Analysis of a promoter polymorphism in the SMDF neuregulin 1 isoform in Schizophrenia.

BACKGROUND/AIMS: Neuregulin 1 (NRG1) is a positional candidate gene in schizophrenia (SZ). Two major susceptibility loci in the NRG1 gene approximately one million nucleotides apart have been identified in genetic studies. Several candidate functional allelic variants have been described that might be involved in disease susceptibility. However, the findings are still preliminary. We recently mapped active promoters and other regulatory domains in several SZ and bipolar disorder (BD) candidate genes using ChIP-chip (chromatin immunoprecipitation hybridized to microarrays). One was the promoter for the NRG1 isoform, SMDF, which maps to the 3' end of the gene complex. Analysis of the SNP database revealed several polymorphisms within the approximate borders of the region immunoprecipitated in our ChIP-chip experiments, one of which is rs7825588. METHODS: This SNP was analyzed in patients with SZ and BD and its effect on promoter function was assessed by electromobility gel shift assays and luciferase reporter constructs. RESULTS: A significant increase in homozygosity for the minor allele was found in patients with SZ (genotype distribution chi(2) = 7.32, p = 0.03) but not in BD (genotype distribution chi(2) = 0.52, p = 0.77). Molecular studies demonstrated modest, but statistically significant allele-specific differences in protein binding and promoter function. CONCLUSION: The findings suggest that homozygosity for rs725588 could be a risk genotype for SZ.

ADHD and growth: anthropometric changes in medicated and non-medicated ADHD boys.

BACKGROUND: ADHD children can show changes in growth and development. Many studies describe these changes as a side effect of stimulant medication. However, changes in somatic development can also appear in non-medicated children. This suggests that the changes could be a manifestation of the disorder itself and not just a side effect of the treatment. MATERIAL/METHODS: This study compared anthropometric characteristics in medicated and non-medicated ADHD boys (n=104, age 4-16 years) with the normal non-clinical population. In contrast to most previous studies, complex anthropometrical measurements were used. RESULTS: The results showed significant differences between children with ADHD and those without the diagnosis, the differences found to be statistically significant (p<0.01) being signs of nutrition (percentage of fat, abdominal circumference) and growth suppression (lower body height, smaller head circumference). Differences between the medicated and non-medicated groups corresponded only to a lower value of body fat in the medicated children. CONCLUSIONS: These results suggest that growth changes in ADHD children may be more specific to the disorder itself than to stimulant treatment.

Brain wave P300: a comparative study of various forms of criminal activity.

BACKGROUND: This comparative and comprehensive study builds on a previous study comparing the P300 wave of impulsively violent delinquents and a non-impulsive non-delinquent group. The purpose was to investigate changes in P300 cognitive evoked potentials, especially the amplitude and latency at the Pz electrode site. MATERIAL/METHODS: The P300 parameters of perpetrators of various types of criminal offences and those of a control group matched for age, gender, and educational status were compared (N=80). There were 20 subjects with impulsively aggressive delinquent behavior. The observed parameters were compared with the neuropsychophysiological correlates of a group of 20 subjects with deliberately (i.e. non-impulsive) violent behavior, a group of 20 delinquents sentenced for property crimes (theft), and 20 non-delinquent non-impulsive nonviolent persons. To differentiate these groups, Eysenck's IVE questionnaire and a structured interview according to DSM IV criteria conducted by a certified forensic psychiatrist were used. RESULTS: The results showed a significantly lower P300 wave amplitude in the impulsively aggressive individuals than in the other groups. No significant differences were found in terms of latency. The results confirm the results of previous studies. CONCLUSIONS: The results suggest the possibility of a neuropsychophysiological correlate of impulsively aggressive individuals behaving in a socially dangerous way. This opens a discussion on the subject of expert evaluation of criminal acts within the context of "uncontrolled affect".

Anthropometric changes in non-medicated ADHD boys.

OBJECTIVES: The aim of the study is to compare complex anthropometric characteristics in non medicated boys with ADHD and normal population. METHODS: Complex anthropometric examination of non-medicated ADHD boys (n=46, average age 11.03 years), statistical and clinical comparison to the actual population growth norm. In contrast to the most of the previous studies, which analyzed mostly only BMI or basic signs of growth as height and weight, the presented study operates with a complex anthropometrical measurement and comparison with actual population norm. RESULTS: The results of the study show significant differences in the signs of nutrition (percentage of fat) and growth indicators (lower values of height) between ADHD and non ADHD children. Further anthropometrical parameters show other possible but in the studied sample statistically non-significant differences. CONCLUSION: Many studies analyzed growth relation to medication of ADHD children, but did not consider that the changes could appear also in non-medicated children and thus they might not be only a side effect of the treatment but a manifestation of the disorder itself. Growth changes in non-medicated children are not described well enough, so the presented study was performed to compare anthropometrics characteristics in ADHD boys with norm of nonclinical population and specify the differences. The results points to hypothesis that the growth changes are primarily caused by the disorder itself.

COMT polymorphisms in impulsively violent offenders with antisocial personality disorder.

OBJECTIVE: The relationship between catechol-O-methyltransferase (COMT) polymorphisms and violent behaviour was tested in highly selected group of non-psychotic violent offenders. METHODS: We conducted an association study comparing 47 male repeatedly sentenced for impulsive violent attacks diagnosed with Antisocial Personality Disorder (APD) with 43 healthy male controls matched on education. Three COMT polymorphisms were analysed: COMT Val158Met and COMT Ala146Val on exon 4, and untranslated polymorphism on the 6th exon, at the regulatory region of the COMT gene with deletion-insertion character del/C. RESULTS: Logistic regression analysis revealed that while Val158Met is not associated with violence in APD, another COMT polymorphism - COMT Ala146Val is more frequent among violent offenders with APD (p=0.017). CONCLUSIONS: To conclude, our findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for violent behaviour in subjects without major mental disorder.

P300 wave: a comparative study of impulsive aggressive criminals.

Event-Related potentials are a simple non-invasive neurophysiological method enabling to comprehend certain aspects of the cognitive processing of information in humans. The best-known component of Event-Related Potentials is the so-called P3 wave. Alterations in the parameters of P300 wave have been discovered in certain personality disorders and in persons with impulsively aggressive behaviour. The purpose of this study is to investigate the changes of these parameters, especially an amplitude and latency in the place of Pz electrode. We examined 15 persons with the impulsive aggressive behaviour and compared them to a population comparable of normal age, gender and approximate degree of education. We used P300 auditory and a neuropsychological Eysenck IVE battery. The results showed that significantly lower amplitudes had been found in the aggressive impulsive subjects as compared to the control group. No statistically significant differences have been discovered in the latency. These results seem to confirm previous studies.

Screening of PIP5K2A promoter region for mutations in bipolar disorder and schizophrenia.

OBJECTIVE: To analyze the promoter region of PIP5K2A, a phosphatidylinositol 4-phosphate 5-kinase that maps to 10p in a region linked to both bipolar disorder and schizophrenia. METHODS: The promoter region was screened by single-strand conformation polymorphism analysis and DNA sequencing. Allele frequencies were determined in a case-control study. Functional significance of a promoter variant was determined by electromobility gel shift assays. RESULTS: Homozygosity for a rare putative promoter variant, -1007C-->T, was found in only two patients with schizophrenia and in no controls or bipolar patients. The variant forms a 7/8 base match for the binding site of Oct-1, a member of the POU homeodomain family. Electromobility gel shift assays revealed increased binding of a brain-specific nuclear protein to the -1007T allele compared with -1007C. CONCLUSION: The data suggest that homozygosity for -1007T could be a rare genetic factor in the development of schizophrenia.

Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia.

BACKGROUND: Genes involved in phosphoinositide (PI) lipid metabolism are excellent candidates to consider in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). One is PIK3C3, a member of the phosphatidylinositide 3-kinase family that maps closely to markers on 18q linked to both BD and SZ in a few studies. METHODS: The promoter region of PIK3C3 was analyzed for mutations by single-strand conformation polymorphism analysis and sequencing. A case-control association study was conducted to determine the distribution of variant alleles in unrelated patients from three cohorts. Electromobility gel shift assays (EMSA) were performed to assess the functional significance of variants. RESULTS: Two polymorphisms in complete linked disequilibrium with each other were identified, -432C- > T and a "C" insert at position -86. The -432T allele occurs within an octamer containing an ATTT motif resembling members of the POU family of transcription factors. In each population analyzed, an increase in -432T was found in patients. EMSAs showed that a -432T containing oligonucleotide binds to brain proteins that do not recognize -432C. CONCLUSIONS: A promoter mutation in a PI regulator affecting the binding of a POU-type transcription factor may be involved in BD and SZ in a subset of patients.

Analysis of SYNJ1, a candidate gene for 21q22 linked bipolar disorder: a replication study.

Linkage analysis has shown that chromosome 21q22 may contain a candidate gene for bipolar disorder (BPD). One potential 21q22 candidate gene we previously analyzed is SYNJ1, which encodes synaptojanin 1, an inositol 5-phosphatase. Previous mutation screening of SYNJ1 identified three rare functional variants, one of which is a polymorphic variant near the intron 12-oxon 12 border. The rare variants were found only in a total of four BPD patients and no controls, and a trend toward significance was found for the intron 12 polymorphism. In an analysis of a new set of 84 bipolar patients, none of the rare variants were detected. There was an increase in allele 2 for the intron 12 polymorphism, similar to our original study, but the result was not significant. The combined data from both studies continue to show a trend toward significance for allele 2 homozygotes in BPD.

Polymorphism screening of PIP5K2A: a candidate gene for chromosome 10p-linked psychiatric disorders.

Lithium is a potent noncompetitive inhibitor of inositol monophosphatases, enzymes involved in phosphoinositide (PI) and inositol phosphate metabolism. A critical component of the PI pathway is phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)), which is hydrolyzed to second messengers and has a direct role in synaptic vesicle function. Interestingly, a number of genes involved in the synthesis and dephosphorylation of PtdIns(4,5)P(2) are found in regions of the genome previously mapped in bipolar disorder (BD) including 10p12, 21q22, and 22q11, among others. Some of these regions overlap with loci mapped in schizophrenia (SZ). One gene involved in PI metabolism that maps to a region of interest is 10p12-linked PIP5K2A, a member of the phosphatidylinositol 4-phosphate 5-kinase family. Polymorphism screening revealed the existence of an imperfect CT repeat polymorphism located near the exon 9-intron 9 splice donor site. A modest difference was found in the distribution of alleles from this highly polymorphic variant when bipolar and schizophrenic subjects were compared with controls; relatively rare short repeat variants were found more commonly in patients and homozygosity for a common long repeat variant was found more commonly in controls. These data suggest that the imperfect CT repeat in PIP5K2A intron 9 should be further investigated as a possible candidate allele for 10p12-linked psychiatric disorders.