Interactome Analyses implicated CAMK2A in the genetic predisposition and pharmacological mechanism of Bipolar Disorder

Bipolar disorder (BPD) is a severe mental illness characterized by fluctuations in mood states, behaviors and energy levels. Growing evidence suggests that genes associated with specific illnesses tend to interact together and encode a tight protein-protein interaction (PPI) network, providing valuable information for understanding their pathogenesis. To gain insights into the genetic and physiological foundation of BPD, we conduct the physical PPI analysis of 184 BPD risk genes distilled from genome-wide association studies and exome sequencing studies. We have identified several hub genes (CAMK2A, HSP90AA1 and PLCG1) among those risk genes, and observed significant enrichment of the BPD risk genes in certain pathways such as calcium signaling, oxytocin signaling and circadian entrainment. Furthermore, while none of the 184 genetic risk genes are well established BPD drug targets, our PPI analysis showed that alpha CaMKII (encoded by CAMK2A) had direct physical PPIs with targets (HRH1, SCN5A and CACNA1E) of clinically used anti-manic BPD drugs, such as carbamazepine. We thus speculated that alpha CaMKII might be involved in the cellular pharmacological actions of those drugs. Using cultured rat primary cortical neurons, we found that carbamazepine treatment induced phosphorylation of alpha CaMKII in dose-dependent manners. Intriguingly, previous study showed that CAMK2A heterozygous knockout (CAMK2A(+/-)) mice exhibited infradian oscillation of locomotor activities that can be rescued by carbamazepine. Our data, in combination with previous studies, provide convergent evidence for the involvement of CAMK2A in the risk of BPD.