Rachel Bachner-Melman

Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA

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 = 14.75, P = 0.001, df = 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 χ2 = 11.73, df = 4, P = 0.019). The association between the AVPR1a RS3 repeat and altruism was also confirmed using two self‐report 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 = 15.04, P = 0.001, df = 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.

The oxytocin receptor (OXTR) contributes to prosocial fund allocations in the dictator game and the social value orientations task.

Background Economic games observe social decision making in the laboratory that involves real money payoffs. Previously we have shown that allocation of funds in the Dictator Game (DG), a paradigm that illustrates costly altruistic behavior, is partially determined by promoter-region repeat region variants in the arginine vasopressin 1a receptor gene (AVPR1a). In the current investigation, the gene encoding the related oxytocin receptor (OXTR) was tested for association with the DG and a related paradigm, the Social Values Orientation (SVO) task. Methodology/Principal Findings Association (101 male and 102 female students) using a robust-family based test between 15 single tagging SNPs (htSNPs) across the OXTR was demonstrated with both the DG and SVO. Three htSNPs across the gene region showed significant association with both of the two games. The most significant association was observed with rs1042778 (p = 0.001). Haplotype analysis also showed significant associations for both DG and SVO. Following permutation test adjustment, significance was observed for 2–5 locus haplotypes (p<0.05). A second sample of 98 female subjects was subsequently and independently recruited to play the dictator game and was genotyped for the three significant SNPs found in the first sample. The rs1042778 SNP was shown to be significant for the second sample as well (p = 0.004, Fishers exact test). Conclusions The demonstration that genetic polymorphisms for the OXTR are associated with human prosocial decision making converges with a large body of animal research showing that oxytocin is an important social hormone across vertebrates including Homo sapiens. Individual differences in prosocial behavior have been shown by twin studies to have a substantial genetic basis and the current investigation demonstrates that common variants in the oxytocin receptor gene, an important element of mammalian social circuitry, underlie such individual differences.

Molecular genetic studies of the arginine vasopressin 1a receptor (AVPR1a) and the oxytocin receptor (OXTR) in human behaviour: from autism to altruism with some notes in between

Converging evidence from both human and animal studies has highlighted the pervasive role of two neuropeptides, oxytocin (OXT) and arginine vasopressin (AVP), in mammalian social behaviours. Recent molecular genetic studies of the human arginine vasopressin 1a (AVPR1a) and oxytocin (OXTR) receptors have strengthened the evidence regarding the role of these two neuropeptides in a range of normal and pathological behaviours. Significant association between both AVPR1a repeat regions and OXTR single nucleotide polymorphisms (SNPs) with risk for autism has been provisionally shown which was mediated by socialization skills in our study. AVPR1a has also been linked to eating behaviour in both clinical and non-clinical groups, perhaps reflecting the social and ritualistic side of eating behaviour. Evidence also suggests that repeat variations in AVPR1a are associated with two other social domains in Homo sapiens: music and altruism. AVPR1a was associated with dance and musical cognition which we theorize as reflecting the ancient role of this hormone in social interactions executed by vocalization, ritual movement and dyadic (mother-offspring) and group communication. Finally, we have shown that individual differences in allocation of funds in the dictator game, a laboratory game of pure altruism, is predicted by length of the AVPR1a RS3 promoter-region repeat echoing the mechanism of this hormones action in the vole model of affiliative behaviours and facilitation of positive group interactions. While still in its infancy, the current outlook for molecular genetic investigations of AVP-OXT continues to be fascinating. Future studies should profitably focus on pharmacogenomic and genomic imaging strategies facilitated by the ease and efficacy of manipulating AVP-OXT neurotransmission by intranasal administration. Importantly, physiological measures, behavioural paradigms and brain activation can be informed by considering between-group and also within-group individual differences defined by common polymorphisms. Ultimately, investigators should strive to develop a cohesive model explaining how genomic variations are translated into individual and group differences in higher-order social behaviours.

Hypnotic Susceptibility: Multidimensional Relationships With Cloninger’s Tridimensional Personality Questionnaire, COMT Polymorphisms, Absorption, and Attentional Characteristics

One hundred and seven healthy volunteers were administered Cloninger’s Tridimensional Personality Questionnaire (TPQ), the Differential Attentional Processes Inventory (DAPI), the Tellegen Absorption Scale (TAS), and the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C). Polymorphisms of catechol O-methyltransferase (COMT), an enzyme involved in dopamine metabolism, were assessed. Highly hypnotizable subjects self-reported greater TPQ persistence, absorption, and focused attentional abilities. Hierarchical multiple regression analyses found that TPQ persistence, COMT, TAS, and the DAPI attentional scales explained 43.8% of the variance in women and 29% in men. Membership was correctly discriminated for the more extreme low (62.1%) and highly (81.5%) hypnotizable groups. These results suggest that highly hypnotizable persons have a more effective frontolimbic attentional system and further suggest the involvement of dopaminergic systems in hypnotizability.

An examination of cognitive versus behavioral components of recovery from anorexia nervosa.

Definitions of “full recovery” from anorexia nervosa (AN) vary, and rarely include the cognitive criteria of lack of body image distortion and fear of weight gain. We investigated the implications of including or excluding cognitive criteria of AN in the definition of “full recovery”. Current symptomatology and personality characteristics associated with AN were assessed and compared in 42 behaviorally but not cognitively recovered women, 32 both behaviorally and cognitively recovered women, and 253 controls. On all measures included, the scores of the behaviorally recovered women were significantly more anorexic-like than those of the women recovered cognitively as well, who were indistinguishable from controls. Criteria for recovery from AN need to be refined and standardized, and cognitive criteria incorporated, to characterize a minority who recover to the extent that their eating attitudes and personality profiles are indistinguishable from those of women with no history of an eating disorder.

Anorexia nervosa, perfectionism, and dopamine D4 receptor (DRD4).

The dopamine D4 receptor (DRD4), a well‐characterized, polymorphic gene, is an attractive candidate for contributing risk to disordered eating and anorexia nervosa (AN). We tested association using UNPHASED for 5 DRD4 polymorphic loci, 3 promoter region SNPs (C‐521T, C‐616G, A‐809G), the 120 bp promoter region tandem duplication and the exon III repeat, in 202 AN trios and 418 control families. Since perfectionism characterizes AN, we tested these five loci for association with the Child and Adolescent Perfectionism Scale (CAPS) in the AN and control groups. Single locus analysis showed significant association between the ‘C’ C‐521T allele and AN. Haplotype analysis also showed significant association, particularly a 4‐locus haplotype (exon III&120 bp repeat&C‐521T&A‐809G). Association was also observed between DRD4 and CAPS scores both for AN and control subjects. The insulin‐like growth factor 2 (IGF2) and the arginine vasopressin 1a receptor (AVPR1a), previously shown to be associated with disordered eating, were also associated with CAPS scores. Three genes associated with AN were also associated with perfectionism. Personality traits are potential endophenotypes for understanding the etiology of eating disorders and one of the several pathways to eating pathology may be mediated by the impact of DNA sequences on perfectionism.

Association of the dopamine D5 receptor with attention deficit hyperactivity disorder (ADHD) and scores on a continuous performance test (TOVA).

Towards further clarifying the role of dopamine D5 receptor (DRD5) microsatellite polymorphism in the etiology of ADHD, we used a robust family based strategy to test for association between DRD5 and this disorder. Additionally, a neuropsychological mechanism by which this allele may confer risk was explored by examining the relationship between DRD5 genotype and scores on a continuous performance test. DNA was obtained from 164 probands and their parents. Additionally, the majority of these probands were administered a computerized continuous performance test, the Test Of Variables of Attention (TOVA). We first confirmed preferential transmission (TDT χ2 = 7.02, P = 0.008) of the 148 base pair allele in 155 informative transmissions (94 transmitted and 61 non‐transmitted 148 bp allele). Additionally, we used a family‐based association test (FBAT) and observed significant multivariate association using FBAT between TOVA scores before methylphenidate administration and the DRD5 microsatellite polymorphism across all four TOVA variables: multi‐allelic, multivariate test χ2 = 16.32, P = 0.037 when the 148 bp allele was compared to all others (collapsed genotype) that was also significant (χ2 = 59.20, P = 0.025) when all 14 alleles (full genotype) were analyzed. Following methylphenidate, no significant association was observed (χ2 = 12.08, P = 0.147 for 148 bp versus all others) and, similarly, for all 14 alleles (χ2 = 47.18, P = 0.343). In summary, the main finding of this report is that the DRD5 repeat polymorphism confers a small but significant risk for ADHD consistent with previous reports. Provisional results in this single investigation suggest that the DRD5 microsatellite also affects performance scores on the TOVA.

Tridimensional personality questionnaire trait of harm avoidance (anxiety proneness) is linked to a locus on chromosome 8p21

Human personality traits are moderately heritable but only recently have specific polymorphisms been associated with particular personality dimensions especially anxiety‐related and novelty‐seeking traits. The first genome‐wide scan for personality traits was recently carried out by Cloninger et al. [1998: Am J Med Genet 81:313–317] and his colleagues and they reported that a region on 8p21 showed linkage to TPQ Harm Avoidance, an anxiety‐related personality trait. Towards replicating and extending these results, we examined both 8p21 and two additional chromosomal regions (1q21–24 and 22q12–13) for linkage to TPQ personality traits by genotyping at least three microsatellite markers in each region in a group of 384 sibling pairs. We found evidence for linkage to TPQ HA at 8p21–23 (Lod score = 2.907) confirming in an independent sample the initial findings by Cloninger and his colleagues.

Link Between Vasopressin Receptor AVPR1A Promoter Region Microsatellites and Measures of Social Behavior in Humans

Abstract. Two markers near the vasopressin receptor (AVPR1A) gene located on chromosome 12q14-15 were tested for linkage to two complex social behaviors in humans: Sibling relationships and self-presentation style. Self-report questionnaires were administered to 552 same-sex siblings from 248 families. Suggestive linkage was observed between both microsatellites (RS1 and RS3) and the Sibling Relationship Questionnaire Conflict scale (RS1: χ2 = 13.65, LOD = 2.96, p = .0001; RS3: χ2 = 14.54, LOD = 3.16, p = .00007) and the Concern for Appropriateness Scale Self-presentational style (RS1: χ2 = 8.25, LOD = 1.79 p = .002; RS3: χ2 = 8.81, LOD = 1.91, p = .002. The current results provide the first provisional evidence that the vasopressin receptor mediates social behavior in humans and links a specific genetic element to perceived sibling interactions.

Association between arginine vasopressin 1a receptor (AVPR1a) promoter region polymorphisms and prepulse inhibition

Arginine vasopressin and the arginine vasopressin 1a (AVPR1a) gene contribute to a range of social behaviors both in lower vertebrates and in humans. Human promoter-region microsatellite repeat regions (RS1 and RS3) in the AVPR1a gene region have been associated with autism spectrum disorders, prosocial behavior and social cognition. Prepulse inhibition (PPI) of the startle response to auditory stimuli is a largely autonomic response that resonates with social cognition in both animal models and humans. Reduced PPI has been observed in disorders including schizophrenia that are distinguished by deficits in social skills. In the current investigation association was examined between PPI and the AVPR1a RS1 and RS repeat regions and PPI in a group of 113 nonclinical subjects. Using a robust family-based strategy, association was observed between AVPR1a promoter-region repeat length, especially RS3) and PPI (30 ms: global p=0.04; 60 ms p=0.006; 120 ms p=0.008). Notably, longer RS3 alleles were associated with greater levels of prepulse inhibition. Using a short/long classification scheme for the repeat regions, significant association was also observed between all three PPI intervals (30, 60 and 120 ms) and both RS1 and RS3 polymorphisms (PBAT: FBAT-PC(2) statistic p=0.047). Tests of within-subject effects (SPSS GLM) showed significant sexxRS3 interactions at 30 ms (p=0.045) and 60 ms (p=0.01). Longer alleles, especially in male subjects, are associated with significantly higher PPI response, consistent with a role for the promoter repeat region in partially molding social behavior in both animals and humans. This is the first report in humans demonstrating a role of the AVPR1a gene in contributing to the PPI response to auditory stimuli.