Yamima Osher

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.

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 × 5-HTTLPR: Hotellings 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.

5-HT2C (HTR2C) serotonin receptor gene polymorphism associated with the human personality trait of reward dependence: interaction with dopamine D4 receptor (D4DR) and dopamine D3 receptor (D3DR) polymorphisms.

We recently reported an association between the long repeat allele of the dopamine D4 exon III receptor polymorphism and a human personality dimension, novelty seeking, as measured by the tridimensional personality questionnaire (TPQ), a personality instrument designed by Cloninger to reflect heritable facets of human temperament. The D4 receptor polymorphism (D4DR) accounts for only a small percent of the variance for this trait, suggesting that additional genes influence both novelty seeking as well as the other temperaments that are inventoried by the Cloninger TPQ. In the current investigation, we examined, in the original cohort of 120 normal volunteers, two additional coding region polymorphisms, a glycine to serine substitution in the dopamine D3 receptor (D3DR) and a cysteine to serine substitution in the 5-HT2C serotonin receptor (HTR2C). Three-way analysis of variance (TPQ score grouped by D4DR, D3DR and 5-HT2C) demonstrated that reward dependence and persistence scores were significantly reduced by the presence of the less common 5-HT2Cser polymorphism. The effect of the serine substitution in this X-linked serotonin receptor polymorphism on reward dependence was also observed when male and female subject groups were separately analyzed. There was also a significant interaction between the two dopamine receptor polymorphisms and the serotonin polymorphism on reward dependence. In particular, the effect of the 5-HT2C polymorphism on reward dependence was markedly accentuated in individuals who had the long version of the D4DR exon III repeat polymorphism. When present in the same individual, the 5-HT2C and dopamine receptor polymorphisms account for 30% of the observed variance for persistence (RD2) and 13% of the variance for reward dependence scores (RD134). However, the number of subjects with both less common D4DR and 5-HT2C polymorphisms is small, underscoring the importance of verifying this interaction in a larger cohort.

Homocysteine-Reducing Strategies Improve Symptoms in Chronic Schizophrenic Patients with Hyperhomocysteinemia

Background An elevated homocysteine level is reported to be a risk factor for several diseases, including Alzheimer’s and cerebrovascular disease. Recently, several studies have reported that homocysteine levels are elevated in many schizophrenic patients. Homocysteine levels can be lowered by oral folic acid, B-12, and pyridoxine. Methods Forty-two schizophrenic patients with plasma homocysteine levels >15 μmol/L were treated with these vitamins for 3 months and placebo for 3 months in a study with a randomized, double-blind, placebo-controlled, crossover design. Results Homocysteine levels declined with vitamin therapy compared with placebo in all patients except for one noncompliant subject. Clinical symptoms of schizophrenia as measured by the Positive and Negative Syndrome Scale declined significantly with active treatment compared with placebo. Neuropsychological test results overall, and Wisconsin Card Sort (Categories Completed) test results in particular, were significantly better after vitamin treatment than after placebo. Conclusions A subgroup of schizophrenic patients with hyperhomocysteinemia might benefit from the simple addition of B vitamins.

TPQ in euthymic manic-depressive patients

Researchers using various psychological measures and instruments have concluded that the personality of remitted bipolars and normal controls are essentially similar. We recently suggested that specific personality traits might be genetic markers for manic-depressive illness. The Tridimensional Personality Questionnaire (TPQ) is a personality questionnaire with heritable subscales and hypothesized anchoring in neurochemistry. We studied the personality of euthymic bipolar manic depressive patients using the TPQ. Subjects were volunteers from the out-patient Lithium Clinic. TPQs were individually administered to 50 euthymic bipolar patients. Persistence is significantly reduced, and harm avoidance and reward dependence significantly increased, compared with U.S. norms. These traits may be part of the genetic diathesis for manic-depressive illness.

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 × 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).

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.

Low persistence in euthymic manic-depressive patients: a replication

BACKGROUND A previous study which compared euthymic Israeli bipolars in a public hospital clinic to US normative data suggested that low Persistence scores on the Tridimensional Personality Questionnaire (TPQ) may be a temperament marker for manic-depressive illness. The current study attempts to replicate that finding. METHODS A new sample of 25 euthymic Israeli bipolars in private treatment was compared to Israeli normal controls matched for gender and ethnic background. All subjects completed Hebrew versions of the TPQ. RESULTS Patients scored lower than controls on the Novelty Seeking and Persistence Scales. LIMITATIONS AND CONCLUSIONS Though sample and effect size are both small, the finding of low Persistence is consistent with that of the earlier study.

Effect of bipolar disorder on lymphocyte inositol monophosphatase mRNA levels

The activity of inositol monophosphatase (IMPase), the lithium (Li)-inhibitable enzyme in the phosphatidylinositol (PI) signal transduction system, has recently been found significantly lower in lymphoblastoid cell lines from bipolar (BP) patients, particularly in Li-responders. To probe for possible quick detection of the disease and prediction of the therapeutic response we repeated our study in fresh lymphocytes. Since IMPase in fresh lymphocytes is inhibited in vivo by ongoing Li treatment and its pre-Li activity cannot be evaluated, IMPase mRNA levels were measured. Relative (to beta-actin) mRNA levels were quantified by reverse transcriptase (RT)-PCR in 5 drug-free and 31 drug-treated BP patients compared with 36 control subjects in fresh lymphocytes. In agreement with our findings with IMPase activity, the small group of drug-free BP patients exhibited approximately 2/3 reduction in IMPase relative mRNA levels compared to control subjects. Approximately 2-fold elevation of these levels toward control values was found for patients treated with Li and other mood stabilizers. The study further suggests the possible importance of IMPase in the aetiology of BP disorder and in the mediation of the therapeutic efficacy of Li. It may be that chronic inhibition of IMPase activity by Li results in up-regulation of its gene at the transcriptional level.

Predominant Polarity of Bipolar Patients in Israel

Summary: Studies in European and American populations have suggested that the course of bipolar illness is most often characterised by a predominance of depressions over manias. The current chart review study suggests that among manic-depressive patients in Southern Israel, a predominately manic course of illness is more common. Unlike some previous studies, no sex differences were noted in type of illness course. Possible explanations for the main finding, including climate-related factors, are discussed.