"NR8564"
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Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
38 l. : il., tab. ; 30 cm
1. Ve velkém vzorku BP pacientů (N= 200-250) a odpovídajícím počtu populačních kontrol pocházejících ze středoevropského etnika provedeme asociační studie dříve identifikovaných mutací a polymorfismů PI genů. 2. Dále identifikujeme klinické charakteristiky asociované s mutacemi a polymorfismy PI genů. Mezi tyto klinické charakteristiky patří například odpověď na léčbu, psychiatrická komorbidita, somatická onemocnění, rodinná anamnéza, psychotické příznaky nebo průběh poruchy.; First, we will conduct association studies of identified mutations in PI pathway genes in a large sample of BD patients (N=250) and a corresponding number of population controls with similar Caucasian middle European ethnic background. Second, we will identify clinical characteristics associated with PI genes variants, such as treatment response, psychiatric co-morbidity, history of physical illnesses, family history, psychosis or course of illness.
- MeSH
- bipolární porucha MeSH
- fenotyp MeSH
- fosfatidylinositoly MeSH
- genetické asociační studie MeSH
- komorbidita MeSH
- lithium MeSH
- polymorfismus genetický MeSH
- signální transdukce MeSH
- výsledek terapie MeSH
- Konspekt
- Psychiatrie
- NLK Obory
- psychiatrie
- biologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
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.
- MeSH
- dospělí MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci MeSH
- genotyp MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- neuregulin-1 MeSH
- promotorové oblasti (genetika) * MeSH
- protein - isoformy genetika MeSH
- proteiny nervové tkáně genetika metabolismus MeSH
- retardační test MeSH
- schizofrenie genetika MeSH
- sekvenční analýza DNA MeSH
- transfekce MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members--alpha, beta, and gamma--which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHalpha enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allele-specific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.
Diagnostické oddělení bipolární afektivní poruchy a schizofrenie podle současných klasifikačních systému ICD-10 i DSM IV má počátek v Kraepelinovi definici poruch „dementia praecox“ a „maniodepresivní psychóza“. Autoři porovnávají obě poruchy a shrnují jejich podobnosti a rozdíly v mnoha charakteristikách od psychopatologie po nálezy zobrazovacích metod s durazem na genetické nálezy, které jsou v současnosti hlavním zdrojem dukazu o určité míře spojitosti mezi bipolární poruchou a schizofrenií.
The diagnostic distinction of bipolar affective disorder and schizophrenia in current classification systems ICD-10 and DSM IV is based on Kraepelin‘s definition of „dementia praecox“ and „maniodepressive psychosis“. The authors review the similarities and distinctions between both disorders in a wide range from psychopathology to neuroimaging methods with an emphasis on genetic findings as a major source of evidence of an overlap between bipolar disorder and schizophrenia.
- MeSH
- antipsychotika farmakokinetika farmakologie terapeutické užití MeSH
- bipolární porucha diagnóza genetika klasifikace MeSH
- finanční podpora výzkumu jako téma MeSH
- genetická predispozice k nemoci MeSH
- komorbidita MeSH
- lidé MeSH
- rizikové faktory MeSH
- schizofrenie diagnóza genetika klasifikace MeSH
- Check Tag
- lidé MeSH
BACKGROUND: The 22q13-linked gene synapsin III is a positional candidate gene for schizophrenia (SZ). One interesting synapsin III single nucleotide polymorphism (SNP), -196G/A, has been identified in the promoter region. The -196A allele results in a 6/8 base match to the core recognition octamer sequence for Oct-1, a member of the POU family of transcription factors. OBJECTIVE: To determine whether or not the -196 SNP is associated with either SZ or bipolar disorder (BD). METHODS: A case control comparison was used to determine whether or not differences in allele or genotype distribution occurred in patients with SZ and BD. Electromobility gel shift assay (EMSA) was used to determine whether the -196 SNP affected protein binding. RESULTS: A trend towards significance was detected when the allele distribution was analyzed in Caucasian patients with SZ (n = 145; 191 controls) and a cohort of subjects from the Czech Republic with BD (n = 82; 94 controls). No association was found in bipolar patients from the United States (n = 127) or in African-American patients with SZ (n = 124; 133 controls). EMSA showed that the region encompassing the -196 SNP binds to a brain protein in an allele-specific manner. CONCLUSIONS: These data, while inconclusive, suggest that -196 SNP should be further investigated as a candidate for 22q13-linked SZ. 2006 S. Karger AG, Basel
