Possibly relevant to these findings, CACNA1C (which encodes a voltage-dependent calcium channel) is one of the best-supported GWAS-identified risk genes for bipolar affective disorder (22) and schizophrenia (23). Further, a large mega-analysis of psychiatric traits also landed on several calcium-system genes as contributing to risk for a set of psychiatric illnesses: two of the four GWS SNPs mapped to voltage-gated calcium channel subunit genes, and calcium signaling pathways were identified as important for the five disorders studied (24). Potassium-calcium signaling may couple neuronal signaling to vasodilation in the brain (25) and opioids can regulate calcium conductance via increasing potassium conductance in μ-opioid receptors (26). One of the genes in the calcium signaling pathway that is strongly associated with OD risk, CAMK2B, modulates activation of ionotropic (including AMPA) glutamate receptors (27). AMPA-mediated glutamatergic signaling in the hippocampus plays an important role in context-dependent sensitization to morphine. Behavioral sensitization in animal models is of interest as a neural basis of addiction (28, 29). LTP (which underlies learning and memory) was also implicated directly in pathway analysis. These pathways may interact to produce
