CHRNA5-CHRNA3-CHRNB4 haplotypes were analyzed. It is advantageous to model the genetic architecture by rational selection of haplotypes that maximizes information about the common variation at this locus and reflects potential underlying biological mechanisms. Three common haplotypes in the region spanning CHRNA5 and the 3′ end of CHRNA3 (12, 15) are defined by rs16969968 and rs680244. The risk allele of rs16969968 primarily occurs on the low mRNA expression allele of rs680244. Together, these variants identify three risk levels involving CHRNA5 representing two distinct mechanisms for nicotine dependence. We used these three haplotypes as our standard of analysis. In the ARIC dataset, these two variants were not genotyped, so two highly correlated SNPs were used as proxies to estimate haplotypes: rs951266 (r2 with rs16969968 is 0.97 in CEU 1000 Genomes Project) and rs6495306 (r2 with rs680244 is 1 in CEU 1000 Genomes Project; http://www.1000genomes.org/).
