Contribution of Variants in CHRNA5/A3/B4 Gene Cluster on Chromosome 15 to Tobacco Smoking: From Genetic Association to Mechanism

Cigarette smoking is the major cause of preventable death and morbidity throughout the world. Many compounds are present in tobacco, but nicotine is the primary addictive one. Nicotine exerts its physiological and pharmacological roles in the brain through neuronal nicotinic acetylcholine receptors (nAChRs), which are ligand-gated ion channels consisting of five membrane-spanning subunits that can modulate the release of neurotransmitters, such as dopamine, glutamate, and GABA and mediate fast signal transmission at synapses. Considering that there are 12 nAChR subunits, it is highly likely that subunits other than alpha 4 and beta 2, which have been intensively investigated, also are involved in nicotine addiction. Consistent with this hypothesis, a number of genome-wide association studies (GWAS) and subsequent candidate gene-based associated studies investigating the genetic variants associated with nicotine dependence (ND) and smoking-related phenotypes have shed light on the CHRNA5/A3/B4 gene cluster on chromosome 15, which encodes the alpha 5, alpha 3, and beta 4 nAChR subunits, respectively. These studies demonstrate two groups of risk variants in this region. The first one is marked by single nucleotide polymorphism (SNP) rs16969968 in exon 5 of CHRNA5, which changes an aspartic acid residue into asparagine at position 398 (D398N) of the alpha 5 subunit protein sequence, and it is tightly linked SNP rs1051730 in CHRNA3. The second one is SNP rs578776 in the 3E(1)-untranslated region (UTR) of CHRNA3, which has a low correlation with rs16969968. Although the detailed molecular mechanisms underlying these associations remain to be further elucidated, recent findings have shown that alpha 5* (where * indicates the presence of additional subunits) nAChRs located in the medial habenulo-interpeduncular nucleus (mHb-IPN) are involved in the control of nicotine self-administration in rodents. Disruption of alpha 5* nAChR signaling diminishes the aversive effects of nicotine on the mHb-IPN pathway and thereby permits more nicotine consumption. To gain a better understanding of the function of the highly significant genetic variants identified in this region in controlling smoking-related behaviors, in this communication, we provide an up-to-date review of the progress of studies focusing on the CHRNA5/A3/B4 gene cluster and its role in ND.