| dc.contributor.advisor | Ehrenreich, Hannelore Prof. Dr. Dr. | de |
| dc.contributor.author | Kästner, Anne | de |
| dc.date.accessioned | 2013-08-09T08:16:42Z | de |
| dc.date.available | 2013-08-09T08:16:42Z | de |
| dc.date.issued | 2013-08-09 | de |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0001-BB0B-B | de |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-3981 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | The influence of common genetic variations in candidate genes on neuropsychiatric phenotypes | de |
| dc.type | cumulativeThesis | de |
| dc.contributor.referee | Ehrenreich, Hannelore Prof. Dr. Dr. | de |
| dc.date.examination | 2013-07-11 | de |
| dc.description.abstracteng | Introduction: Psychiatric disorders are ‘complex diseases’. A large proportion of the phenotypic variation of psychiatric conditions like schizophrenia and autism can be attributed to additive genetic effects (80%-90%). Genome-wide association studies (GWAS) comparing groups of schizophrenia patients and groups of putative healthy control subjects found multiple common single nucleotide polymorphisms (SNPs) of small effect sizes to be associated with the risk for schizophrenia. However, besides not explaining much of the variance in liability to schizophrenia, the biological and phenotypical relevance of most genetic variants identified by GWA studies remains mostly obscure. Aims: To contribute to uncovering the ‘missing/hidden’ heritability of schizophrenia and to understand how certain genes or genotypes contribute to the phenotype, the present thesis work suggests not to base genetic analyses on clinical diagnoses anymore but to decompose schizophrenia into quantitative behavioral traits. A increase in statistical power should be achieved by comparing the low and high extremes of quantitative phenotypes or by studying the entire distributions with respect to certain candidate genes or functional gene complexes Method: Specific aspects of the schizophrenia phenotype were operationalized and quantified using the GRAS (Göttingen Research Association for Schizophrenia) data collection. Hypotheses for specific phenotype-genotype relationships were instigated by mouse models of loss and gain of function or by known biological functions/expression patterns of the genes. Results: It could be shown that the endogenous EPO/EPOR system has a role in aspects of cognitive functioning in schizophrenic patients and cognitively inferior healthy controls (project I). Moreover, an association of schizophrenia risk gene neuregulin1 with central olfactory processing could be detected (project II). The gene encoding glycoprotein M6a was identified to be involved in the risk to develop claustrophobia (project III). Lastly, common genetic variants in the transcriptional regulator MECP2 were identified to influence the severity of impulsivity and aggression (project IV). The functional relevance of certain candidate genes for specific aspects of behavior could be further substantiated by mouse models of loss and gain of function of the respective proteins. Mechanistic insight was obtained by studying the influence of SNPs located in the regulatory regions (5’ and 3 regions) of the genes on the regulability of expression. Projects I III and I converge on the finding that those genotypes associated with superior expression of the phenotype (superior cognition, claustrophobia, less impulsivity) showed elevated flexibility i gene expression. For project I (EPO/EPOR variants), this higher regulability might potentially be mediated by genotype-dependent transcription factor binding whereas for projects III and I flexible regulation o gene expression was shown to be influenced by certain brain-expressed microRNAs. Conclusion: The present thesis work comprises several examples highlighting the importance of defining subphenotypes of schizophrenia to reduce intra-group variability and to be able to genetically compare phenotypic cases and controls. The introduced phenotype-genotype association approach may eventually assist the description of biological pathways contributing to the emergence of dysfunctional behaviors. This is crucial for the development of novel therapeutic targets addressing predominantly affected symptom clusters. | de |
| dc.contributor.coReferee | Lass, Uta Prof. Dr. | de |
| dc.contributor.thirdReferee | Bickeböller, Heike Prof. Dr. | de |
| dc.subject.eng | schizophrenia | de |
| dc.subject.eng | autism | de |
| dc.subject.eng | genetics of psychiatric disorders | de |
| dc.subject.eng | translational neuroscience | de |
| dc.subject.eng | mouse models of psychiatric disorders | de |
| dc.subject.eng | phenotype-based genetic association study | de |
| dc.subject.eng | genome-wide association study | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0001-BB0B-B-9 | de |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 756704960 | de |