Our study of common variants identified a splice site acceptor variant allele (rs2273500-C) as being associated with (1) increased risk of nicotine dependence at genome-wide significance, (2) decreased CHRNA4 expression in human brain and (3) increased lung cancer risk likely through its effect on smoking. Future studies with a large sample of brain-specific CHRNA4 exon-specific sequences and FTND measurements are needed to validate and elucidate the splicing mechanism involving rs2273500 and its effect on nicotine dependence risk. Nonetheless, our new evidence revealing a common SNP with important regulatory features, along with a newly discovered functional rare variant,91 firmly establish CHRNA4 as an important susceptibility gene for nicotine dependence and its adverse health consequences.
