The goal of this study was to investigate if gene expression measured from RNA sequencing contains enough signal to separate healthy and afflicted individuals in the context of phenotype prediction. We observed that standard machine learning methods alone performed somewhat poorly on the disease phenotype prediction task; therefore we devised an approach augmenting machine learning with topological data analysis. We describe a framework for predicting phenotype values by utilizing gene expression data transformed into sample-specific topological signatures by employing feature subsampling and persistent homology. The topological data analysis approach developed in this work yielded improved results on Parkinson’s disease phenotype prediction when measured against standard machine learning methods. This study confirms that gene expression can be a useful indicator of the presence or absence of a condition, and the subtle signal contained in this high dimensional data reveals itself when considering the intricate topological connections between expressed genes.