Our study is the first to detect the association between HTR1A and alcohol and nicotine co-dependence at a genome-wide significance level. HTR1A is located in 5q11.2-q13. It encodes the 5-HT1A receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). This receptor is a G protein-coupled receptor (GPCR) that is coupled to Gi/Go and mediates inhibitory neurotransmission. In the central nervous system, 5-HT1A receptors exist in the cerebral cortex, hippocampus, septum, amygdala, and raphe nucleus in high densities. The activation of 5-HT1A receptor has been shown to increase dopamine release in the medial prefrontal cortex, striatum, and hippocampus, to impair cognition, learning, and memory by inhibiting the release of glutamate and acetylcholine in various areas of the brain, or to increase impulsivity and inhibition of addictive behaviors. This activation is therefore likely to be related to the development of alcohol dependence or nicotine dependence. This is consistent with our findings that the risk alleles of the variants in the IPO11-HTR1A region for alcohol and nicotine co-dependence increased the expression of HTR1A. Additionally, a well-known and functional promoter SNP of HTR1A, C-1016G
