A multiomic network approach uncovers disease modifying mechanisms of inborn errors of metabolism

For many inborn errors of metabolism (IEM) the understanding of disease mechanisms remains limited in part explaining their unmet medical needs. We hypothesize that the expressivity of IEM disease phenotypes is affected by the activity of specific modifier pathways, which is controlled by rare and common polygenic variation. To identify these modulating pathways, we used RNA sequencing to generate molecular signatures of IEM in disease relevant tissues. We then integrated these disease signatures with multiomic data and gene regulatory networks generated from animal and human populations without overt IEM. We identified and subsequently validated glucocorticoid signaling as a candidate modifier of mitochondrial fatty acid oxidation disorders, and we re-capitulated complement signaling as a modifier of inflammation in Gaucher disease. Our work describes a novel approach that can overcome the rare disease-rare data dilemma, and reveal new IEM pathophysiology and potential drug targets using multiomics data in seemingly healthy populations.