In summary, we have strong evidence that at least four distinct variants in CHRNA5-CHRNA3-CHRNB4, CHRNB3-CHRNA6 and CHRND-CHRNG influence nicotine dependence risk. These four significant nicotinic receptor findings, though important, together account for less than 10% of the phenotypic variance in our sample, indicating that additional risk factors are yet to be discovered and illustrating the challenge of complex disease genetics. Our ongoing work will continue the search for other genes and epistatic effects; we will also extend our analyses to diverse population samples having contrasting LD structure, as such studies can help narrow down among correlated SNPs and localize the most likely functional source of an association signal. Ultimately, determining the mechanism of action for these variants via functional studies can help improve prevention and cessation therapies.
