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

We performed Enrichr analyses on panels of clustered upregulated genes from our iLINCS clustering analysis. Top cell signaling pathways included forkhead box O (FOXO), mitogen-activated protein kinase (MAPK), and Wnt signaling pathways ( Figure S4 ). These pathways often interact and all have important roles in cell metabolism, inflammation, cellular proliferation, oxidative stress prevention, and apoptosis (62) (63) (64) (65) . Analysis of gene ontology (GO) cellular components for our panels of clustered upregulated genes included several microtubule and cytoskeletal components ( Figure S5 ), while the top hits for GO molecular function included protein kinase C (PKC) and MAPK binding ( Figure S6 ). Our protein-protein interactions analysis ( Figure S7 ) yielded multiple hits for protein kinases such as RPS6KA3, MAPK14, GSK3B, and CDK1. We also found hits for proteins involved in protein degradation and protein ubiquitination (CUL1 and SKP1), chromatin remodeling (PCNA and HDAC1), and an estrogen receptor (ESR1).