There is a great deal of recent direct and indirect genetic data showing clinical and biological links between schizophrenia (SCZ) and autism spectrum disorders (ASD). Specifically, various candidate gene and linkage analyses as well as studies of copy number variants (CNVs) have yielded a handful of genes that seem to be involved in both diagnoses. Many of the proteins related to these psychosis candidate genes contribute, in a convergent and complementary manner, to the plasticity of synapses. Such convergence suggests that the main neurochemical deregulations in SCZ and/or ASD may lead to or be associated with inefficient control of cortical input onto subcortical striatal dopamine, as well as inefficient cortico-cortical connectivity and function. Despite their high potential interest, the contribution of white matter (WM) proteins (and their genes) in these causative pathways have been less extensively studied than grey matter (GM) related genes. We hypothesize that: i) genetic variability of WM related genes will be associated with ASD and SCZ, and ii) some genetic variants will be specifically associated with ASD and early-onset SCZ (E-SCZ) but not with adult-onset forms of psychosis.
The specific aims are: i) to analyze single nucleotide polymorphisms (SNPs) in WM related genes in samples of ASD and SCZ patients, their relatives, and healthy subjects, ii) to explore the relationship of these genetic variants (SNPs or haplotypes) to particular WM phenotypes obtained by MRI studies, and iii) to identify genotypic-phenotypic relationships underlying the similarities and dissimilarities among these disorders, placed along the impaired neurodevelopment continuum.
The AUSZ_[EUCan] project is a collaborative European project, funded by the Network of European Funding for Neuroscience Research – ERA-NET NEURON, that proposes an integrative approach to SCZ and ASD, with a special focus on WM abnormalities. Candidate gene-wide genotyping will be performed on the already available ERA-NET blood samples (from patients with early- and adult-onset SCZ or ASD, their relatives, and healthy subjects). This approach will be taken in three independent Caucasian population-based samples from France and Spain (n=2000).
The selected candidate genes include those involved in myelin structure, oligodendrocyte development, synaptic plasticity and axonal regeneration, transcription and signalling factors and cell adhesion molecules and receptors (e.g. MAG, CNP, MBP, QKI, NOGO, OLIG2, NRXN1), all putatively involved in the etiology of SCZ and ASD. The selection of tagSNPs was based on the HapMap CEU population to cover the genetic variability of these genes. In addition, the known and predicted interactions of the proteins encoded by the selected genes have been taken into account in order to construct a candidate gene network and perform interaction analyses among them.
The genotyping will be conducted in two phases: the first in late 2012 and the second in 2013. The first phase will allow the genotyping of 128 SNPs in 15 genes in 2000 subjects using the TaqMan OpenArray® Real Time PCR System. Here we will present the preliminary results of the first genotyping phase.
Candidate gene analyses may help to identify WM related genes associated with ASD and SCZ.
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