When a genetic association is found, it represents not only an association with the tested genetic variants, but also an association with untested, highly correlated SNPs that can span across many genes on the same chromosome. The replication of genetic association justifies the continued search for the specific associated genetic variants that change biological function. First, the association marked by rs16969968 is correlated with genetic variants that extend across 6 genes on chromosome 15 in populations of European descent. See Figure 2. These genes include the α5-α3-β4 nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4), and correlated SNPs are also located in the following genes: iron-responsive element binding protein 2 (IREB2), an iron regulatory protein; LOC123688, a putative protein of unknown function; and α4 proteasome subunit protein (PSMA4), a protein that cleaves other proteins. The most plausible genes that may influence smoking behavior in this region are the family of nicotinic receptor genes. To understand the biological relationship of the genetic association with nicotine dependence, lung cancer and COPD, we must determine which of these correlated SNPs alter biological function.
