelty Seeking score was found when boys having all three minor DRD2 alleles and the DRD4 7R allele were contrasted to those without any of these alleles. Neither the DRD2 nor the DRD4 polymorphisms dif- ferentiated total Harm Avoidance score. Whereas subjects having all three minor DRD2 alleles had a significantly higher Re- ward Dependence 2 (Persistence) score than subjects without any of these alleles, no sig- nificant difference in this personality score was found between subjects with and with- out the DRD4 7R allele. In conclusion, DRD2 and DRD4 polymorphisms individually as- sociate with Novelty Seeking behavior. However, the combined DRD2 and DRD4 polymorphisms contribute more markedly to this behavior than when these two gene polymorphisms are individually considered. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:257–267, 1998. © 1998 Wiley-Liss, Inc. KEY WORDS: D 2 dopamine receptor gene; D 4 dopamine receptor gene; polymorphism; personality; novelty seeking; reward INTRODUCTION Family, twin, and adoption studies have provided convergent evidence for the importance of hereditary factors in a variety of human traits and disorders [Plo- min et al., 1994]. The specific nature of these factors have remained elusive until the recent advent of mo- lecular genetic techniques, the application of which has led to spectacular identification of single genes in rare disorders with simple Mendelian patterns of inheri- tance. However, it has been a great challenge to iden- tify genes in human behavioral traits and disorders where no simple patterns of inheritance are known, and wherein minor genes in various combinations may conspire with environmental factors to produce a vari- ety of phenotypes. Neurotransmitter genes are among key candidates for evaluation in complex behaviors and behavioral dis- orders. In this regard, the dopaminergic system has received a great deal of attention since a large body of knowledge implicates this system in brain reward mechanisms [Wise and Rompre, 1989; Koob, 1992; Sch- ultz et al., 1995]. That dopaminergic genes are involved in behavioral disorders was first revealed when the D 2 dopamine receptor (DRD2) gene was found to be in- volved in alcoholism [Blum et al., 1990]. Specifically, the minor TaqI A allele (A1) of the DRD2 was observed to be associated with a severe form of alcoholism. Whereas controversy has arisen because some studies found a lack of significant association of the DRD2 al- lele with this disorder, more recent investigations have revealed that the type of controls and alcoholics used [Noble et al., 1994d; Neiswanger et al., 1995; Lawford et al., 1997] are important determinants in this asso- ciation [for recent review, see Noble, 1997]. It should, however, be noted that besides alcoholism, the DRD2 Contract grant sponsor: Adele C. Smithers and The Chris- topher D. Smithers Foundation; Contract grant sponsor: NIAAA; Contract grant number: AA-08020. *Correspondence to: Dr. Ernest P. Noble, Department of Psy- chiatry and Biobehavioral Sciences, Neuropsychiatric Institute, University of California, Los Angeles, CA 90024-1759. E-mail: epnoble@ucla.edu Received 30 September 1997; Revised 30 December 1997 American Journal of Medical Genetics (Neuropsychiatric Genetics) 81:257–267 (1998) © 1998 Wiley-Liss, Inc.