Human altruism is a widespread phenomenon that puzzled evolutionary biologists since Darwin. Economic games illustrate human altruism by showing that behavior deviates from economic predictions of profit maximization. A game that most plainly shows this altruistic tendency is the Dictator Game. We hypothesized that human altruistic behavior is to some extent hardwired and that a likely candidate that may contribute to individual differences in altruistic behavior is the arginine vasopressin 1a (AVPR1a) receptor that in some mammals such as the vole has a profound impact on affiliative behaviors. In the current investigation, 203 male and female university students played an online version of the Dictator Game, for real money payoffs. All subjects and their parents were genotyped for AVPR1a RS1 and RS3 promoter-region repeat polymorphisms. Parents did not participate in online game playing. As variation in the length of a repetitive element in the vole AVPR1a promoter region is associated with differences in social behavior, we examined the relationship between RS1 and RS3 repeat length (base pairs) and allocation sums. Participants with short versions (308-325 bp) of the AVPR1a RS3 repeat allocated significantly (likelihood ratio 5 14.75, P 5 0.001, df 5 2) fewer shekels to the 'other' than participants with long versions (327-343 bp). We also implemented a family-based association test, UNPHASED, to confirm and validate the correlation between the AVPR1a RS3 repeat and monetary allocations in the dictator game. Dictator game allocations were significantly associated with the RS3 repeat (global P value: likelihood ratio x 2 5 11.73, df 5 4, P 5 0.019). The association between the AVPR1a RS3 repeat and altruism was also confirmed using two selfreport scales (the Bardi-Schwartz Universalism and Benevolence Value-expressive Behavior scales). RS3 long alleles were associated with higher scores on both measures. Finally, long AVPR1a RS3 repeats were associated with higher AVPR1a human post-mortem hippocampal messenger RNA levels than short RS3 repeats (one-way analysis of variance (ANOVA): F 5 15.04, P 5 0.001, df 5 14) suggesting a functional molecular genetic basis for the observation that participants with the long RS3 repeats allocate more money than participants with the short repeats. This is the first investigation showing that a common human polymorphism, with antecedents in lower mammals, contributes to decision making in an economic game. The finding that the same gene contributing to social bonding in lower animals also appears to operate similarly in human behavior suggests a common evolutionary mechanism.

Dancing, which is integrally related to music, likely has its origins close to the birth of Homo sapiens, and throughout our history, dancing has been universally practiced in all societies. We hypothesized that there are differences among individuals in aptitude, propensity, and need for dancing that may partially be based on differences in common genetic polymorphisms. Identifying such differences may lead to an understanding of the neurobiological basis of one of mankind's most universal and appealing behavioral traits—dancing. In the current study, 85 current performing dancers and their parents were genotyped for the serotonin transporter (SLC6A4: promoter region HTTLPR and intron 2 VNTR) and the arginine vasopressin receptor 1a (AVPR1a: promoter microsatellites RS1 and RS3). We also genotyped 91 competitive athletes and a group of nondancers/nonathletes (n = 872 subjects from 414 families). Dancers scored higher on the Tellegen Absorption Scale, a questionnaire that correlates positively with spirituality and altered states of consciousness, as well as the Reward Dependence factor in Cloninger's Tridimensional Personality Questionnaire, a measure of need for social contact and openness to communication. Highly significant differences in AVPR1a haplotype frequencies (RS1 and RS3), especially when conditional on both SLC6A4 polymorphisms (HTTLPR and VNTR), were observed between dancers and athletes using the UNPHASED program package (Cocaphase: likelihood ratio test [LRS] = 89.23, p = 0.000044). Similar results were obtained when dancers were compared to nondancers/nonathletes (Cocaphase: LRS = 92.76, p = 0.000024). These results were confirmed using a robust family-based test (Tdtphase: LRS = 46.64, p = 0.010). Association was also observed between Tellegen Absorption Scale scores and AVPR1a (Qtdtphase: global chi-square = 26.53, p = 0.047), SLC6A4 haplotypes (Qtdtphase: chi-square = 2.363, p = 0.018), and AVPR1a conditional on SCL6A4 (Tdtphase: LRS = 250.44, p = 0.011). Similarly, significant association was observed between Tridimensional Personality Questionnaire Reward Dependence scores and AVPR1a RS1 (chi-square = 20.16, p = 0.01). Two-locus analysis (RS1 and RS3 conditional on HTTLPR and VNTR) was highly significant (LRS = 162.95, p = 0.001). Promoter repeat regions in the AVPR1a gene have been robustly demonstrated to play a role in molding a range of social behaviors in many vertebrates and, more recently, in humans. Additionally, serotonergic neurotransmission in some human studies appears to mediate human religious and spiritual experiences. We therefore hypothesize that the association between AVPR1a and SLC6A4 reflects the social communication, courtship, and spiritual facets of the dancing phenotype rather than other aspects of this complex phenotype, such as sensorimotor integration.

Genetic effects on behavior were evaluated at a time in early development when we hypothesized that environmental influences are minimal and least likely to confound associations between temperament and genes. The behavioral effects of two common polymorphisms linked respectively in some, but not all, studies to novelty seeking (dopamine D4 receptor -D4DR) and neuroticism and harm avoidance (serotonin transporter promoter region -STPR) were examined in a group of 81 two-week-old neonates. Neonate temperament was evaluated using the Brazelton neonatal assessment scale (NBAS). Multivariate tests of significance showed a significant association of D4DR across four behavioral clusters pertinent to temperament including orientation, motor organization, range of state and regulation of state. A significant multivariate interaction was also observed between D4DR and STPR. The effect of the homozygous short STPR genotype (s/s) was to lower the orientation score for the group of neonates lacking the long form (L) of D4DR. When adult subjects were grouped by the STPR polymorphism there is no significant effect of L-D4DR in those subjects homozygous for the STPR short form (s/s) whereas in the group without the homozygous genotype the effect of L-D4DR is significant and accounts for 13% of the variance in novelty seeking scores between groups.

Increasing evidence suggests that two nonapeptides, arginine vasopressin and oxytocin, shape human social behavior in both nonclinical and clinical subjects. Evidence is discussed that in autism spectrum disorders genetic polymorphisms in the vasopressin-oxytocin pathway, notably the arginine vasopressin receptor 1a (AVPR1a), the oxytocin receptor (OXTR), neurophysin I and II, and CD38 (recently shown to be critical for social behavior by mediating oxytocin secretion) contribute to deficits in socialization skills in this group of patients. We also present first evidence that CD38 expression in lymphoblastoid cells derived from subjects diagnosed with autism is correlated with social skill phenotype inventoried by the Vineland Adaptive Behavioral Scales. Additionally, we discuss molecular genetic evidence that in nonclinical subjects both AVPR1a and OXTR genes contribute to prosocial or altruistic behavior inventoried by two experimental paradigms, the dictator game and social values orientation. The role of the AVPR1a is also analyzed in prepulse inhibition. Prepulse inhibition of the startle response to auditory stimuli is a largely autonomic response that resonates with social cognition in both animal models and humans. First results are presented showing that intranasal administration of arginine vasopressin increases salivary cortisol levels in the Trier Social Stress test. To summarize, accumulating studies employing a broad array of cutting-edge tools in psychology, neuroeconomics, molecular genetics, pharmacology, electrophysiology, and brain imaging are beginning to elaborate the intriguing role of oxytocin and arginine vasopressin in human social behavior. We expect that future studies will continue this advance and deepen our understanding of these complex events.

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...

No abstract

Although aggressive, violent, and dangerous behavior in man has multifactorial causes, genetic factors are estimated by twin and adoption studies to substantially contribute to the development of such conduct. Recently, homozygosity of a low enzyme activity variant of the catechol O-methyltransferase (COMT) gene was reported to be associated with aggressive behavior in a group of schizophrenic patients. We observe a similar tendency in a group of 30 schizophrenic patients who were confined to a maximum-security psychiatric facility for homicide. Significant excess (46.7% versus 21.0%) homozygosity of the low activity COMTmet/met genotype was observed in 30 mostly male (28 of 30) homicidal schizophrenic patients compared with 415 control subjects (Pearson chi(2) = 10.53, P = 0.005, df = 2). No difference in COMT genotype was found between 62 nonviolent schizophrenic patients and the 415 control subjects (chi(2) = 0.963, P > 0.1, df = 2). A trend for excess (46.7% versus 25.8%) homozygosity of the low activity COMTmet/met genotype was also observed when the homicidal schizophrenic subjects were compared directly with the nonviolent schizophrenic patients (chi(2) = 4.03, P = 0.1, df = 2). Similarly, an excess of the low activity COMTmet allele was observed in homicidal versus nonviolent schizophrenic patients (chi(2) = 2.92, P = 0.087, df = 2). Similar results were obtained if only male subjects were examined. No significant difference was found between control (257 Ashkenazi and 152 non-Ashkenazi Jews) COMT genotypes in the two principal ethnic groups examined (chi(2) = 3.79, P > 0.1, df = 2). Finally, no association was observed between homicidal behavior in schizophrenic patients and the dopamine D4 exon III repeat length polymorphism (D4DR) and the serotonin transporter promoter-region polymorphism (5-HTTLPR). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:628-633, 1999.