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978-3-8439-2310-1, Reihe Biologie
Stephanie Jeanette Prinz
Analysis of Genotype-Phenotype Relationships based on Drug Side Effects, Disease Symptoms and Mouse Phenotypic Traits
136 Seiten, Dissertation Technische Universität München (2015), Hardcover, A5
Phenotypic phenomena in the human organism, including diseases or drug effects, are formed by the complex interplay between genotype and environmental influences. Understanding the impact of genetic factors affecting pathologies and their treatment is important for prediction and control of disease onset and progression. In order to avoid poor effectiveness and unwanted effects of current drug interventions, it is necessary to expand the knowledge of the molecular mechanisms related to disorders and drug action.
In this work, I present a systematic analysis of phenotypic information of single gene perturbations in mice, human diseases and drugs. First, the phenotypes of the three different perturbation scenarios were investigated in a comparative fashion. The correlation between different gene properties and the phenotypic impact at the organ system level was examined using a novel measurement, the organ system heterogeneity. This analysis also induced the development of a publicly available database, Organ System Heterogeneity DB. In order to get more detailed insight into genotype-phenotype relationships, a new ontology-based phenotypic similarity approach was devised comparing drugs to diseases and to mouse genes, respectively. The analysis of phenotypically related pairs revealed an enrichment in molecular and clinical associations. This investigation also enabled the proposal of a list of novel precautions or potential contraindications for 486 drugs. The similarity of drug side effects and mouse phenotypic traits could further deepen the mechanistic understanding of drug action. Phenotypically similar drug-gene pairs showed a strong enrichment in physical and indirect drug-target connections, causative drug target-side effect relationships, as well as pharmacogenetic associations. The potential of this approach to uncover novel and established molecular determinants of drugs was validated by in vitro assays. The experimental verification of a formerly unknown relationship between the drug oxandrolone and prokineticin receptor 2 substantiated the capability to generate novel insights.
This investigation improves the understanding of drug mode of action, adverse effects as well as genetic variation affecting drug response. The analysis reveals insight into the complex interactions underlying the treatment of diseases and helps to ameliorate clinical medicine by advancing drug efficacy, drug safety and personalize treatments.