Abstract
The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. We used Ingenuity Pathway Analysis to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA–related pathway, compared to those time periods when the same individual did not use the drug. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA-related purine, oxidative stress, and glutamatergic signaling pathways are among primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists – which have shown beneficial effects in an experimental Adcyap1−/− mouse model for schizophrenia – could be potential treatments even before the full manifestation of illness involving dopaminergic abnormalities.
Highlights
The first effective pharmacological treatments for schizophrenia were discovered more than 60 years ago, and ever since, all of them have been full or partial dopamine D2-receptor antagonists
In the Finnish dataset, the most significant pathways were regulated by P2RY11 purine receptor and losartan potassium, both including several genes coding glutamate receptors and transporters (Supplementary Figs. 1 and 2)
A recent study (Narla et al, 2017) using the US dataset found that hepatic fibrosis/hepatic stellate cell activation was the most significant signaling pathway in Ingenuity Pathway Analysis (IPA) analysis, and extracellular matrix (ECM) organization the most significant signaling pathway in Reactome analysis, but these findings were not highlighted because the study focused on FGFR1
Summary
The first effective pharmacological treatments for schizophrenia were discovered more than 60 years ago, and ever since, all of them have been full or partial dopamine D2-receptor antagonists. There is increasing evidence that, in addition to dopaminergic defects, abnormal glutamatergic, GABAergic, and serotoninergic signaling, as well as inflammation and oxidative stress contribute to the pathophysiology of schizophrenia (McCutcheon et al, 2020; Yang and Tsai, 2017) These variants contribute to complex molecular pathways in abnormal brain development leading to mental illness. The pathophysiology of neurological and psychiatric disorders can be modeled using human induced pluripotent stem cell (hiPSC)-derived neurons These studies (Brennand et al, 2011; Tiihonen et al, 2019) have tried to identify abnormalities related to illness by analyzing how differentially expressed genes (DEGs) interact in established pathways such as GO and KEGG, based on previous literature on gene functions, but no reproducible results identifying novel potential treatments have been published using these analyses. We used IPA in two independent hiPSC-neuron datasets as well as a national pharmacoepidemiological database in order to find potential novel treatments based on molecular pathways underlying schizophrenia, and to study whether any of these findings are consistent and reproducible
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