Some other lessons can be tentatively learned from the CHRNA5–CHNRA3–CHRNB4 locus62. First, it is now relatively clear that multiple, statistically independent signals coexist in this relatively small genomic region. The associated linkage disequilibrium blocks are substantially larger than conventionally conceived, and they cover several genes. The association signals observed extend to IREB2, covering a genomic distance of more than 200 Kb (refs. 46,53). Second, as noted above, even the same variant affects multiple phenotypes. The CHRNA5–CHNRA3–CHRNB4 locus has been shown to be associated with nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcohol dependence and cocaine dependence. Third, somewhat troublingly, using different methods for assessing the broad construct of nicotine dependence leads to different results. Traditionally, nicotine dependence is defined either by the American Psychiatric Association’s Diagnostic and Statistical Manuals1 or the Fagerström Test for Nicotine Dependence44. However, these two measures do not agree well. More interestingly, CPD, which was generally considered to be only a rough index of nicotine dependence inferior to more complete assessment tools, has often proven to be the most robust phenotype for this locus.
