Genetic studies of smoking and nicotine dependence have recently made significant progress with both candidate gene and GWAS approaches. In 2007, the non-synonymous single-nucleotide polymorphism (SNP) rs16969968, which changes the amino acid from aspartate to asparagine in the α5 subunit of the nicotinic acetylcholine receptor (CHRNA5), was identified as a risk variant associated with nicotine dependence39. Several independent studies40–42, including our own43, quickly confirmed the association of this and another highly correlated SNP, rs1051730, with several inter-related measures of nicotine dependence, including number of cigarettes smoked per day (CPD) and nicotine dependence as assessed by the Fagerström test for nicotine dependence44. In more recent investigations, including collaborative studies involving very large samples45–47, the CHRNA5–CHRNA3–CHRNB4 locus has been consistently shown to be associated with CPD with extremely low P-values. Several statistically independent association signals appear across this region46. A priori, it seemed likely that variants in nicotinic receptors would be specific to genetic risk for nicotine dependence. As a reminder of how potentially complex the genetic substrate for SUD may be, however, several studies have now suggested that these genes may contain variants associated with risk for alcohol, cocaine and opiate use and misuse43,48–50.
