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

In addition to postmortem interval, pH, and age, we performed secondary analyses (using t-tests) to examine ethanol use, smoking, and laterality as grouping variables in our schizophrenia subjects and found no significant effects. We also performed t-tests after removing antipsychotic naïve subjects and all targets remained significant. No subjects had any dependence for cocaine, sedatives, cannabis, amphetamines, hallucinogens, inhalants, or opioid dependence (only subject 828 took morphine for pain). Subjects with prolonged agonal states were not included in this cohort. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/338392 doi: bioRxiv preprint differentially expressed L1000 genes from our 6 seed gene KD signatures. The panels of clustered differentially expressed L1000 genes were carried forward to Enrichr analyses. We also performed iLINCS connectivity analyses and identified peroxisome proliferator-activated receptor (PPAR) agonists as promising therapeutic targets with the potential to "reverse" glycolytic deficits as well as the associated changes in the L1000 genes. Finally, we The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/338392 doi: bioRxiv preprint The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/338392 doi: bioRxiv preprint The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/338392 doi: bioRxiv preprint type (PFKM); G lucose-6-phosphate isomerase (GPI); 6-phosphofructo-2-kinase (PFKFB2); lactate dehydrogenase A (LDHA); hexokinase 1 (HK1).