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four TPQ personality dimensions. was used to assess personality dimensions in thisThe 5-HTTLPR polymorphism was analyzed for 120 berg equilibrium (l/l = 0.20, l/s = 0.55 and s/s = 0.25). Normal personality traits, as measured by dimenAs shown in Table 1, no significant differences in mean sional scales of personality assessment, are partially TPQ scores for each of the four personality dimensions inherited and between 30-60% of the observed vari-(HA, RD134, RD2 and NS) were observed when the ance can be accounted for by genes. [1][2][3][4] Only recently, subjects were grouped according to 5-HTTLPR genohowever, have several candidate gene polymorphisms type (one-way Anova; HA by genotype, l/l, s/l, s/s: been connected with particular human temperament F = 0.366, P = 0.694). Nor was any difference observed traits. [5][6][7][8][9][10][11] . We reported an association between a human when the l/l vs l/s and s/s genotypes were compared personality trait, Novelty Seeking, and the long repeat (HA by genotype: F = 0.100, P = 0.752). No significant allele of the D4 dopamine receptor exon III polymordifference in genotype frequency was observed phism. 5 Although our results were confirmed by between the Ashkenazi and non-Ashkenazi cohort another laboratory 7 employing a different personality ( 2 = 0.52, P = 0.77, Pearson). Nor was any significant difference observed between TPQ scores and 5-questionnaire in an ethnically distinct population, in

Keywords: personality; polymorphism; tridimensional personality questionnaire; catechol O-methyltransferase; dopamine D4 receptor; serotonin transporter promoter Dopamine D4 receptor (DRD4), serotonin transporter promoter regulatory region (5-HTTLPR) and catechol Omethyltransferase (COMT) polymorphisms were examined for association with TPQ personality factors in 455 subjects. Significant interactions were observed by multivariate analysis, (COMT × 5-HTTLPR: Hotelling's Trace = 2.3, P = 0.02) and by subsequent univariate 3-way ANOVA when Novelty Seeking (NS) was the dependent variable: 5-HTTLPR × D4DR (F = 6.18, P = 0.03) and COMT × 5-HTTLPR (F = 4.42, P = 0.03). In the absence of the short 5-HTTLPR allele and in the presence of the high enzyme activity COMT val/val genotype, NS scores are higher in the presence of the DRD4 seven-repeat allele. The effect of these three polymorphisms on NS was also examined using a within-families design. Siblings who shared identical genotype groups for all three polymorphisms (COMT, DRD4 and 5-HTTLPR) had significantly correlated NS scores (intraclass coefficient = 0.39, F = 2.26, P = 0.008, n = 49) whereas sibs with dissimilar genotypes in at least one polymorphism showed no significant correlation for NS scores (intraclass coefficient = 0.177, F = 1.43, P = 0.09, n = 110). Similar interactions were also observed between these three polymorphisms and Novelty Seeking when the 150 independently recruited and non-related subjects were analyzed. The current results are consistent with two earlier reports in which we demonstrated an interaction between the 5-HTTLPR and DRD4 polymorphisms in 2-week-old neonates, in the same children assessed again at 2 months of age and in adults. Molecular Psychiatry Twin studies demonstrate that personality traits measured by several self-report questionnaires including the TPQ 1 and NEO-PI-R 2 are partially inherited and between 30-60% of the observed variance can be accounted for by genes. Only recently, however, have common genetic polymorphisms especially DRD4 and 5-HTTLPR, been provisionally assigned to particular temperament factors. [3][4][5] It seems reasonable that as additional genetic information is inventoried for various cohorts, associations between DRD4, 5-HTTLPR and other candidate genes and complex phenotypes will be further clarified. We, 6-8 and others, 9-11 have begun to examine multiple interactions between common genetic polymorphisms and complex behavioral traits. The catechol O-methyltransferase (COMT) gene contains a common, functional polymorphism in which a val-to-met amino acid substitution markedly reduces enzyme activity to about 20% of wild-type (val) levels. 12 Recent studies have suggested a role for COMT in behaviors often associated with impulsivity and disinhibition, 13-15 although to our knowledge, this gene has yet to be examined for a role in normal human personality.In the current study we initially examined using multivariate ANOVA four TPQ personality factor scores for 455 subjects grouped by three polymo...