Purpose: 22q11.2 deletion syndrome (22q11.2DS) and Williams syndrome (WS) are common neurogenetic microdeletion syndromes. The aim of the present study was to compare the neuropsychiatric and neurocognitive phenotypes of 22q11.2DS and WS. Methods: Forty-five individuals with 22q11.2DS, 24 with WS, 22 with idiopathic developmental disability (DD) and 22 typically developing (TD) controls were compared for the rates of psychiatric disorders as well as cognitive executive and visuospatial functions. Results: We found that while anxiety, mood and disruptive disorders had an equally high prevalence among individuals with 22q11.2DS, WS and DDs, the 22q11.2DS group had the highest rates of psychotic disorders and the WS group had the highest rates of specific phobia. We also found that the WS group demonstrated more severe impairments in both executive and visuospatial functions than the other groups. WS and 22q11.2DS subjects had worse Performance-IQ than Verbal-IQ, a feature typical of non-verbal learning disorders. Conclusion: These findings offer a wide perspective on unique versus common phenotypes in 22q11.2DS and WS.

This is the first study of a possible molecular genetic basis for schizophrenia with obsessive-compulsive disorder (OCD). We performed a case–control association study of the catechol-O-methyltransferase (COMT) Val158Met polymorphism in schizophrenia–OCD patients, OCD and healthy controls. One hundred and thirteen schizophrenia–OCD patients, 79 OCD patients and 171 control subjects were genotyped for the Val158Met polymorphism in the COMT gene. There was no significant difference in allele and genotype distribution of the COMT gene between schizophrenia–OCD patients and healthy controls. The low-activity Met allele and Met/Met genotype were more frequent in OCD men than in schizophrenia–OCD and control individuals. This difference, however, was not statistically significant following correction for multiple comparisons. These results do not support the hypothesis that the COMT Val158Met gene polymorphism is associated with liability to schizophrenia–OCD.

Relationships between the serotonin transporter promoter polymorphism (5-HTTLPR), platelet serotonin transporter (SERT) binding and clinical phenotype were examined in 32 suicidal and 28 non-suicidal Ashkenazi Israeli adolescent psychiatric inpatients. The 5-HTTLPR polymorphism was not associated with transporter binding or with suicidality or other clinical phenotypes. However, in the suicidal group, a significant positive correlation between platelet SERT density and anger scores (n=32, r=.40; p=.027) and a negative correlation between platelet count and trait anxiety (n=32, r=-.42; p=.034) were observed.

Anorexia nervosa (AN) is a severe and complex psychiatric disorder with a significant genetic contribution. Previously, we found an association between AN and the 158Val/Met polymorphism of the catechol-O-methyltransferase (COMT) gene in a family-based study of 51 Israeli AN trios. In the present study, we extended the original sample to include 85 family trios [66 AN restricting (AN-R) and 19 bingeing/purging (AN-BP) subtype] and performed a family-based transmission disequilibrium test (TDT) analysis for five SNPs in the COMT and two in the adjacent ARVCF gene. Association was found between AN-R and several SNPs in the COMT-ARVCF region including the 158Val/Met polymorphism. TDT analysis of 5-SNP haplotypes in AN-R trios revealed an overall statistically significant transmission disequilibrium (P < 0.001). Specifically, haplotype B [COMT-186C-408G-472G(158Val)-ARVCF-659C(220Pro)-524T(175Val)] was preferentially transmitted (P < 0.001) from parents of AN-R patients to their affected daughters, while haplotype A [COMT-186T-408C-472A(158Met)-ARVCF-659T(220Leu)-524C(175Ala)] was preferentially (P = 0.01) not transmitted. Haplotype B was associated with increased risk (RR 3.38; 0.95CI 1.98-6.43) while haplotype A exhibited a protective effect (RR 0.40; 0.95CI 0.21-0.70) for AN-R. Preferential transmission of the risk alleles and haplotypes from the parents was mostly contributed by the fathers. No significant transmission disequilibrium of alleles or haplotypes was found for AN-BP trios. The risk and protective haplotypes may carry molecular variations in the COMT gene or its vicinity that are relevant to the pathophysiology of restrictive anorexia nervosa in the Israeli-Jewish population.

The human small-conductance Ca(2+)-activated potassium channel gene KCNN3 has been involved in mechanisms underlying neuronal function and plasticity. A multiallelic CAG repeat polymorphism within the KCNN3 has been associated with schizophrenia and bipolar disorder. We have previously reported in a family-based study that longer CAG repeats are preferentially transmitted to patients with anorexia nervosa (AN). The present study extends the analysis of KCNN3 allele distribution to a larger series of AN female patients and control groups, incorporating information on ethnicity and co-morbidities associated with AN. The data analysis is presented while considering separately the two alleles of each individual, namely a minor (shorter) and a major (longer) allele. This study has found that the KCNN3 allele distribution in the general Israeli population does not differ significantly in at least four Jewish ethnic groups of Ashkenazi, North African, Iraqi, and Yemenite origin. These have been used as control groups in a matched case-control analysis that has demonstrated a significant over-representation of KCNN3 alleles with longer CAG repeats among AN patients (P < 0.001 for the major allele and P = 0.035 for allele sum). Under dichotomization, a significantly higher prevalence of the L allele (>19 repeats) has been observed among AN patients (P < 0.001). While considering AN and co-morbid phenotypes, a tendency towards longer (L) alleles has been observed in the subset of patients with obsessive-compulsive disorder (OCD) co-morbidity. These findings further implicate KCNN3 as a significant contributor to predisposition to AN.

Some studies have suggested possible association of the dopamine receptor subtype 4 (DRD4) gene exon III 48 bp repeat polymorphism with novelty seeking behavior. As suicidal behavior in adolescents is linked to risk taking behavior, we evaluated the association of suicidality with DRD4 polymorphism in Israeli inpatient suicidal adolescents. Sixty-nine inpatient adolescents who recently attempted suicide were assessed by structured interview and rating scales for detailed clinical history, diagnoses, suicide intent and risk, impulsivity, violence, and depression. The frequency of DRD4 alleles was compared between the suicidal inpatients and 167 healthy control subjects. No significant association between the DRD4 polymorphism and suicidal behavior was found. Analysis of the suicide-related measures demonstrated a significant difference in depression severity between suicidal inpatients homozygote and heterozygote for the DRD4 alleles (p=0.003). The relevance of this finding to increased depression severity in suicidal adolescents, if replicated, is as yet unclear.

This study examined the possible association between the polymorphism in the dopamine receptor DRD4 gene and response to risperidone among 24 Israeli Jewish adolescent inpatients with first-episode schizophrenia. Response was categorically determined by a change of >40% on the Brief Psychiatric Rating Scale (BPRS). No significant association was found between the DRD4 genotype and clinical response, although carriers of <7 repeat alleles demonstrated higher response rate (10/20 vs. 0/4, P=0.11). Studies in larger groups of adolescent schizophrenia patients are warranted to clarify the possible association between DRD4 exon III repeat alleles and the response to risperidone.

The serotonin transporter-linked promoter region polymorphism (5-HTTLPR) is thought to be associated with some serotonin dysfunction-related psychopathologies such as depression and anxiety disorders. Suicide and suicide-related behaviors such as violence, aggression, and impulsivity have been reproducibly associated with serotonin dysfunction and are partially genetic. This study examined the association of 5-HTTLPR with suicidal behavior and related traits in Israeli suicidal adolescent inpatients using the haplotype relative risk (HRR) method that controls for artifacts caused by population stratification. Forty-eight inpatient adolescents who recently attempted suicide were assessed by structured interviews for detailed clinical history, diagnoses, suicide intent, suicide risk, impulsivity, violence, and depression. Blood samples were collected and DNA extracted from patients and their biological parents. The 5-HTTLPR allele frequencies were tested for association with suicidality by the HRR method. In addition, the relationship between genotypes and phenotypic severity of several clinical parameters was analyzed. No significant allelic association of the 5-HTTLPR polymorphism with suicidal behavior was found (chi square = 0.023; P = 0.88). Analysis of variance of the suicide-related trait measures for the three genotypes demonstrated a significant difference in violence measures between patients carrying the LL and LS genotypes (9.50+/-4.04 vs. 5.36+/-4.03; P = 0.029). This study suggests that the 5-HTTLPR polymorphism is unlikely to have major relevance to the pathogenesis of suicidal behavior in adolescence but may contribute to violent behavior in this population.

The association of suicidality with polymorphism A218C in intron 7 of tryptophan hydroxylase (TPH) gene remains controversial. The aim of this study was to use family-based methods to examine this association in adolescents in order to eliminate the difficulty of sampling a control group from the same ethnic population. Eighty-eight inpatient adolescents who recently attempted suicide were assessed by structured interview for detailed clinical history, diagnoses, suicide intent, suicide risk, impulsivity, aggression, and depression. DNA samples were collected from all subjects, from both biological parents of 40 subjects and from one parent of 9 subjects; TPH allele frequencies were calculated and tested for association to phenotype, stratified by severity, using the haplotype relative risk (HRR) and transmission disequilibrium test (TDT) methods (n = 49). The frequencies were also compared for all the Jewish subjects (n = 84) to the known frequencies of these alleles in healthy Jewish populations. There was no significant allelic association of A218C polymorphism with suicidal behavior or other phenotypic measures according to the HRR method (chi-square = 0.094; P = 0.76), the TDT (chi-square = 0.258; P = 0.61), or association analysis to known population frequencies (chi-square = 1.667, P = 0.19 for Ashkenazi, and chi-square = 0.810, P = 0.37 for non-Ashkenazi). Analysis of variance with the Scheffè test demonstrated a significant difference between CC and AA genotypes in suicide risk and depression among the patients (n = 88). The findings suggest that polymorphism A218C has no major relevance to the pathogenesis of adolescent suicidal behavior, but may have a subtle effect on some related phenotypes.

Anorexia nervosa (AN) is a common, severe and disabling psychiatric disorder, characterized by profound weight loss and body image disturbance. 1 Family and twin studies indicate a significant genetic contribution 2,3 and pharmacological data suggest possible dysfunction of the serotonergic 4,5 and dopaminergic 6–9 pathways. Catechol-O-methyltransferase (COMT) is a candidate gene for mediating susceptibility to AN since it is involved in the dopamine catabolism 10 and because its functional polymorphism (Val/Met 158) determines high (H) and low (L) enzymatic activity alleles. 11 Fifty-one Israeli AN patients and their parents were genotyped with the COMT polymorphism. Using the haplotype relative risk (HRR) method it was found that the frequency of the H allele among alleles transmitted to AN patients from their parents was significantly higher than in those not transmitted (68% vs 51% χ 2 = 5.20, df = 1, P = 0.023, odds ratio: 2.01). Transmission disequilibrium test (TDT) revealed that out of 49 heterozygote parents the H allele was transmitted to AN patients 33 times while the L allele was transmitted only 16 (McNemar's χ 2 = 5.90, df = 1, P = 0.015). Our study suggests that the COMT gene is associated with genetic susceptibility to AN, and that individuals homozygous for the high activity allele (HH) have a two-fold increased risk for development of the disorder.

Serotonergic neurotransmission has been implicated in suicidal behavior. Polymorphisms in the genes coding for tryptophan hydroxylase, serotonin receptor 2A and serotonin transporter were investigated in a sample of suicide attempters (n = 165) and healthy control subjects (n = 99). No significant differences were found for any of the investigated polymorphisms. Neither did any significant differences emerge in comparison with control subjects when the suicide attempters were grouped into different diagnostic categories: unipolar disorder (n = 45), adjustment disorder (n = 37), substance use disorder (n = 37) and personality disorder, cluster B (n = 36). The results suggest that alleles defined by the investigated polymorphisms do not represent a major determinant in suicide attempt. However, a highly significant (P = 0.001; odds ratio, 1.47; 99% confidence interval, 1.42-1.53) allelic association between tryptophan hydroxylase and suicide attempt is indicated after pooling our data with literature data. In light of previous data, a possible association between the tryptophan hydroxylase polymorphism and a phenotype that may become differently stratified within differently selected samples of suicide attempters is discussed.

The serotonin transporter gene (SLC6A4), which plays a key role in the serotonergic pathway in the brain, is a candidate for mediating genetic susceptibility to various psychiatric disorders. There are two predominant alleles in the polymorphic promotor region [5-HT transporter gene-linked polymorphic region (5-HTTLPR)] of this gene: a long and a short allele with 16 and 14 repeat units, respectively. The short allele has lower activity and is associated with several psychiatric disorders and personality traits. We identified and sequenced a novel allele with 13 repeat units, 23 base pairs shorter than the common short allele. This unique allele was detected in a schizophrenic patient of Jewish Libyan origin. The patient exhibited extreme aggressive behavior and committed suicide after several attempts. The novel short allele was not detected in 172 healthy control subjects and 361 patients with various mental disorders. The presence of a very short unique allele in a severely aggressive schizophrenic patient may reflect a specific effect on the particular phenotype, although it is unlikely that this allele has a major contribution to susceptibility to schizophrenia. The role of the allele in serotonin transport and possible association with disease phenotype should be further investigated.

Obsessive-compulsive disorder (OCD) is a severe and disabling anxiety disorder with a marked genetic contribution. Pharmacological data indicated involvement of the serotonergic and dopaminergic systems. We studied the association between OCD and six candidate genes encoding important components of the serotonergic and dopaminergic pathways in 75 biologically unrelated patients and 172 ethnically matched controls (Ashkenazi and non-Ashkenazi Jews). Polymorphisms in the following genes were studied: tryptophan hydroxylase (TPH), serotonin 2A receptor (HTR2A), serotonin 2C receptor (HTR2C), serotonin transporter (5-HTT), dopamine receptor D4 (DRD4), and dopamine transporter (DAT1). The genotypic and allelic distribution of all polymorphisms tested did not show statistically significant differences between patients and controls. Our results suggest that these polymorphisms do not play a major role in the genetic predisposition to OCD, although a minor contribution cannot be ruled out.

An association between long alleles of a variable number tandem repeat (VNTR) polymorphism in the dopamine receptor D4 gene and the extraversion related personality traits Excitement and Novelty Seeking has been reported in healthy subjects.In an attempt to replicate the previous findings, 256 healthy Caucasian volunteers were analysed for a potential relationship between the dopamine receptor D4 exon III VNTR polymorphism and Extraversion as assessed by the Revised Neo Personality Inventory (NEO PI-R). The present study did not yield evidence for an association between Extraversion and the dopamine receptor D4 polymorphism.

Dopaminergic neurotransmission has been implicated in suicidal behaviour. The 48 bp-repeat polymorphism in the gene coding for dopamine receptor D4 was investigated in a sample of suicide attempters (n = 165) and healthy control subjects (n = 99). No association between suicide attempts and this polymorphism was observed. Neither did any significant differences emerge in comparison with control subjects when the suicide attempters were grouped into different diagnostic categories: unipolar (n = 45), anxiety (n = 23), adjustment (n = 37) and personality disorders, cluster B (n = 36). The results suggest that alleles defined by the investigated polymorphism do not have a major impact on suicidal behaviour.

The human serotonin transporter (hSERT) gene is a promising candidate for mediating the genetic susceptibility for various psychiatric conditions such as mood1 and obsessive-compulsive disorders.2 Two polymorphic sites in this gene attracted much interest: a VNTR of 17-bp repeats in intron two,3 and an insertion/deletion in the 5′-flanking promoter region (5-HTT gene-linked polymorphic region-5-HTTLPR)4 creating a short (S) and a long (L) allele. The 5-HTTLPR polymorphism is situated in a GC-rich region composed of 20–23 bp repeating units. The S and L alleles have 14 and 16 repeat-elements respectively. Positive associations of the 5-HTTLPR polymorphism with mood disorders,5 anxiety-related personality traits,6 autism7 and late-onset Alzheimer's8 disease have been published, although some non replications were also reported.9,10 Here we report a novel allele (termed LJ) in the 5-HTTLPR site. This allele is longer than the L allele by 43 bp, has 18 repeat units and contains two copies of the insertion/deletion sequence arranged in tandem. The LJ allele was found in individuals of Libyan and Tunisian Jewish origin but not in Moroccan or Ashkenazi Jews.

Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%.1 The importance of the genetic component is well accepted,2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects.