Correction: AVPR1a and SLC6A4 Gene Polymorphisms Are Associated with Creative Dance Performance.

[This corrects the article DOI: 10.1371/journal.pgen.0010042.].

Vasopressin needs an audience: neuropeptide elicited stress responses are contingent upon perceived social evaluative threats.

The nonapeptide arginine vasopressin (AVP) plays an important role in hypothalamus-pituitary-adrenal axis regulation and also functions as a social hormone in a wide variety of species, from voles to humans. In the current report we use a variety of stress inducing tasks, including the Trier Social Stress Test (TSST) and intranasal administration of AVP to show that intranasal administration of this neuropeptide leads to a significant increase in salivary cortisol and pulse rate, specifically in conditions where subjects perform tasks in the presence of a social evaluative threat (task performance could be negatively judged by others). In contrast, in conditions without a social evaluative threat (no task condition, modified TSST without audience and bike ergometry), subjects receiving AVP did not differ from subjects receiving placebo. Thus exogenous AVP's influence is contingent upon a circumscribed set of initial conditions that constitute a direct threat to the maintenance of our social selves. Stress evoked by social threat is an integral part of social life and is related to self-esteem and in extreme forms, to poor mental health (e.g., social phobia). Our findings suggest that AVP is a key component in the circuit that interlaces stress and social threat and findings offer inroads to our understanding of individual differences in sociability and in stress response elicited in threatening social situations.

Preliminary effects of bupropion and the promoter region (HTTLPR) serotonin transporter (SLC6A4) polymorphism on smoking behavior in schizophrenia.

In the current study, we investigated how individual variants in the serotonin promoter gene, previously associated with smoking cessation and linked to anxiety-related personality traits, were associated with individual differences in responsiveness to bupropion and cognitive behavioral therapy (CBT) in a clinical population. We hypothesize that subjects with the long allele may be less responsive to treatment. Altogether 61 schizophrenic patients (46 M, 15 F) on stable neuroleptic medication were initially enrolled in a smoking reduction program (prospective, double-blind, placebo-controlled) including cognitive behavioral therapy plus placebo or CBT plus bupropion. Additionally, subjects were genotyped for a polymorphism in the serotonin transporter (SLC6A4). Thirty-two subjects (23 M, 9 F) completed a 14-week course of treatment. While both groups of subjects demonstrated significant reductions in smoking behavior due to CBT, subjects receiving bupropion did not show significant differences in smoking behavior when compared to placebo. In addition, analysis by SPSS repeated measures multivariate showed a significant sex by SLC6A4 genotype interaction on the number of cigarettes smoked. Only male subjects with at least one short promoter region allele (short/short and short/long combined) showed a reduction in cigarette consumption as a result of treatment. This study provides preliminary evidence of how polymorphisms in the serotonin transporter can be informative in predicting individual responses to smoking reduction therapy.

BDNF Val66Met polymorphism is associated with HPA axis reactivity to psychological stress characterized by genotype and gender interactions.

BACKGROUND: A key protein in maintaining neuronal integrity throughout the life span is brain-derived neurotrophic factor (BDNF). The BDNF gene is characterized by a functional polymorphism, which has been associated with stress-related disorders such as anxiety-related syndromes and depression, prompting us to examine individual responses by Genotype and Sex to a standardized social stress paradigm. Gender differences in BDNFxstress responses were posited because estrogen induces synthesis of BDNF in several brain regions. METHODS: 97 university students (51 females and 46 males) participated in a social stress procedure (Trier Social Stress Test, TSST). Indices of stress were derived from repeated measurement of cortisol, blood pressure, and heart rate during the TSST. All subjects were genotyped for the Val66Met polymorphism. RESULTS: Tests of within-subject effects showed a significant three-way interaction (SPSS GLM repeated measures: Time (eight levels)xBDNF (val/val, val/met)xSex: p=0.0002), which reflects gender differences in the pattern of cortisol rise and decline during the social challenge. In male subjects, val/val homozygotes showed a greater rise in salivary cortisol than val/met heterozygotes. In female subjects, there was a trend for the opposite response, which is significant when area under the curve increase (AUCi) was calculated for the val/val homozygotes to show the lowest rise. Overall, the same pattern of results was observed for blood pressure and heart rate. CONCLUSIONS: These results indicate that a common, functionally significant polymorphism in the BDNF gene modulates HPA axis reactivity and regulation during the TSST differently in men and women. Findings may be related to gender differences in reactivity and vulnerability to social stress.

AVPR1a and SLC6A4 gene polymorphisms are associated with creative dance performance.

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.

Association between tryptophan hydroxylase 2, performance on a continuance performance test and response to methylphenidate in ADHD participants.

The main objective of this study was to examine neuropsychological mechanisms mediating the association between tryptophan hydroxylase 2 (TPH2) and attention deficit hyperactivity disorder (ADHD). A continuous performance test (T.O.V.A.) was administered to 344 participants diagnosed with DSM IV ADHD who were also genotyped for eight TPH2 intronic SNPs. Association between TPH2 (single SNPs and haplotypes), ADHD, and performance on the T.O.V.A. were tested using robust family-based association tests as implemented in two statistical genetic programs: UNPHASED and PBAT. Association was only observed between an eight locus haplotype and ADHD DSM IV combined type III (global P = 0.036). Robust association was observed between TPH2 single SNPs (and haplotypes) and performance on the T.O.V.A., especially Errors of Omission (eight locus haplotypes, global P = 0.038). Significant associations were also observed between TPH2 and improvement (before-after scores) in T.O.V.A. Total Response Variability scores following acute methylphenidate challenge (eight locus haplotypes, global P = 0.009). Using the MFBAT program, significant multivariate association was observed between single SNPs and haplotypes [eight locus haplotypes and all four T.O.V.A. variables (PBAT-GEE P = 0.013)]. The two most common TPH2 eight locus haplotypes were in a Yin Yang configuration and the Yang haplotype was the risk haplotype for both DSM IV ADHD and deficits in neuropsychological performance. The current investigation shows that risk for ADHD conferred by TPH2 variants is partially mediated by serotonergic mechanisms impacting some facets of executive function. Importantly, improvement in T.O.V.A. performance, especially on Response Time Variability, following methylphenidate was also associated with TPH2.

Association study of COMT gene Val158Met polymorphism with auditory P300 and performance on neurocognitive tests in patients with schizophrenia and their relatives.

A number of studies have reported an association between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and neuropsychological traits in patients with schizophrenia, their relatives and healthy controls, with the Met allele carriers performing better on neurocognitive tasks than those with the Val allele. But the association was not confirmed in all studies. The present paper was aimed at further investigation of the COMT gene relationship with some neurocognitive traits, assessing mainly working and verbal memory, and to P300 event-related potentials (auditory oddball). A total sample of 319 individuals, including schizophrenic patients, their relatives and controls, was studied. No significant differences in performance of neurocognitive tasks were found by Val158Met genotypes. An association was observed between the Met/Met genotype and higher amplitude in centro-parietal area in relatives. Factors that could explain the non-replication of previous studies on the COMT gene polymorphism and neurocognitive traits are discussed. We suggest here that (1) Val158Met polymorphism rather exerts a modifying influence on brain activation in general than impacts directly on performance of the particular neurocognitive test, and (2) P300 amplitude seems to be a correlate of this activation reflecting, along with information processing, the subject's affective and personality features.

Association between the insulin-like growth factor 2 gene (IGF2) and scores on the Eating Attitudes Test in nonclinical subjects: a family-based study.

OBJECTIVE: An interesting candidate gene for eating disorders is the gene for insulin-like growth factor 2 (IGF2). Located on chromosome 11p15.5, IGF2 is a member of the insulin family of polypeptide growth factors that is involved in development and growth. Consistent with its profile of metabolic actions, an association has been reported between a single nucleotide polymorphism (SNP) in the 3' untranslated region of the IGF2 gene (ApaI) and body mass index. This investigation extended these studies and investigated the psychological and behavioral implications of this hormone's impact on metabolism and body composition. METHOD: The authors tested nonclinical subjects from 376 families for three IGF2 SNPs and for eating disorders, as reflected in scores on the 26-item Eating Attitudes Test, a self-report questionnaire widely used as a screening instrument. RESULTS: A highly significant association was observed between the IGF2 ApaI G allele and scores on the Eating Attitudes Test overall and each of its subscales (bulimia, dieting, and oral control). Additionally, a significant association was observed between this polymorphism and body mass index. CONCLUSIONS: The current finding that the IGF2 ApaI G polymorphism, which predisposes to weight gain, may also contribute to the pathology of eating disorders is intriguing. Neurotransmitter modulation of appetitive behavior is the focus of most hypotheses regarding the etiology of severe eating disorders. The current results to some measure challenge this view, and inborn metabolic tendencies to weight gain in some women may trigger constant dieting, which in predisposed individuals eventually leads to severe eating disorders.

Association of the serotonin transporter gene with smoking behavior.

OBJECTIVE: In an ongoing molecular genetic study of temperament, participants were genotyped to examine the association of smoking with two polymorphisms of the serotonin transporter gene (SERT): the promoter region, 5-HTTLPR, and an intronic variable-number-of-tandem-repeats region (VNTR). METHOD: Full information was available for 330 families, and 244 "ever smokers" were identified (54 past smokers, 190 current smokers). The average number of cigarettes smoked per day was 13.12, and the mean Fagerstrom Tolerance Questionnaire score was 4.79. Associations of genotype, Tridimensional Personality Questionnaire scores, and smoking phenotype were tested by using a robust family design with a variance-components framework and by case-control analysis. RESULTS: There was a significant excess of the 5-HTTLPR long allele with the 12-repeat VNTR in current smokers, past smokers, and ever smokers, compared to participants who had never smoked. The results from the population design were confirmed in the family-based analysis. No association was observed between two quantitative measures of smoking and the polymorphisms. A weak association was observed between novelty seeking and the VNTR polymorphism and between reward and 5-HTTLPR. Smokers, regardless of gender, scored significantly higher on novelty seeking and did not differ on harm avoidance or reward. CONCLUSIONS: There was a highly significant association between SERT and the categorical definition of smoking, irrespective of dependence level, suggesting that this gene influences the initiation of smoking. Mediation analysis failed to substantiate the hypothesis that novelty seeking partially mediates the effect of SERT on smoking. SERT appears to independently contribute to novelty seeking and smoking.

Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study.

In an exploratory study, 11 common polymorphisms were examined for contributing to longevity including: apolipoprotein E (apoE), methylenetetrahydrofolate reductase (MTHFR), cathepsin D (CAD), superoxide dismutase 2 (SOD2), angiotensinogen (AGT) and insulin-like growth factor 2 (IGF2), Leiden factor 7, p53 oncogene, dopamine D4 receptor (DRD4) and the serotonin transporter (SERT). Genotype and allele frequencies of these genes were compared in 224 older (75 years) Jewish Jerusalem residents of Ashkenazi ethnicity to a group of 441 younger subjects (22 years). Nominally significant results provide suggestive evidence in the Ashkenazi group that apoE, MHTFR, SOD2, IGF2 ApaI, and factor VII are risk factors for a single outcome, survival to 75. Overall, the more genetically homogenous Ashkenazi ethnic group showed evidence for association in five genes examined suggesting that future studies in this population would gainfully focus on this ethnic group.

Arginine vasopressin 1a receptor RS3 promoter microsatellites in schizophrenia: a study of the effect of the "risk" allele on clinical symptoms and facial affect recognition.

We studied AVPR1A RS3 polymorphism in schizophrenic patients and controls. AVPR1A RS3 was not associated with schizophrenia. The allele 327bp implicated in autism and social behavior was associated with negative symptoms and tended to be linked to patient facial affect recognition suggesting its impact on schizophrenia social phenotypes.

AVPR1A variant associated with preschoolers' lower altruistic behavior.

The genetic origins of altruism, defined here as a costly act aimed to benefit non-kin individuals, have not been examined in young children. However, previous findings concerning adults pointed at the arginine vasopressin receptor 1A (AVPR1A) gene as a possible candidate. AVPR1A has been associated with a range of behaviors including aggressive, affiliative and altruistic phenotypes, and recently a specific allele (327 bp) of one of its promoter region polymorphisms (RS3) has been singled out in particular. We modeled altruistic behavior in preschoolers using a laboratory-based economic paradigm, a modified dictator game (DG), and tested for association between DG allocations and the RS3 "target allele." Using both population and family-based analyses we show a significant link between lower allocations and the RS3 "target allele," associating it, for the first time, with a lower proclivity toward altruistic behavior in children. This finding helps further the understanding of the intricate mechanisms underlying early altruistic behavior.

Arginine vasopressin and oxytocin modulate human social behavior.

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.

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 between a functional dopamine D4 receptor promoter region polymorphism (-C521T) and pre-eclampsia: a family-based study.

Although many candidate genes have been studied in pre-eclampsia (PE), the important class of catecholamine receptors that contribute to sympathetic tone and blood pressure regulation has yet to be investigated. We therefore examined the dopamine D4 receptor (DRD4) gene. We performed a prospective family-based study in 50 families (patient and both her parents) who were genotyped for three DRD4 promoter regions. These single-nucleotide polymorphisms (SNPs) were tested for association using family-based association test (FBAT) that also included two quantitative measures, aspartate aminotransferase [serum glutamic oxalacetic transaminase (SGOT)] and systolic blood pressure. SNPs were assayed using a commercially available SNAPSHOT kit and PCR products were analysed in an ABI 310 DNA analyser. A significant association (preferential transmission of the T allele from a heterozygous parent to affected mother) was observed between the -C521T SNP and PE (P = 0.019). Significant association was also observed between the -521T allele and two-dimensional measures of PE : GOT (P = 0.039) and systolic blood pressure (P = 0.036). The DRD4 promoter region -C521T SNP that reduces transcriptional efficiency of this gene is suggested to contribute to developing PE. Additionally, DRD4 -521 TT homozygosity may be a marker for severe PE.

Fine mapping of a region on chromosome 8p gives evidence for a QTL contributing to individual differences in an anxiety-related personality trait: TPQ harm avoidance.

The chromosome 8p region is of interest in human behavioral genetics since it harbors a susceptibility region not only for schizophrenia but also for anxiety-related personality traits such as harm avoidance and neuroticism. Towards verifying our preliminary linkage finding of a QTL for TPQ harm avoidance at chromosome 8p, we have now genotyped altogether 24 micro-satellite markers in 377 families. Using three methods (maximum likelihood binomial or MLB, MERLIN, and an associated one parameter model), we observed significant results (P values from 0.002 to 0.0004) for linkage to harm avoidance in this region. A peak multipoint LOD score of 2.76 (P value 0.0002) was obtained with the MLB method. The region-wide empirical P value was 0.002 [0.001-0.0046]. Although, the peak position varied somewhat according to the method (D8S1048 for MLB, D8S1463 for the two other methods), for three methods D8S1810 ( approximately 60 cM) is within 1-2 cM of the peak for harm avoidance. This marker is of particular interest since it is proximate (<0.5 cM) of the core haplotype that in several recent studies show significant association with schizophrenia near neuroregulin 1. Although association studies with microsatellite markers need to be interpreted cautiously, using the Haplotype Trend Regression test one marker, D8S499 ( approximately 60 cM), showed an empirical P value of 2 x 10(-5) for allele 3, which confers a decreased harm avoidance score. Altogether, the current linkage and association results suggest the possibility that the same locus near the neuroregulin 1 gene on chromosome 8p confers risk for both an anxiety-related personality trait as well as schizophrenia. We hypothesize that this common genetic factor may contribute to emotional liability during early development, which constitutes a predisposing factor for major psychosis.

Association between a vasopressin receptor AVPR1A promoter region microsatellite and eating behavior measured by a self-report questionnaire (Eating Attitudes Test) in a family-based study of a nonclinical population.

OBJECTIVES: Considerable evidence including twin and family studies suggests that biologic determinants interact with cultural cues in the etiology of anorexia and bulimia nervosa. A gene that makes "biologic sense" in contributing susceptibility to these disorders, and to our knowledge not previously investigated for this phenotype, is the vasopressin receptor (AVPR1A), which we have tested for association with eating pathology. METHODS: We genotyped 280 families with same-sex siblings for two microsatellites in the promoter region of the AVPR1A gene. Siblings completed the 26-item Eating Attitudes Test (EAT) and the Drive for Thinness (DT) and Body Dissatisfaction (BD) subscales of the Eating Disorders Inventory (EDI). The Quantitative Transmission Disequilibrium Test program (QTDT), which employs flexible and powerful variance-components procedures, was used to test for an association between EAT scores and the two AVPR1A promoter region microsatellites, RS1 and RS3. RESULTS: A significant association (p = .036) was detected between the RS3 microsatellite and EAT scores. The strongest association was between RS3 and the Dieting subscale of the EAT (p = .011). A significant association was also observed between the EDI-DT and the RS3 microsatellit (p = .0450). CONCLUSIONS: We demonstrate for the first time an association between a microsatellite polymorphism in the AVPR1A promoter region and scores on the EAT as well as with the EDI-DT. The strongest association was observed between the RS3 microsatellite and the Dieting subscale of the EAT. The relevant phenotype appears to tap severe dietary restriction for weight loss purposes.

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.