1Psychiatr. Genet. 2008 Dec 18: 295-301
TitlePolymorphisms of coding trinucleotide repeats of homeogenes in neurodevelopmental psychiatric disorders.
AbstractAutism (MIM#209850) and schizophrenia (MIM#181500) are both neurodevelopmental psychiatric disorders characterized by a highly genetic component. Homeogenes and forkhead genes encode transcription factors, which have been involved in brain development and cell differentiation. Thus, they are relevant candidate genes for psychiatric disorders. Genetic studies have reported an association between autism and DLX2, HOXA1, EN2, ARX, and FOXP2 genes whereas only three studies of EN2, OTX2, and FOXP2 were performed on schizophrenia. Interestingly, most of these candidate genes contain trinucleotide repeats coding for polyamino acid stretch in which instability can be the cause of neurodevelopmental disorders. Our goal was to identify variations of coding trinucleotide repeats in schizophrenia, autism, and idiopathic mental retardation.
We screened the coding trinucleotide repeats of OTX1, EN1, DLX2, HOXA1, and FOXP2 genes in populations suffering from schizophrenia (247 patients), autism (98 patients), and idiopathic mental retardation (56 patients), and compared them with control populations (112 super controls and 202 healthy controls).
Novel deletions and insertions of coding trinucleotide repeats were found in the DLX2, HOXA1, and FOXP2 genes. Most of these variations were detected in controls and no difference in their distribution was observed between patient and control groups. Two different polymorphisms in FOXP2 were, however, found only in autistic patients and the functional consequences of these variations of repeats have to be characterized and correlated to particular clinical features.
This study did not identify specific disease risk variants of trinucleotide repeats in OTX1, EN1, DLX2, HOXA1, and FOXP2 candidate genes in neurodevelopmental psychiatric disorders.
SCZ Keywordsschizophrenia
2Pharmacogenet. Genomics 2008 Sep 18: 751-9
TitleModel-based gene selection shows engrailed 1 is associated with antipsychotic response.
Abstractschizophrenia is an highly heritable complex disorder with a significant impact on public health. A variety of antipsychotics are available for treatment of the disorder and individual response to treatment is variable. To date, only a limited number of potential candidate genes have been examined for genetic association with treatment response. As there is lack of understanding of disease etiology and variation in treatment response, a large number of additional genes are potential targets for investigation. A variety of strategies for selecting candidate genes for further investigation are available and in most cases information used is weighed and ranked intuitively by the investigator. We sought to find genes that may influence treatment response in a less biased manner, after integrating heterogeneous data sources related to schizophrenia.
A method to select liability and treatment response candidate genes for schizophrenia using multiple data sets was constructed. The method successfully selected DTNBP1, a strong candidate gene for schizophrenia. We then evaluated novel genes picked by the method. Thirty-six single nucleotide polymorphisms in two genes engrailed 1 (EN1) and secretin receptor (SCTR) were genotyped in the Clinical Antipsychotic Trials of Intervention Effectiveness study sample. Outcomes analyzed were the Positive and Negative Syndrome Scale and six different neurocognitive measures.
Several of the seven single nucleotide polymorphisms genotyped in the EN1 gene were associated with schizophrenia symptoms (smallest P value=0.0061) and the effects of antipsychotics on symptoms (smallest P value=2.4x10). The estimated probabilities of being a false discovery were 0.14 for symptoms and 0.0012 for drug response.
These findings show that EN1 may influence individual variation in response to antipsychotics. In addition, model-based data integration of schizophrenia-related data seems to improve the prior probability of selecting genes that have an effect on antipsychotics response.
SCZ Keywordsschizophrenia
3Neural Dev 2011 -1 6: 23
TitleEn1 and Wnt signaling in midbrain dopaminergic neuronal development.
AbstractDopaminergic neurons of the ventral mesodiencephalon are affected in significant health disorders such as Parkinson's disease, schizophrenia, and addiction. The ultimate goal of current research endeavors is to improve the clinical treatment of such disorders, such as providing a protocol for cell replacement therapy in Parkinson's disease that will successfully promote the specific differentiation of a stem cell into a dopaminergic neuronal phenotype. Decades of research on the developmental mechanisms of the mesodiencephalic dopaminergic (mdDA) system have led to the identification of many signaling pathways and transcription factors critical in its development. The unraveling of these pathways will help fill in the pieces of the puzzle that today dominates neurodevelopment research: how to make and maintain a mdDA neuron. In the present review, we provide an overview of the mdDA system, the processes and signaling molecules involved in its genesis, with a focus on the transcription factor EN1 and the canonical Wnt pathway, highlighting recent findings on their relevance--and interplay--in the development and maintenance of the mdDA system.
SCZ Keywordsschizophrenia