Reference:
ANRn.a.8-MNPSn.a.007
Abstract:
Psychotic disorders (schizophrenia, bipolar disorder, pervasive developmental disorders) are disabling disorders of variable clinical expression ?, ?d resulting interaction between genetic and environmental factors during critical periods of brain development. Some candidate genes have been identified . Among them, neuregulin, RGS4, DISC1, reelin, BDNF and glutamatergic receptors are involved in the formation of neurites, whose dysfunction may be common to psychotic disorders. In addition, genes involved in methylation are also associated with an increased risk of psychosis. ?s overall objective of this project is to test the hypothesis that ?psychotic disorders are associated with a change in methylation of peripheral genome, and in particular that genes involved in the formation of neurites are altered in psychotic patients with developmental abnormalities methylation. To test this hypothesis, we will include a large cohort of families of psychotic patients of Caucasian origin ?, of which at least 150 have a documented history of ?in utero exposure to synthetic hormones. Subjects will be tested for early environmental factors ?s history of psychiatric disorders and developmental characteristics. We will study (1) the influence of ??early exposure to hormones on neurod�velopmentales ??characteristics and in particular we compare sibling pairs discordant (2) genetic susceptibility markers in 864 subjects in a combination of design ?intra- family, focusing on 73 genes involved in neurite formation by SNP genotyping broadband (and functional map HapMap SNPs) on microarrays manner. (3) variants of 38 genes involved in methylation (methylation-trans metabolism, ?DNA methylation, and histone modifications) SNP genotyping on the same chip. In addition, we look for mutations in the MECP2 gene encoding by High-Resolution Melting ??in a subgroup of patients (4) methylation of the genome of 27,000 CpG islands using informative HumanMethylation27 chips and ?s study transcriptome using chips Human-6 v2 from blood cells of 80 sibling pairs discordant. (5) Based on these steps, we analyze the promoter methylation of certain genes candidates including CpG islands by bisulfite sequencing after treatment and ?expression quantitative real-time PCR. (6) Finally, always based on the previous steps, we use an in vitro assay to explore the formation of extensions “neuron-like” of monocyte-derived dendrocytes as a witness ?s functional effect of polymorphisms of genes involved in the formation neurite and / or modified methylation patterns. – Verification of frequency and severity ?increased developmental characteristics after early exposure to synthetic hormones and among affected sib compared to unaffected. – Association of variants of candidate genes for developmental forms of psychosis as well as identification of new polymorphisms ? – Influence of interaction ?gene methylation ?with early exposure to the hormone therapy on the methylation modulating the level of expression in leukocytes ?forming extensions and “neuron-like” by dendrocytes. Overall, this project should help to identify candidate genes involved in gene x environment interactions or gene x environment x ?s origin of major psychoses gene. Furthermore, the in vitro test may be a biomarker for psychoses, reflecting both genetic factors and environmental
PROJECT DETAILS
beginning: 2009.
end: 2012.
Country of research: France
Counry of funding source: France
Funding organization: The French National Research Agency
Financing: NATIONAL FUNDINGS – 400 000 €