Results of animal studies indicate that both α4 and β2 subunits influence key addiction-related processes.13 CHRNA4 and CHRNB2 have long been considered among the strongest functional candidate genes in the genome when it comes to nicotine addiction and related phenotypes, and an efficacious smoking cessation aid (varenicline) was developed as a partial agonist of the α4β2 isoforms.19 A large number of candidate gene studies have targeted CHRNA4 and CHRNB2, but the results have been inconclusive. In a companion paper4 we show that common markers within CHRNA4 exhibit genome-wide significant association with score on the Fagerström Test of Nicotine Dependence (FTND),20 the most widely used measure of nicotine addiction. The genome-wide association study of FTND was limited to the study of common variants,4 and here we study rare variants within CHRNA4, by testing eight missense variants in CHRNA4 for association with FTND.
