Biomedical subjects

R P Ebstein

Publications and source records attributed to R P Ebstein.

At least 37 records · Page 2Linked to original sources

PubMed2001

A family-based study of the Cys23Ser 5HT2C serotonin receptor polymorphism in schizophrenia.

The 5HT2C receptor has a high affinity for clozapine, a nontypical neuroleptic, and has therefore been postulated to play a role in mediating negative symptoms and neuroleptic response in schizophrenia. In the current study, the Cys23Ser 5HT2C serotonin receptor polymorphism was examined for linkage to schizophrenia by genotyping 207 nuclear families consisting of both parents and schizophrenic child and using the transmission disequilibrium test to examine possible preferential transmission of these alleles from 68 heterozygous mothers to their ill child. No evidence was obtained for preferential transmission of the Cys23Ser 5HT2C alleles in schizophrenia in either of the two main ethnic groups examined (German and Palestinian Arab) or in the combined cohort (TDT chi-square = 0.00, NS).

Adolescent↗

PubMed2001

Family-based association study of the serotonin transporter promoter region polymorphism (5-HTTLPR) in attention deficit hyperactivity disorder.

Low serotonin activity has been associated in both animal and human studies with measures of impulsivity, aggression, and disinhibited behaviors. Recently, a common 44-bp deletion in the promoter region of the serotonin transporter (5-HTTLPR) that results in reduced transcription and lower transporter protein levels was described. Toward unraveling a possible role of the 5-HTTLPR polymorphism in childhood disruptive behaviors, we examined this gene in attention deficit hyperactivity disorder (ADHD), a heterogeneous childhood disorder in which three phenotypes are recognized by DSM IV criteria: inattentive (type I), hyperactive-impulsive (type II), and combined type (type III). By using the haplotype relative risk design, a group of 98 triads (both parents and proband child) were tested for a possible association between 5-HTTLPR and ADHD. A significant decrease in the short/short 5-HTTLPR genotype was observed in the ADHD type III combined group (10.29% vs. 30.88%) compared with the HRR-derived control group (likelihood ratio = 9.62, P = 0.008, n = 68 triads). Similar results were observed when allele frequencies were compared (likelihood ratio = 3.81, P = 0.05, n = 136 alleles). These first findings should be interpreted cautiously until replicated in independently recruited clinical samples.

Adolescent↗

PubMed2001

Genes for human personality traits: "endophenotypes" of psychiatric disorders?

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Exons↗

PubMed2001

Inositol monophosphatase activity in brain and lymphocyte-derived cell lines of bipolar patients.

BACKGROUND: Inositol monophosphatase (IMPase) activity was reported to be low in lymphocyte-derived cell lines of bipolar patients. METHODS: IMPase activity was measured spectrophotometrically as inorganic phosphate liberated from inositol-1-phosphate. RESULTS: The previously reported reduction was replicated in a new, small group of bipolar patients. The reduction is not present in cell lines of unipolar or schizophrenic patients. IMPase activity in postmortem frontal and occipital cortical samples of unipolar, bipolar and schizophrenic patients was not different from controls. CONCLUSIONS: A reduction in lymphocyte-derived IMPase activity without a parallel reduction in cortical IMPase activity could be due to the fact that most leukocyte IMPase activity is the product of the IMPA-2 gene.

Adult↗

PubMed2000

Personality and polymorphisms of genes involved in aminergic neurotransmission.

Genetic factors significantly contribute to the determination of human personality traits assessed by self-report questionnaires. However, only in the past few years have common genetic polymorphisms especially the dopamine D4 receptor and the serotonin transporter promoter region been associated with specific personality traits such as novelty seeking and harm avoidance, respectively. The effects of these genes are modest and several genes are likely accounting for individual differences in personality dimensions that can be attributed to genetic factors. Molecular genetic studies of adult personality have also been extended to investigations of early human temperament and some of the genes associated with adult personality traits are also contributing to the earliest developmental expressions of human behavior. Additionally, some of these same genes have also been implicated in various types of abnormal behavior including addiction, obsessive-compulsive disorder, attention deficit, depression, aggression and psychosis. Future research directions will no doubt take advantage of the bioinformatics revolution coinciding with the completion of the first phase of the human genome project. It should soon be possible to identify many of the genes contributing to specific personality traits and to better define their role in determining normal and abnormal behavior from early development through adulthood.

Animals↗

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

Failure to replicate an association between the catechol-O-methyltransferase polymorphism and attention deficit hyperactivity disorder in a second, independently recruited Israeli cohort.

Attention Deficit Disorder with Hyperactivity↗

PubMed2000

No association between the dopamine D3 receptor Bal I polymorphism and schizophrenia in a family-based study of a Palestinian Arab population.

Several recent meta-analyses appear to show a weak but significant effect of both forms of the gly/ser DRD3 polymorphism in conferring risk for schizophrenia. Since most studies have employed the artifact-prone case-control design, we thought it worthwhile to examine the role of this polymorphism using a robust family-based strategy in an ethnic group not previously systematically studied in psychiatric genetics, Palestinian Arabs. We failed to obtain any evidence in 129 Palestinian triads, using the haplotype relative risk (allele frequency: Pearson chi-square = 0.009, P > 0.1, df = 1, n = 258 alleles) or transmission disequilibrium test design (chi-square = 0.38, P > 0.1, n = 86 families) for association/linkage (or increased homozygosity) of the DRD3 Bal I polymorphism to schizophrenia in our sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:778-780, 2000.

Alleles↗

PubMed2000

Evidence for linkage by transmission disequilibrium test analysis of a chromosome 22 microsatellite marker D22S278 and bipolar disorder in a Palestinian Arab population.

A number of linkage studies suggest a schizophrenia susceptibility locus on chromosome 22, particularly with microsatellite marker D22S278 (22q12). In addition to some evidence for linkage to schizophrenia in this region, linkage to bipolar disorder using this marker has also been reported. We tested a group of 60 Bipolar I triads and an expanded group of 79 Bipolar I and Bipolar II triads recruited from a Palestinian Arab population for linkage with the D22S278 marker. Significant linkage was observed using the extended transmission disequilibrium test for multiallelic markers (ETDT) for both Bipolar I (P = 0.031) and the expanded group of Bipolar I and Bipolar II (P = 0.041). These weakly positive results are at least consistent with the hypothesis that this region of chromosome 22 might harbor a susceptibility locus for both major psychoses and should be considered for more intensive study. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:836-838, 2000.

Alleles↗

PubMed2000

Confirmation of an excess of the high enzyme activity COMT val allele in heroin addicts in a family-based haplotype relative risk study.

A previous case control study by Vandenbergh et al. [1997: Am J Med Genet 74:439-442] showed an association between the high activity catechol O-methyltransferase (COMT) polymorphism and polysubstance abuse in a group of North American subjects. In the current study we confirm these results by genotyping 38 Israeli heroin addicts and both parents using a robust family-based haplotype relative risk (HRR) strategy. There is an excess of the val COMT allele (likelihood ratio = 4.48, P = 0.03) and a trend for an excess of the val/val COMT genotype (likelihood ratio = 4.97, P = 0.08, 2 df) in the heroin addicts compared to the HRR control group. We also genotyped an additional 101 nonrelated heroin addicts and 126 control subjects using a case control design and found no significant difference in COMT val allele frequency (25.4% vs. 29.7%, likelihood ratio = 1.04, P = 0.31). A significant difference is observed in COMT allele frequency among the three principal Israeli ethnic groups (Ashkenazi Jewish, non-Ashkenazi Jewish, and Palestinian Arab) in a large group of control subjects we have so far examined (chi-square = 7.9, P = 0.019, df = 2, n = 1,422 alleles) suggesting that population stratification is responsible for our failure to observe an excess of the COMT val allele when using the case-control design.

Alleles↗

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

Failure to replicate an excess of the long dopamine D4 exon III repeat polymorphism in ADHD in a family-based study.

The DRD4 exon III repeat polymorphism has been associated in adults with Novelty Seeking personality traits and in children with attention deficit hyperactivity disorder (ADHD) in some but not all studies. In a previous report we failed to observe preferential transmission of the long DRD4 repeat in ADHD compared to the haplotype relative risk (HRR) derived control group in a group of 49 triads (both parents and ADHD child) recruited in the Jerusalem area. In the current study we independently recruited an additional group of 49 triads from a different geographical location (Petak Tikvah) in Israel but having a similar ethnic background. In contrast to previous findings from a number of groups, in the current study an excess of the long DRD4 alleles was observed in the HRR control group compared to the ADHD subjects (Likelihood ratio = 5.50, P = 0. 02). In the expanded Israeli group of 98 triads so-far examined for the DRD4 repeat polymorphism there is an excess of the long alleles in the HRR control group (Likelihood ratio = 3.81, P = 0.05). These results attest to the complexity of ADHD inheritance and the likelihood that genetic heterogeneity characterizes this disorder especially across ethnic and cultural boundaries.

Adolescent↗

PubMed2000

A transcription-activating polymorphism in the ACHE promoter associated with acute sensitivity to anti-acetylcholinesterases.

Hypersensitivity to acetylcholinesterase inhibitors (anti-AChEs) causes severe nervous system symptoms under low dose exposure. In search of direct genetic origin(s) for this sensitivity, we studied six regions in the extended 22 kb promoter of the ACHE gene in individuals who presented adverse responses to anti-AChEs and in randomly chosen controls. Two contiguous mutations, a T-->A substitution, disrupting a putative glucocorticoid response element, and a 4-bp deletion, abolishing one of two adjacent HNF3 binding sites, were identified 17 kb upstream of the transcription start site. Allele frequencies for these mutations were 0.006 and 0.012, respectively, in 333 individuals of various ethnic origins, with a strong linkage between the deletion and the biochemically neutral H322N mutation in the coding region of ACHE. Heterozygous carriers of the deletion included a proband who presented with acute hypersensitivity to the anti-AChE pyridostigmine and another with unexplained excessive vomiting during a fourth pregnancy following three spontaneous abortions. Electromobility shift assays, transfection studies and measurements of AChE levels in immortalized lymphocytes as well as in peripheral blood from both carriers and non-carriers, revealed functional relevance for this mutation both in vitro and in vivo and showed it to increase AChE expression, probably by alleviating competition between the two hepatocyte nuclear factor 3 binding sites. Moreover, AChE-overexpressing transgenic mice, unlike normal FVB/N mice, displayed anti-AChE hypersensitivity and failed to transcriptionally induce AChE production following exposure to anti-AChEs. Our findings point to promoter polymorphism(s) in the ACHE gene as the dominant susceptibility factor(s) for adverse responses to exposure or to treatment with anti-AChEs.

Acetylcholinesterase↗

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↗