TGFBR2 gene expression and genetic association with schizophrenia

TGFBR2 gene is a tumor suppressor gene located at chromosome 3p22, and the locus is reported to be linked with schizophrenia susceptibility. According to the previous studies, a reduced incidence of cancer is observed in schizophrenic patients compared with the general population and tumor suppressor genes may be associated with schizophrenia. We measured the mRNA expression of TGFBR2 gene in the peripheral leukocytes from 19 medication-free schizophrenics and 25 medication-free major depressive patients compared with age- and sex-matched control subjects using a quantitative real-time PCR method. We also followed up the TGFBR2 mRNA expression levels from 13 schizophrenics after several weeks - antipsychotic treatments. The TGFBR2 mRNA levels of medication free schizophrenics were significantly higher than those of control subjects and decreased to almost the same level as controls after antipsychotic treatment. On the other hand, the TGFBR2 mRNA levels of medication-free major depressive patients were not significantly different from controls. In genetic studies, we failed to find any association between the TGFBR2 gene and schizophrenia with 10 SNPs of TGFBR2 gene in Japanese subjects (279 subjects each) and there was no significant difference with haplotype analysis, either. Our results suggest that the TGFBR2 gene itself does not link to schizophrenia but that the TGFBR2 mRNA levels in the peripheral leukocytes may be a potential state marker for schizophrenia.     

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder.

Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 2 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants. Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele and the other of the long allele. Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus. These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects. Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism.     

No significant association between the genetic polymorphisms in the GSK-3 beta gene and schizophrenia in the Chinese population

The GSK-3 beta gene encodes a protein kinase which is abundant in the brain, and its product is involved in signal transduction cascades of neuronal cell development, energy metabolism and body pattern formation. Previous studies have suggested that GSK-3 beta might act as a potential candidate locus for schizophrenia susceptibility. We genotyped six SNPs within the gene and conducted a case-control study involving 329 schizophrenic patients and 288 healthy subjects in the Chinese population. We examined allele and genotype frequencies and haplotype distributions in the subtype of paranoid schizophrenic patients as well as schizophrenic subjects in general. Our results fail to replicate the association of the GSK-3 beta gene with susceptibility to schizophrenia in the Chinese population.     

Catatonia in autistic disorder: A sign of comorbidity or variable expression?

Catatonia, once solely attributed to schizophrenia, is now thought to be associated with many disorders. Autistic disorder shares some symptoms with catatonia, namely, mutism, echopraxia/echolalia, and sterotypes. Catatonia in autism may therefore be a variant of the autistic condition. However, organic deficits and psychiatric disorders, such as bipolar disorder, have also been deficits and psychiatric disorders, such as bipolar disorder, have also been linked with the manifestation of catatonia. Individuals with autism presenting with these comorbid conditions may therefore be at increased risk for catatonia. Little is written of the association of autism and catatonia to clarify the possibility of catatonia as a variant or a sign of a comorbid condition. The authors discuss three autistic patients and suggest specific etiologies for the symptoms of catatonia which presented in these cases. The therapeutic and diagnostic importance of comorbid disorders in autism is stressed.     

Attention deficit and hyperactivity disorder: review of genetic association studies

Attention Deficit and Hyperactivity Disorder (ADHD) is a common idiopathic childhood neurodevelopmental disorder, exacting a significant clinical and public health toll. It impairs schooling and social adaptation, resulting in high rates of depression, conduct disorder, school dropouts, and substance abuse, and necessitating exposure of many children to prolonged courses of stimulant psychotropic medication. Although the biological basis of ADHD is unknown, it has been shown to possess considerable heritability. Candidate gene association studies proved to be a productive strategy leading to replicated association findings of genetic loci contributing to susceptibility to ADHD. Based on the mechanism of action of stimulant drugs effective in the alleviation of ADHD symptoms, current association studies have focused mainly on dopaminergic genes. Promising exploratory findings have also been reported for genes affecting other neurotransmitter systems. The current article reviews the rationale, methodology, and main findings in the field, and outlines future directions. Locating the actual genes mediating ADHD susceptibility will have far reaching implications for understanding the pathophysiology of ADHD as well as for understanding mechanisms of therapeutic drug action and genetic determinants of response.     

No genetic association between NCAM1 gene polymorphisms and schizophrenia in the Chinese population

Background

The neural cell adhesion molecule 1(NCAM1, aliases NCAM and CD56) is a cell-surface molecule which makes homophilic adhesion between neural cells involved in cell migration, axon outgrowth and synaptic plasticity. Recent studies reported that NCAM1 might act as a candidate schizophrenia susceptibility gene.

Method

We genotyped five SNPs (rs1943620, rs1836796, rs1821693, rs686050, rs584427) within the NCAM1 gene and conducted a case-control study in 288 schizophrenic patients and 288 healthy subjects in the Chinese Han population. We compared allele and genotype frequencies and haplotype distributions between cases and controls.

Result

No significant differences in allele and genotype frequencies were found for each single SNP between schizophrenic patients and healthy subjects. Moreover, there were no significant differences in haplotype distributions between cases and controls (global χ² = 1.318, P = 0.725, df = 3).

Conclusion

Our study suggests that the five SNPs within NCAM1 gene we studied may not play a major role in the schizophrenia susceptibility in the Chinese Han population.     

Genetic association study of CSNK1E gene in bipolar disorder and circadian characteristics

Abstract

Background: A circadian rhythm disturbance is one of the essential components of the phenotype of bipolar disorder. It has been reported that casein kinase 1 epsilon (CSNK1E), a member of the clock gene family, is associated with psychiatric phenotypes.

Objectives: We performed a genetic association study to determine the genetic role of CSNK1E in bipolar disorder and circadian rhythm disturbances in the Korean population.

Methods: The present study included 215 patients with bipolar disorder and 773 controls. Circadian characteristics were measured by the Korean version of the Composite Scale of Morningness (CS). Single-nucleotide polymorphisms (SNPs) of CSNK1E, rs1534891 and rs2075984, were genotyped. Chi-square analyses were performed to evaluate associations involving alleles and genotypes. Haplotype analysis was also performed, and the permutation p value was calculated. We also tested further associations involving these SNPs and scores on the CS.

Results: We found a positive association between SNP rs2075984 and bipolar disorder in both the allelic (p?=?.003) and genotypic (p?=?.006) distributions. No allelic or genotypic association between SNP rs1534891 and bipolar disorder was observed. A significant association of haplotype with bipolar disorder was found (p?=?.033). However, no association between the CS and the genotype of either SNP was found in the total sample.

Conclusion: CSNK1E SNP rs2075984 seemed to play a significant role in the development of bipolar disorder in this Korean sample. This association does not seem to relate to the phase preference measured by the CS. Further studies on CSNK1E with larger samples and more SNPs are necessary.     

Attention deficit hyperactivity disorder symptoms in pervasive developmental disorders: association with autistic behavior domains and coexisting psychopathology

BACKGROUND: Symptoms as in attention deficit hyperactivity disorder (ADHD) are frequent among individuals with pervasive developmental disorders (PDD). The aim of the present study was to examine the impact of inattention, hyperactivity and impulsivity on the clinical phenotype of children and adolescents with PDD. SAMPLING AND METHODS: A total of 182 subjects (41 females) diagnosed as having PDD were split into a high (PDD+) and a lower (PDD) attention problem group using the median of the Child Behavior Checklist (CBCL) syndrome scale 'attention problems' (median T score = 75). The groups were compared with regard to the degree of coexisting psychopathology, as measured by the remaining 7 CBCL subscales, and autistic core features assessed by the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule using a multivariate analysis of covariance adjusted for age, IQ and socioeconomic status. RESULTS: The PDD+ subjects exhibited a significantly higher degree of general psychopathology than the subjects in the PDD subgroup, regarding both internalizing and externalizing symptoms. In addition, the PDD+ subgroup tended to exhibit more impairments on the social interaction scale of the ADI-R. CONCLUSIONS: Clinicians should adjust treatment plans to ensure comprehensive and effective treatment for both PDD and associated ADHD. A dual diagnosis may be essential to the implementation of effective treatments.     

The human secretin gene in children with autistic spectrum disorder: screening for polymorphisms and mutations

We screened 29 children with autism for mutation in the human secretin gene using single-strand conformation polymorphism. No mutation was detected in exon 2, 3, or 4. Polymerase chain reaction and DNA sequence of 5' variable number of tandem repeats showed two polymorphisms with deletion or duplication of a repeat unit that failed to show any gene expression with transient transfection assay. We did not find evidence of a relationship between human secretin gene mutation and autism.     

Niaprazine in the treatment of autistic disorder.

Niaprazine is a histamine H1-receptor antagonist with marked sedative properties. It has been employed in subjects with behavior and sleep disorders. No data concerning the use of niaprazine in subjects with autistic disorder are reported in the literature. The authors performed an open study to assess niaprazine efficacy in a sample of 25 subjects with autistic disorder and associated behavior and sleep disorders. Niaprazine was administered at 1 mg/kg/day for 60 days. A positive effect was found in 52% of patients, particularly on hyperkinesia, unstable attention, resistance to change and frustration, mild anxiety signs, heteroaggressiveness, and sleep disorders. Statistical comparison between responders and nonresponders showed no influence on niaprazine effect by age over or under 12 years, presence of neurologic signs, epilepsy, or abnormalities seen on brain imaging. Niaprazine was more efficacious in subjects with a mild or moderate degree of mental retardation. No side effects were observed. Because of its sedative effects and good tolerability, niaprazine can be used as a first-choice drug to improve behavior and sleep disorders in patients with autistic disorder.     

Serotonin 1A receptor gene,schizophrenia and bipolar disorder: An association study and meta-analysis

Several investigations have reported associations between serotonin 1A (5-HT1A) receptor and major psychiatric disorders, such as schizophrenia and bipolar disorder (BP), making the 5-HT1A receptor gene (HTR1A) a good candidate gene for the pathophysiology of schizophrenia and BP. To evaluate the association between HTR1A and schizophrenia and BP, we conducted a case-control study of Japanese population samples with two single- nucleotide polymorphisms (SNPs), including rs6295 (C-1019G) in HTR1A. In addition, we conducted a meta-analysis of rs6295, which has been examined in other studies. Using one functional single- nucleotide polymorphism (SNP; rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (857 schizophrenic patients, 1028 BP patients and 1810 controls) in the Japanese population. Two association studies for schizophrenia and three association studies for BP, including this study, met our criteria for the meta-analysis of rs6295. We found an association between HTR1A and Japanese BP in a haplotype-wise analysis, the significance of which remained after Bonferroni correction. In addition, we detected an association between rs6295 and BP in the meta-analysis (fixed model: P(Z) = 0.000400). However, we did not detect an association between HTR1A and schizophrenia in the allele/genotype-wise, haplotype-wise or meta-analysis. HTR1A may play an important role in the pathophysiology of BP, but not schizophrenia in the Japanese population. In the meta-analysis, rs6295 in HTR1A was associated with BP patients.     

Oxytocin and autistic disorder: alterations in peptide forms.

BACKGROUND: Oxytocin (OT) is synthesized as a prohormone that is sequentially processed to peptides. These peptides are the bioactive amidated form (OT) and the C-terminal extended peptides, OT-Gly, OT-Gly-Lys and OT-Gly-Lys-Arg, which are designated together as OT-X. As an extension of our previous study finding decreased plasma OT in autism, studies were conducted to determine whether there were changes in OT peptide forms in autistic children. METHODS: Twenty eight male subjects (97 +/- 20 months; range, 70-139 months), diagnosed with DSM-IV autistic disorder through observation and semi-structured interview, were compared with 31 age-matched nonpsychiatric control subjects (106 +/- 22 months; range, 74-140 months). Using OT antisera with different specificity for the peptide forms, we measured plasma OT and OT-X in each group. RESULTS: T tests showed that there was a decrease in plasma OT (t = 4.4, p <.0001), an increase in OT-X (t = 2.3, p <.03) and an increase in the ratio of OT-X/OT (t = 4.5, p <.0001) in the autistic sample, compared with control subjects. CONCLUSIONS: The results suggest that children with autistic disorder show alterations in the endocrine OT system. Deficits in OT peptide processing in children with autism may be important in the development of this syndrome.     

Mutation screening of the UBE3A/E6-AP gene in autistic disorder

Previous reports of individuals with autistic disorder with maternal duplications of 15q11-q13, the Prader-Willi/Angelman syndrome region, suggest this area as a source of candidate genes in autistic disorder. Maternal truncation mutations in UBE3A, which encodes for E6-AP ubiquitin-protein ligase, have been shown to cause Angelman syndrome, which can also result from the absence of maternal chromosomal material from this region. Despite showing no evidence for imprinting in other tissues, this gene was recently discovered to be preferentially maternally expressed in human brain and expressed solely from the murine maternal chromosome in the hippocampus and cerebellar Purkinje cells, regions implicated in the neuropathology of autism. Based on this evidence, the coding region and a putative promoter region were sequenced in ten autistic subjects. Several polymorphisms were detected, but no evidence was found for a functional mutation. Evidence for likely altered regulation of UBE3A expression in maternal 15q11-q13 duplications suggests further investigation of the regulatory regions of this gene in autistic disorder.     

No association between obsessive-compulsive disorder and the 5-HT(1Dbeta) receptor gene

OBJECTIVE: Serotonin abnormalities may be involved in the etiopathogenesis of obsessive-compulsive disorder (OCD). The silent G-to-C substitution at nucleotide 861 of the coding region of the 5-HT(1Dbeta) receptor gene may be associated with liability to OCD. The aim of this study was to investigate this association in an Italian OCD study group. METHOD: Genotyping for 5-HT(1Dbeta) was performed for 79 nuclear families of probands with OCD. The transmission/disequilibrium test was used to determine transmission of the alleles from parents to offspring. RESULTS: Of the 79 families, 48 were informative for the analysis, i.e., both parents were genotyped for 5-HT(1Dbeta), and at least one parent was heterozygous. No preferential transmission of either allele of the 5-HT(1Dbeta) gene was observed. CONCLUSIONS: These data do not support a role for the 5-HT(1Dbeta) receptor gene in conferring susceptibility to OCD.     

Comorbidity of autistic disorder in children and adolescents

Although considerable research has been done on various aspects of autism, information about the prevalence of coincident psychiatric disorders that may complicate this syndrome, is negligible. In this paper, we present preliminary data on the presentation of other psychiatric disorders in children and adolescents with autism. Out of an outpaticent sample of 68 autistic children and adolescents, 6 (9%) presented with an associated psychiatric disorder. Depression was the most common diagnosis. None of the patients was given a diagnosis of schizophrenia. Clinical and research implications of the findings are discussed.

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Zusammenfassung Obwohl zu verschiedenen Aspekten des Autismus viel geforscht wurde, gibt es kaum Informationen zur koinzidentiellen Prävalenz von psychiatrischen Störungen, die das Syndrom komplizieren könne. In dieser Arbeit stellen wir vorläufige Daten über begleitende psychiatrische Störungen bei Kindern und Jugedlichen mit Autismus vor. Von 68 ambulant behandelten Kindern und Jugendlichen mit Autismus zeigten 9% eine assoziierte psychiatrische Störung. Depression war die häufigste Diagnose. Bei keinem der Patienten war die Diagnose Schizophrenie gestellt worden. Klinische und wissenschaftliche Implikationen dieser Befunde werden diskutiert.

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Résumé Bien qu'une recherche considérable ait été enterprise concenant les différents aspects de l'autisme, l'information sur la prévalence des troubles psychiatriques coïcidant et pouvant compliquer ce syndrome reste négligeable. Dans ce travail, nous présentons des faits préliminaires concernant les autres troubles psychiatriques chez les enfants et les adolescents avec autisme. Parmi un échantillon de 68 enfants et adolescents autistes vus en consultation: 6 (9%) présentaient un trouble psychiatrique associé La dépressio était le diagnostic le plus commun. Aucun des patients n'a eu un diagnostic de schizophrénie. Les implications de ces faits pour la clinique et la recherche sont discutées.