α7, α8, α9, and α10 are able to form functional receptors, but other α subunits require the presence of β subunits to form functional receptors. In mammals, nAchR subunits have been found to be encoded by 17 genes, and of these, nine genes encoding α-subunits and three encoding β-subunits are expressed in the brain. β2 subunit-containing nAChRs (β2nAChRs) and α7nAChRs are widely expressed in the brain, whereas other nAChR subunits have more restricted expression. The pentameric assembly of nAChRs is subjected to the subunits that are produced in various cell types such as in the human lung where epithelial and muscular pentamers largely differ. CHRNA5/A3/B4 An important nAchR gene cluster (CHRNA5/A3/B4) contains the genes encoding for the α5, α3 and β4 subunits. Genetic studies have identified single nucleotide polymorphisms (SNPs) in the chromosomal locus encoding these three nAChR genes as risk factors for nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease. The CHRNA5/A3/B4 nAChR subunit genes are found in a tight cluster in chromosomal region 15q24–25. The nAChR subunits encoded by this locus form the predominant nicotinic receptor subtypes expressed in the peripheral nervous system (PNS) and other key central nervous system (CNS) sites, such as the medial habenula, a structure between the limbic forebrain and midbrain involved in major cholinergic circuitry pathways. Further research of the CHRNA5/A3/B4 genes have revealed that “neuronal” nAChR genes are also expressed in non-neuronal cells where they are involved in various fundamental processes, such as inflammation. The CHRNA5/A3/B4 genes are co-expressed in many cell types and the transcriptional activities of the promoter regions of the three genes are regulated by many of the same transcription factors, demonstrating that their clustering may reflect control of gene expression. CHRNA6/CHRNB3 CHRNB3 and CHRNA6 are also grouped in a gene cluster, located on 8p11. Multiple studies have shown that SNPS in the CHRNB3–CHRNA6 have been linked to nicotine dependence and smoking behavior, such as two SNPs in CHRNB3, rs6474413 and rs10958726. Genetic variation in this region also displays influence susceptibility to use drugs of abuse, including cocaine and alcohol consumption. Nicotinic receptors containing α6 or β3 subunits expressed in brain regions, especially in the ventral tegmental area and substantia nigra, are important for drug behaviors due to their role in dopamine release. Genetic variation in these genes can alter sensitivity to drugs of abuse in numerous ways, including changing the amino acid structure