Several of the top-ranked variants are mapped to loci that were not previously implicated in substance use and other psychiatric disorders. KCNA4 encodes a potassium voltage-gated channel protein. Potassium voltage-gated channels have been implicated in opioid dependence18, the long-acting narcotic analgesic narcotic l-alpha-acetylmethadol40, and alcohol-preferring rats treated with lamotrigine41. Mutations in GNAO1, which encodes the alpha subunit of the G-alpha heterotrimeric G-protein signal-transducing complex, cause early-onset epileptic encephalopathy and severe developmental delay42–44. GNAO1 expression is upregulated in a mouse model of morphine dependence, and the knock-down of the gene in these animals led to reduced opioid withdrawal behaviors45. Although the exact function of the enzyme encoded by CPVL has not been confirmed, its expression is upregulated in the postmortem prefrontal cortex from users of cocaine, cannabis, and phencyclidine46. The CPVL variant associated with stimulant dependence, rs11764430, is an eQTL for CHN2, which regulates axonal pruning via the Rac-GTPase system47 and plays a pivotal role in axon guidance. A CHN2 variant has been associated with smoking behavior48. Significant association of a quantitative serum measure of methylation of the CHN2 promoter with methamphetamine dependence was observed in a Chinese sample49.
