published_or_final_version / Psychiatry / Master / Master of Medical Sciences

abstract / Psychiatry / Doctoral / Doctor of Philosophy

The present study employed the Rust Inventory of Schizotypal Cognitions (RISC) to identify an experimental group of schizotypics (as well as an appropriate control group). It was hypothesized that these individuals would show patterns on a battery of neuropsychological tests (e.g., Category Test, Tactual Performance Test, and Trails B from the Halstead-Reitan Neuropsychological Battery; Expressive Speech, Memory, and Intellectual Processes Scales from the Luria-Nebraska Neuropsychological Batter; and the Rey Complex Figure Test) similar to those exhibited by actual schizophrenics. Findings indicated that schizotypes do show a pattern of deficits on neuropsychological tests similar to those observed in diagnosed schizophrenics. These results lend validity to the RISC as an instrument for use in selecting those at-risk for schizophrenia. They also illustrate a possible neuropsychological vulnerability marker for schizophrenia. / Department of Psychological Science

Complex diseases, unlike Mendialian diseases, are often characterized by genetic heterogeneity and multifactorial inheritance, involving defects in genes from the same or multiple alternative pathways. Many congenital diseases and psychiatric disorders are complex diseases, and incur heavy health care burden on the society. With the advancement in high-throughput genotyping technologies and the availability of the human single nucleotide polymorphism (SNP) catalogue, genome-wide association study (GWAS) has been widely used to investigate the genetic component of complex diseases. Copy number variations (CNV) can also be identified using the data from the same SNP array. Aiming to identify more disease susceptibility loci for complex diseases, separate GWAS using a case-control design were conducted on anorectal malformations (ARMs) and schizophrenia. ARMs are rare congenital diseases with heterogeneous phenotypes which could probably be explained by the genetic heterogeneity among patients, while schizophrenia is a common psychiatric disorder that is well known for its multigenic inheritance. The GWAS studies on ARM and schizophrenia included 4,369 (patients: N=363; controls: N=4,006) and 1,231 Han Chinese (patients: N=381; controls: N=850) respectively. The two studies were mainly focused on investigating the contribution of rare CNVs to the diseases, involving analyses on global CNV burden, rare CNV association, protein-protein interaction (PPI) network, pathway and chromosomal aberrations. The associations of SNPs with ARMs were also examined. Apart from elucidating the genetic components in these two diseases, a systematic analysis on four CNV detection programs (CNV partition, PennCNV, QuantiSNP and iPattern) was also undertaken. In the study of schizophrenia, a new approach in CNV filtering which was based on latent class analysis was adopted to gather information from multiple CNV prediction programs. The study of ARMs revealed 79 genes which were disrupted by CNVs in patients only. In particular, a de novo duplication of DKK4 (an antagonist of WNT signaling) was identified, and addition of Dkk4 protein was demonstrated to cause ARMs in mice. Another 10 genes uniquely disrupted in ARMs patients are also related to WNT signaling. Interestingly, this pathway was also significantly inferred by CNV in patients with schizophrenia. A different set of genes related to WNT signaling was disrupted in ARMs patients and patients with schizophrenia. WNT signaling is crucial for the development of multiple parts in the embryo. The contribution of different WNT signaling pathways at different development stages may vary. Apart from the WNT signaling pathway, other genes with biological relevance were also implicated in the two studies through gene-network and pathway analyses. The results from these two GWAS studies support our existing understanding of complex diseases that defects in various interacting genes could contribute to the same disease. In summary, the CNV results from the two studies have demonstrated the genetic heterogeneity nature of these two complex diseases. The findings also uncovered a set of putative disease candidate genes, which can be used as reference materials for future genetic research for ARMs and schizophrenia. / published_or_final_version / Psychiatry / Doctoral / Doctor of Philosophy

No description available.

Although heritability estimates of schizophrenia are high, studies attempting to identify specific genes for schizophrenia have been only modestly successful. Strategies to improve the power of genetic studies include the creation of homogeneous subtypes of schizophrenia based on symptom presentation, and the identification of behavioural abnormalities that reflect the presence of genes for schizophrenia ("behavioural markers of risk") even in the absence of the full clinical disorder. Oculomotor abnormalities are one of the most well-documented markers of risk. It is not known whether abnormalities in motor control are specific to the oculomotor system or whether they are found as well in other domains such as skeletomotor control. It is also not known whether different types of schizophrenia-related symptoms, which presumably have distinct neural bases, are associated with different behavioural abnormalities. / This thesis investigates oculomotor and skeletomotor function in clinically unaffected individuals who are at elevated risk for schizophrenia based on their scores on either a positive-symptom schizotypy questionnaire (Perceptual Aberration Scale) (n = 21) or a negative-symptom schizotypy questionnaire (Physical Anhedonia) (n = 20), and in Controls (n = 29). / In Manuscript 1, we review the evidence suggesting that skeletomotor deficits are present in neuroleptic-naive schizophrenia patients and high-risk populations. The review supports the notion of skeletomotor dysfunction in these groups and underscores the lack of studies using instrumentation to characterize the deficits. In Manuscript 2, we compare the oculomotor performance of positive-symptom and negative-symptom schizotypes to that of controls. Results suggest that smooth pursuit deficits identify high-risk individuals with either positive or negative symptomatology, while antisaccade deficits identify primarily individuals with positive symptoms. In Manuscript 3, we use high-speed instrumentation and kinematic measures to evaluate skeletomotor function, and to assess the relationship between oculomotor and skeletomotor deficits in positive and negative-symptom schizotypes. This study revealed differential patterns of skeletomotor deficits in positive- and negative-symptom schizotypy, with both patterns suggestive of frontal-striatal dysfunction. In general, oculomotor and skeletomotor deficits were not associated. / Together these results support the notion of motor deficits across domains in risk for schizophrenia. In addition, they highlight the importance of distinguishing between positive and negative symptomatology when investigating the pathophysiology of risk for schizophrenia.

Schizophrenia is a disabling psychiatric and neurodevelopmental disorder that represents a tremendous public health burden. Despite the inroads made in the treatment of its symptoms, understanding its etiology and pathophysiology remains challenging due to the genetic heterogeneity of the disease and the corresponding complexity of the neural systems which it affects. In recent years, the development of next generation sequencing and substantial progress in the field of psychiatric genetics have revealed the important role of individually rare but collectively common heritable and de novo mutations (DNMs) in the complex genetic architecture of schizophrenia. Previously, we had identified SETD1A encoding a histone methyltransferase, as a high-risk gene for schizophrenia, which has been confirmed extensively through follow-up meta-analyses. This discovery emphasized the important role that neural gene regulation plays in the coordination of complex cognitive processes. However, it is unclear how to translate a ubiquitous molecular process such as chromatin modification into a mechanistic and disease-specific insight. Our previous comprehensive analysis of mutant mice carrying a loss of function (LoF) allele in the Setd1a orthologue uncovered the role of SETD1A in gene regulation, neuronal architecture, synaptic plasticity, neuronal ensemble activity and cognitive function and showed that neurocognitive deficits that derive from Setd1a deficiency can be reversed by pharmacological interventions during adulthood. Our previous ChIP-Seq analysis showed a striking overlap between SETD1A, MEF2, and LSD1 targets at enhancers in the prefrontal cortex (PFC). Since MEF2 is an activity dependent transcription factor, we hypothesized that SETD1A may also modulate activity-dependent gene expression in the brain. To elucidate the effects of Setd1a deficiency on activity-dependent transcription, we established an in vitro neuronal activity dependent gene (ADG) expression assay and identified genes modulated by neuronal activity using ChIP-Seq and RNA-Seq assays. We found a remarkable overlap of a dynamic pattern of activity-dependent recruitment of SETD1A, LSD1 and MEF2 to enhancers of ADGs. Our results showed Setd1a deficiency affects transcription in an activity-dependent manner and transcriptional alteration induced by Setd1a deficiency under neuronal activation can be attenuated by inhibition of LSD1 activity. In addition, we investigated how SETD1A modulates MEF2 transactivation activity by performing luciferase assays. Our results suggest that SETD1A represses MEF2 activity but the repression is unlikely to be mediated by lysine methylation. We also performed behavioral analyses of Setd1a+/- mice and found that the social behavior and social memory were impaired in female Setd1a+/- mice but remained intact in male Setd1a+/- mice. Ultimately, future work is underway to analyze the targets of SETD1A, which in turn could lead to the development of therapeutic strategies to reverse the progression of schizophrenia.

Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: see item for full text / AFRIKAANSE OPSOMMING: sien item vir volteks

Thesis (MSc (Genetics))--University of Stellenbosch, 2007. / ENGLISH ABSTRACT: Rapidly expanding knowledge of the human genome allows new insight into the interaction between drugs and DNA. The heterogeneic nature of schizophrenia is known to cause different patients to display dissimilar drug responses, reflecting distinct genetic profiles. Resulting adverse side effects include tardive dyskinesia (TD), a movement disorder associated with the long-term use of antipsychotic drugs. The identification of a pharmacogenetic basis of TD may have significant clinical implications in the treatment of schizophrenia, allowing individualised prescription of antipsychotic drugs and eventual elimination of undesirable side effects. The current study focussed on a number of South African Xhosa schizophrenia patients, some of whom have been diagnosed with TD. The investigation sought to establish whether the underlying mechanism causing the disorder to manifest only in some individuals, might be attributed to differences in DNA sequences, i.e. genomic susceptibility. A number of candidate polymorphisms in the CYP and MDR1 genes were evaluated in three separate analyses. (The same approach was followed in each investigation, and only known polymorphisms were selected.) The incidences of the various variants were compared between TD and non-TD patients. In addition, potential predisposing factors, i.e. tobacco and cannabis smoking and anhedonia, were taken into consideration. These were analysed concurrently with DNA data and TD status.

Orientador: Emmanuel Dias-Neto / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-10T18:55:55Z (GMT). No. of bitstreams: 1 Martins-de-Souza_Daniel_D.pdf: 2995342 bytes, checksum: bba6d65f7fb9ab2fd672a1027a054163 (MD5) Previous issue date: 2008 / Resumo: A esquizofrenia é um distúrbio mental debilitante que afeta aproximadamente 1% da população mundial, caracterizado por sintomas produtivos como delírios e alucinações e sintomas negativos como apatia e decréscimo das emoções. Nesta tese, realizamos estudos do transcriptoma e do proteoma em tecido cerebral de pacientes com esquizofrenia, buscando identificar genes e proteínas envolvidas com esta doença. Em nossas análises transcricionais, utilizamos a técnica de Serial Analysis of Gene xpression (SAGE), uma abordagem ainda inédita em esquizofrenia. Os dados permitiram a análise de mais de 20 mil transcritos, e apontaram para o possível envolvimento de genes associados a processos como mielinização, função sináptica, metabolismo energético e homeostase de cálcio, incluindo genes anteriormente envolvidos com esquizofrenia, e também uma boa parcela de genes até então não associados com a doença. Uma pequena fração destes novos marcadores foi avaliada por Real-Time PCR permitindo a confirmação de alguns achados de SAGE. ossas análises de proteoma foram feitas com as técnicas de eletroforese de duas dimensões, seguida por espectrometria de massas e pela técnica de shotgun proteomics, também inédita em esquizofrenia. Estas análises foram realizadas com amostras de diferentes regiões cerebrais, incluindo córtex pré-frontal e lobo temporal anterior, e apontaram para alterações quantitativas em proteínas relacionadas com a homeostase de cálcio, citoesqueleto, metabolismo energético e de oligodendrócitos. De modo geral, observamos uma boa consistência entre os resultados obtidos quando estudamos diferentes classes de marcadores potenciais (genes e proteínas). Por muitas vezes os genes alterados não corresponderam a alterações quantitativas nas mesmas proteínas, no entanto, na maior parte dos casos, observamos alterações consistentes nas mesmas vias. Observamos a regulação diferencial do metabolismo de oligodendrócitos, energético, sináptico e revelamos a provável alteração da homeostase de cálcio em cérebros de pacientes com esquizofrenia, além de identificarmos genes e proteínas diferencialmente expressas nunca relacionadas à doença. Nossos dados reforçam achados prévios, apontam potenciais biomarcadores e podem fornecer novas pistas na compreensão da esquizofrenia / Abstract: Schizophrenia is a mental debilitating disorder that affects 1% of the world population. It is characterized by positives symptoms such as delirium and hallucinations and negative symptoms such as apathy and emotion decrease. Here, we have studied the ranscriptome and proteome of brain samples of patients with schizophrenia, in an attempt to identify genes and proteins markers of the disease. Our transcriptome analyses of pre-frontal cortex were performed with Serial Analysis of Gene Expression (SAGE), here used for the first time in the study of schizophrenia. The data obtained allowed the analysis of approximately 20,000 transcripts, which suggested the importance of myelinization, synaptic function, energy metabolism and calcium homeostasis, in the genesis of schizophrenia. A series of genes previously implicated in the disease were identified, together with new potential markers which were revealed here for the first time. A small fraction of these was validated using realtime PCR, which confirmed some of the SAGE findings. Two-dimensional gel electrophoresis, mass spectrometry and shotgun proteomics were the approaches used here for large-scale protein analysis in schizophrenia. These approaches were used in brain samples derived from distinct areas such as pre-frontal cortex and anterior temporal lobe, and indicated quanitative alterations of proteins involved with calcium homeostasis, energy and oligodendrocyte metabolism and cytoskeleton. In general, a good correlation was observed when the different approaches (transcriptome and proteome) were used. In may cases, the alterations of some genes was not reflected by a correspondent alteration of the encoded protein. However, in most cases, reproducible alterations were found in the same pathways. Beside the identification of new schizophrenia-related genes and proteins, we also confirmed the the differential regulation of oligodendrocyte, synaptic and energetic metabolism, in this disease.Our data reinforce previous findings, and suggest new potential biomarkers that may contribute to the understanding of schizophrenia / Doutorado / Bioquimica / Doutor em Biologia Funcional e Molecular