The confirmed association within loci containing CACNA1C and other voltage-gated calcium channel genes supports the rekindled interest in calcium channel antagonists as potential treatments for BD, with similar examination ongoing for other genes implicated in SCZ GWAS 59. Other genes within novel BD-associated loci include those coding for other ion channels and transporters (SCN2A, SLC4A1), neurotransmitter receptors (GRIN2A) and synaptic components (RIMS1, ANK3). Further study will confirm whether or not these are the causal genes in the loci. These processes are important in neuronal hyperexcitability60, an excess of which has been reported in iPSC derived neurons from BD patients, and which has been shown to be affected by the classic mood stabilizing drug lithium 61. In addition, SMR eQTL and mQTL analyses implicate GLT8D1, which is involved in proliferation and differentiation of neural stem cells 62. Pathway analyses reveal new genetic evidence for insulin secretion and endocannabinoid signaling in BD. There is evidence of insulin action in the brain 63 and in BD 64. The endocannabinoid system has possible roles in schizophrenia 65,66 and depression 67. Top genes appearing in these pathways include calcium and potassium channel subunit, MAP kinase and GABA-A receptor subunit genes (Supplementary Table 18).
