The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia

BACKGROUND: A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors. PRESENTATION OF THE HYPOTHESIS: Based on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia. TESTING THE HYPOTHESIS: Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis suggests glial cells as the locus of the genes-environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments

Linkage studies on chromosome 22 in familial schizophrenia

As part of a systematic search for a major genetic locus for schizophrenia we have examined chromosome 22 using 14 highly polymorphic markers in 23 disease pedigrees. The markers were distributed at an average distance of 6.6 cM, covering 70-80% of the chromosome. We analyzed the data by the lod score method using five plausible genetic models ranging from dominant to recessive, after testing the power of our sample under the same genetic parameters. The most positive lod score found was 1.51 under a recessive model for the marker D22S278, which is insufficient to conclude linkage. However, an excess of shared alleles in affected siblings (P < .01) was found for both D22S278 and D22S283. For D22S278, the A statistic was equal to the lod score (1.51) and therefore did not provide additional evidence for linkage allowing for heterogeneity, but the Liang statistic was more significant (P = .002). Our results suggest the possibility that the region around D22S278 and D22S283 contains a gene which contributes to the aetiology of schizophrenia.link_to_subscribed_fulltex

Analysis of CAG/CTG repeat size in Chinese subjects with schizophrenia and bipolar affective disorder using the repeat expansion detection method

Background: Family studies of schizophrenia and bipolar affective disorder provide evidence for genetic anticipation, which (in common with a number of mendelian disorders), may be caused by triplet repeat expansion. This hypothesis is strengthened by evidence from repeat expansion detection (RED) analysis revealing association between the psychoses and long CAG/CTG trinucleotide repeats. Methods: We performed RED on Hah Chinese subjects with schizophrenia (82), bipolar affective disorder (43), and normal controls (61), using a CTG10 oligonucleotide. Results: Comparison between cases and controls revealed no significant association between long repeats and affected status. We also found no detectable association with age at onset and repeat length in either bipolar affective disorder or schizophrenia. Overall, the size distribution of CAG/CTG repeats in Chinese subjects was not significantly different from those reported previously for Caucasian subjects. Conclusions: These findings indicate that CAG/CTG repeat expansion is not likely to be a major etiological factor for psychosis in Chinese populations.link_to_subscribed_fulltex

Investigações epidemiológicas sobre demência nos países em desenvolvimento

Na medida em que a população mundial está envelhecendo, a demência está se constituindo em importante problema de saúde pública, particularmente nos países em desenvolvimento. Investigações epidemiológicas nestes países são escassas e apresentam dificuldades metodológicas adicionais, principalmente no que se refere à adequação sociocultural dos instrumentos utilizados para a definição de casos. Tendo em vista estas preocupações, foi fundado o "Grupo de Pesquisa em Demência 10/66", que é constituído por uma rede internacional de pesquisadores, predominantemente de países em desenvolvimento. O nome do grupo tem como referência o paradoxo de que menos de 10% dos estudos populacionais sobre demência são dirigidos aos 2/3 ou mais de casos de pessoas com demência que vivem em países em desenvolvimento. O objetivo do artigo é atualizar informações da literatura sobre as diferenças de prevalência e incidência de demência encontradas em países desenvolvidos e em desenvolvimento

Investigações epidemiológicas sobre demência nos países em desenvolvimento

Na medida em que a população mundial está envelhecendo, a demência está se constituindo em importante problema de saúde pública, particularmente nos países em desenvolvimento. Investigações epidemiológicas nestes países são escassas e apresentam dificuldades metodológicas adicionais, principalmente no que se refere à adequação sociocultural dos instrumentos utilizados para a definição de casos. Tendo em vista estas preocupações, foi fundado o "Grupo de Pesquisa em Demência 10/66", que é constituído por uma rede internacional de pesquisadores, predominantemente de países em desenvolvimento. O nome do grupo tem como referência o paradoxo de que menos de 10% dos estudos populacionais sobre demência são dirigidos aos 2/3 ou mais de casos de pessoas com demência que vivem em países em desenvolvimento. O objetivo do artigo é atualizar informações da literatura sobre as diferenças de prevalência e incidência de demência encontradas em países desenvolvidos e em desenvolvimento

Catechol-O-methyltransferase polymorphisms and schizophrenia: A transmission disequilibrium study in multiply affected families

Catechol-O-methyltransferase (COMT) metabolizes catecholamines such as dopamine, noradrenaline and adrenaline. It exists as common high and low activity alleles in the population (determined by a valine 158 methionine polymorphism), and high red blood cell activity of COMT has previously been associated with schizophrenia. To examine the relationship between COMT and schizophrenia genetically, the transmission disequilibrium test was performed on 22 multiply affected Caucasian and Japanese families genotyped for val158met and a second, silent, polymorphism (C256G), using PCR based assays. The high activity val158 allele was transmitted from parents to the affected individuals more frequently than the low activity met158 allele, although this was not statistically significant. Combining this data with a previous study using Chinese family trios with schizophrenia gave a highly significant result (p = 0.0015). The G256 allele was also transmitted preferentially to the affected offspring, and this was statistically significant when schizophrenia, schizoaffective disorder and unspecified functional psychosis were included in the definition of the affected phenotype (p = 0.03). Overall, these findings may indicate an effect of COMT alleles on susceptibility to schizophrenia, or reflect linkage disequilibrium with a different causative polymorphism in the vicinity. Other reported associations of COMT with obsessive compulsive and rapid cycling bipolar disorder indicate that the COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.link_to_subscribed_fulltex

A novel functional polymorphism within the promoter of the serotonin transporter gene: Possible role in susceptibility to affective disorders

The serotonin transporter (5-HTT) is a candidate locus for aetiological involvement in affective disorders. Biochemical studies in suicides and depressed patients suggest that 5-HT uptake function is frequently reduced in affective illness. Furthermore, 5-HTT is targeted by widely used antidepressant drugs such as fluoxetine. We have performed an association study of a short variant of the 5-HTT-linked polymorphic region (5-HTTLPR), which restricts transcriptional activity of the 5-HTT promoter leading to low functional expression of the 5-HTT, in 454 patients with bipolar or unipolar affective disorder and 570 controls, derived from three European Centres (London, Milan and Würzburg). In all three centres, the frequency of the low activity allele was higher in patients than in controls (50% vs 45% in London, 45% vs 43% in Milan, 47% vs 40% in Würzburg). Although these differences were not individually significant, a stratified analysis of all three samples gave a significant overall odds ratio of 1.23 (95% confidence interval 1.02-1.49, P = 0.03). The excess of the homozygous low-activity genotype among the patients was even greater (odds ratio 1.53, 95% confidence interval 1.04-2.23, P = 0.02), suggesting partial recessivity of the low-activity allele. Given the functional role of 5-HTT, our findings suggest that 5-HTTLPR-dependent variation in functional 5-HTT expression is a potential genetic susceptibility factor for affective disorders. If this finding is replicated, further work on genetic variants with low 5-HTT activity may facilitate the differential diagnosis of affective disorders, the assessment of suicidal behaviour, and the prediction of good clinical response to antidepressants.link_to_subscribed_fulltex