Here we conducted one of the first few GWAS investigations to search for novel genetic factors underlying smoking behavior. Using an Affymetrix 500K array, we successfully genotyped and analyzed a total of 379,319 single nucleotide polymorphisms (SNPs) for 840 unrelated Caucasians, including 417 males and 423 females. We identified a cluster of nine SNPs upstream of the IL15 gene, which achieved strong association with smoking status in males. One particular SNP, rs17354547, is highly conserved across multiple species. This SNP, together with several other ones, are located at potential transcription factor binding sites, suggesting their functional importance, possibly by regulating IL15 gene expression. Furthermore, this SNP was replicated in an African-American (AA) cohort, where it was associated with several nicotine dependence (ND) phenotypes, and all of the nine SNPs were replicated in silico for association with smoking status in a Framingham Heart Study (FHS) Caucasian sample. Our findings suggest a novel mechanism for smoking behavior, where the IL15 pathway may play an important role.
