Interaction Networks and perturbed cellular Functions in Schizophrenia [thesis]

Konrad Klockmeier, Universitätsbibliothek Der FU Berlin
Schizophrenia (SCZ) is a devastating psychiatric disease with a worldwide prevalence of approximately 1%. It is therefore one of the leading causes of public health burden. Twin studies suggest that the impact of heritable factors causing SCZ is very high. Thus, in the recent past huge efforts were made to identify the genetic factors responsible for the disease. Many genes and genomic variations have already been associated with schizophrenia, but the interplay of these genes, as well as the
more » ... ecise mechanism of how they are involved in the development of schizophrenia is still not fully understood. To get a deeper insight into the role of SCZ associated genes I used protein-protein interaction analyses combined with bioinformatical methods. My goal was to answer three mayor questions: The first question was, if schizophrenia associated proteins form clusters within protein-protein interaction networks and how these clusters are involved in functional processes. For that reason, a propagation-based algorithm was invented that identified five clusters with high potential for SCZ relevance. The two highest scoring clusters represented known synaptic complexes and were validated with LuTHy assays. The second question was, if there is a potential SCZ relevance of a set of 39 protein coding candidate genes of a small exome sequencing study and if their importance could be prioritized. Therefore, a protein-protein interaction network was created, using the HIPPIE database, including all medium high confident interactions of these genes. In a next step the density of SCZ associated proteins within the created network were compared to all HIPPIE proteins, not already included in the created network and their connectivity to SCZ related proteins. Chi-squared tests revealed indeed a significant enrichment of schizophrenia associated proteins within the created candidate protein-protein interaction network. In order to rank candidate genes, the browser based ToppNet tool was used. The third question should shed light on th [...]
doi:10.17169/refubium-26269 fatcat:pb2twj5lijdhdmjameb2l4xaay