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I Gritsenko

Publications and source records attributed to I Gritsenko.

14 recordsLinked to original sources
PubMed2006

Polymorphisms in the dopamine D4 receptor gene (DRD4) contribute to individual differences in human sexual behavior: desire, arousal and sexual function.

Although there is some evidence from twin studies that individual differences in sexual behavior are heritable, little is known about the specific molecular genetic design of human sexuality. Recently, a specific dopamine D4 receptor (DRD4) agonist was shown in rats to induce penile erection through a central mechanism. These findings prompted us to examine possible association between the well-characterized DRD4 gene and core phenotypes of human sexual behavior that included desire, arousal and function in a group of 148 nonclinical university students. We observed association between the exon 3 repeat region, and the C-521T and C-616G promoter region SNPs, with scores on scales that measure human sexual behavior. The single most common DRD4 5-locus haplotype (19%) was significantly associated with Desire, Function and Arousal scores. The current results are consistent with animal studies that show a role for dopamine and specifically the DRD4 receptor in sexual behavior and suggest that one pathway by which individual variation in human desire, arousal and function are mediated is based on allelic variants coding for differences in DRD4 receptor gene expression and protein concentrations in key brain areas.

Family Health↗
PubMed2000

Exploratory association study between catechol-O-methyltransferase (COMT) high/low enzyme activity polymorphism and hypnotizability.

Only recently have studies of electrocortical activity, event-related potentials, and regional cerebral blood flow begun to shed light on the anatomical and neurobiological underpinnings of hypnosis. Since twin studies show a significant heritable component for hypnotizability, we were prompted to examine the role of a common, functional polymorphism in contributing to individual differences in hypnotizability. A group of 109 subjects (51 male, 59 female) were administered three psychological instruments and tested for the high/low enzyme activity COMT val-->met polymorphism. We observed a significant correlation between hypnotizability measured by the Stanford Hypnotic Susceptibility Scale (SHSS:C), ability to partition attention (Differential Attentional Processes Inventory or DAPI), and absorptive capacities (Tellegen Absorption Scale or TAS). The effect of COMT on the various dependent variables was initially examined by multivariate analysis that corrects for multiple testing. The dependent variables were SHSS:C hypnotizability scores, four attentional subscales of the DAPI, and TAS total score grouped by the COMT genotype (val/val, val/met, met/met) as the independent variable. Hotelling's Trace statistic was significant when scores were grouped by the COMT genotype (Hotelling's T(2) = 1.88, P = 0.04. Post-hoc testing using the Bonferroni correction shows that the only significant difference is between the val/met vs. the val/val COMT genotypes on hypnotizability. This association was significant for men but not for women. As for all case-control studies, these results need to be interpreted cautiously and require replication. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:771-774, 2000.

Adult↗
PubMed2000

A haplotype relative risk study of the dopamine D4 receptor (DRD4) exon III repeat polymorphism and attention deficit hyperactivity disorder (ADHD).

Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive-impulsive, and combined type. Several investigations have recently examined the role of the dopamine DRD4 exon III repeat polymorphism in ADHD. The long 7 repeat allele of this receptor was shown in three family-based studies, but not in one case control design, to be a risk factor for this disorder. We now report an additional family-based study of DRD4 exon III repeat region and ADHD. However, in the current study we fail to observe preferential transmission of the DRD4 exon III long 7 repeat allele, chi(2) = 0. 142, P < 0.1, df = 1. Nor was any preferential transmission observed when genotypes were compared, chi(2) = 0.180, P > 0.1, df = 1. Possible reasons are discussed, especially lack of sufficient power in analying more refined phenotypes, why the current results in contrast to previous findings fail to support a role for the long form of the DRD4 receptor as a putative risk factor for ADHD.

Alleles↗
PubMed2000

Association between tridimensional personality questionnaire (TPQ) traits and three functional polymorphisms: dopamine receptor D4 (DRD4), serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT).

Dopamine D4 receptor (DRD4), serotonin transporter promoter regulatory region (5-HTTLPR) and catechol O-methyltransferase (COMT) polymorphisms were examined for association with TPQ personality factors in 455 subjects. Significant interactions were observed by multivariate analysis, (COMT x 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 x D4DR (F = 6.18, P = 0.03) and COMT x 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 (2000) 5, 96-100.

Adolescent↗
PubMed2000

An interaction between the catechol O-methyltransferase and serotonin transporter promoter region polymorphisms contributes to tridimensional personality questionnaire persistence scores in normal subjects.

Persistence (RD2) is a subscale of the reward dependence trait, one of the three major personality factors assessed by the Tridimensional Personality Questionnaire (TPQ). Subjects with high RD2 scores are characterized as industrious, hard-working, ambitious, perfectionistic. TPQ scores were examined in 577 normal subjects inventoried for two common genetic polymorphisms, the catechol O-methyltransferase (COMT) valine to methionine (val to met) amino acid substitution that determines high and low enzyme activity, and the serotonin transporter promoter region 44 bp deletion (5-HTTLPR) linked in some studies to harm avoidance or neuroticism. When TPQ RD2 scores are grouped by COMT and 5-HTTLPR polymorphisms and analyzed by two-way ANOVA, significant main effects for COMT (F = 2. 98, p = 0.05) and 5-HTTLPR (F = 4.27, p = 0.04) and a significant interaction COMT x 5-HTTLPR (F = 6.18, p = 0.002) are observed. In the presence of COMT homozygosity (val/val or met/met genotypes), the presence of the short 5-HTTLPR allele raises RD2 scores. The effect of these two polymorphisms on RD2 was also examined using a within-families design. Siblings in our data set who shared identical genotypes had significantly correlated RD2 scores (intraclass coefficient = 0.34, F = 2.03, p = 0.002, n = 67), whereas sibs with dissimilar genotypes in at least one polymorphism showed no significant correlation for RD2 scores (intraclass coefficient = 0.105, F = 1.23, p = 0.16, n = 92).

Adolescent↗
PubMed1999

Homicidal behavior in schizophrenia associated with a genetic polymorphism determining low catechol O-methyltransferase (COMT) activity.

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.

Adult↗
PubMed1999

Haplotype relative risk study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): association of the high-enzyme activity Val allele with ADHD impulsive-hyperactive phenotype.

Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive-impulsive, and combined type. Both environmental and genetic factors contribute to the etiology of this complex disease. In the current investigation, a catechol-O-methyltransferase (COMT) polymorphism that codes for a high versus low enzyme COMT activity was examined using family-based methods for a role in ADHD. Using a haplotype relative risk design and a parent-to-proband allele transmission test with 48 ADHD triads, we found an association between COMT and illness (chi(2) = 4.72, p = 0.03, df = 1). In particular, the impulsive-hyperactive type of ADHD (excluding inattention) ascertained by Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria (chi(2) = 8.34, p = 0.004, df = 1), by the Conners Teaching Rating Hyperactivity scale (Pearson chi(2) = 5.32, p = 0.02, df = 1) as well as by the Continuous Performance Test False Alarm scale (chi(2) = 2.78, p = 0.096, df = 1) were associated with the high enzyme activity COMT val allele. Similar results were obtained if genotype frequencies were compared. It should be noted that the association between the high-enzyme activity COMT val allele that increases CNS dopamine (and norepinephrine) clearance is consistent with the use of methylphenidate, an agent that increases dopamine (and norepinephrine) turnover, in the treatment of this disorder. These provisional findings suggest that newly developed COMT inhibitors such as tolcapone, applied in Parkinson's disease, might in due time be considered in the treatment of ADHD.

Adolescent↗
PubMed1998

Dopamine D4 receptor and serotonin transporter promoter in the determination of neonatal temperament.

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.

Anxiety↗
PubMed1997

Dopamine D4 receptor gene polymorphisms: relation to ethnicity, no association with schizophrenia and response to clozapine in Israeli subjects.

The dopamine D4 receptor (DRD4) is a candidate gene in the search for a genetic etiology of schizophrenia and for pharmacogenetic factors in the response to antipsychotic treatment. Previous work has not found linkage or association of a polymorphism in exon 3 of this gene with diagnosis of schizophrenia or response to clozapine. In this study we examined this association in Israeli schizophrenic subjects treated with clozapine, compared to ethnically matched controls. Another polymorphism of this gene, in exon 1, was also studied. Both polymorphisms showed no association with schizophrenia or treatment response. A significant difference in allelic distribution of DRD/ exon 3 polymorphism was found between Ashkenazi and non-Ashkenazi control subjects.

Antipsychotic Agents↗
PubMed1997

Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects.

Only in the past decade has a role of heredity in substance abuse been established as a result of extensive twin and family studies. More recently, several candidate genes have been investigated for their possible role in alcoholism and cocaine abuse. Specific genetic factors in opioid substance abuse have not been investigated in man, although animal studies suggest that quantitative trait loci (QTLs) can be identified that predispose mice both to morphine and alcohol preference. Central dopaminergic pathways figure prominently in drug-mediated reinforcement suggesting that dopamine receptors are likely candiadates for association with substance abuse in man. In addition, we recently reported an association between a human personality trait, Novelty Seeking and the long alleles (represented chiefly by the 7-repeat) of the D4 dopamine receptor (D4DR) exon III polymorphism. The personality trait of Novelty Seeking is also more pronounced in substance abusers, who score higher in this dimension than control subjects. The twin role of dopamine receptors in mediating Novelty Seeking and drugreinforcement prompted us to examine a group of Israeli heroin addicts for prevalence of the D4DR repeat polymorphism. We now show that the 7-repeat allele is significantly over-represented in the opioid-dependent cohort and confers a relative risk of 2.46. To our knowledge this is the first report of an association between a specific genetic polymorphism and opioid addiction.

Adult↗
PubMed1997

No association between the serotonin transporter gene regulatory region polymorphism and the Tridimensional Personality Questionnaire (TPQ) temperament of harm avoidance.

A functional polymorphism in the upstream regulatory region of the serotonin transporter gene has been recently reported to be associated with anxiety-related traits assessed by the NEO-PI-R. Individuals both hetero- and homozygous for the short form of a highly repetitive regulatory element in this gene have significantly higher neuroticism scores. We have attempted to replicate these findings in a normal cohort of 120 individuals, whom we have previously examined for association between personality dimensions and other serotonergic and dopaminergic receptor polymorphisms. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality dimensions in this cohort. No association was observed in the present study between individuals grouped by the long and short form of the transporter gene and any of the personality dimensions measured by the TPQ including Harm Avoidance, which incorporates many aspects of anxiety and is correlated with NEO-PI-R Neuroticism.

Adult↗
PubMedDate not supplied

Additional evidence for an association between the dopamine D4 receptor (D4DR) exon III repeat polymorphism and the human personality trait of Novelty Seeking.

The long alleles (> or =6 repeats) of the dopamine D4 dopamine receptor exon III polymorphism have been linked in some, but not all, studies to Novelty Seeking (NS), one of four personality traits defined by Cloninger's tridimensional personality questionnarie (TPQ). In order to further examine the robustness of our original observation we have recruited an additional cohort similar in demographic structure to the original cohort. Although no significant difference in mean NS scores was observed when the new subjects (n=94) were grouped by presence (NS=17.83 +/- 1.16) or absence (NS=16.45 +/- 0.65) of the 7 repeat allele, a significant difference in range of NS scores was observed (non-parametric Moses range test, P = 0.01). The effect of the seven allele was also significant in those individuals scoring highest on NS (>1 standard deviation from the mean; t-test, t=5.13, P=0.002). In the expanded cohort (n=218) a significant effect of the seven allele on NS is demonstrated by both parametric (t=2.26, P=0.01) and non-parametric (range test, P=0.004) statistical tests. The effect is also observed in both principal ethnic groups (Ashkenazi and non-Ashkenazi Jews). In the expanded cohort the effect is significant in female (t=2.2, P=0.03, n=98) but not in male subjects (t=1.12, P>0.1, n=116). We discuss both direct and indirect evidence that in our opinion continues to support a modest role for the long alleles of the dopamine D4 receptor repeat polymorphism in the determination of NS behavior at least in some population groups.

Adult↗