Control backbone detection in omnigenic disease neighborhood targeting core module

Thousands of genes are perturbed by disease mutations, forming an omnigenic neighbourhood with core and peripheral regions in genetic interaction network. Understanding the control paths of peripheral effects on core is a key step toward advancing the knowledge about genetic architecture underlying the disease. Here, we proposed a Control Backbone extraction method in omnigenic disease neighborhood (CBackbone) to magnify unique peripheral effects targeting on core. We indicate critical edges in the omnigenic neighbourhood from multiple control properties: control category, role in control range and change in the number of controlled cores after removing. We found that while numerous edges with weak criticality are removed, a few critical edges can effectively maintain the peripheral control effect targeting on the core region, presenting us an outstanding control backbone. We systematically analysed backbones of 10 diseases, highlighting the most central results, which show how 21% edges can consolidate peripheral signals. As a case study, CBackbone of asthma highlights the control paths from known peripheral drug targets to its core, we identified control paths of genes that regulates relaxation of bronchial smooth muscle, inflammation, and improvement of immune function, elucidating the therapeutic effects of theophylline (dimethylxanthine).