Connectivity analyses of bioenergetic changes in schizophrenia: Identification of novel treatments

Courtney R. Sullivan; Catharine A. Mielnik; Sinead M. O’Donovan; Adam J. Funk; Eduard Bentea; Erica A.K. DePasquale; Zhexing Wen; Vahram Haroutunian; Pavel Katsel; Amy J. Ramsey; Jarek Meller; Robert E. McCullumsmith

With the goal of identifying small drug-like molecules with inverse signatures, we probed iLINCS for chemical perturbagens that result in L1000 transcriptomic signatures that are highly discordant (anti-correlated as denoted by negative concordance values) with each seed gene knockdown signature (potentially reversing the seed gene knockdown signature). This was done individually for each seed gene knockdown signature (unclustered) and the top 20 discordant chemical perturbagen signatures were recorded (Table S4 ). PFKFB2 had no discordant signatures, while GPI and PFKM had less than 20. Perturbagens appearing multiple times for the same seed gene are either in different cell lines or were administered to cells at different concentrations. We also recorded the top 20 overall discordant chemical perturbagen signatures across all seed gene knockdown signatures (Table S5 ). The top 20 overall discordant chemical perturbagen signatures were in the VCAP cell line. When duplicates were removed, 12 unique discordant chemical perturbagen signatures remained (Table 4 ). This list was use to select an FDA approved drug for preclinical trials.