these effects were relatively modest (LOD scores between 1.5 and 4) and the same loci were not identified in all samples. A genome-wide linkage scan for nicotine dependence identified only one locus with a strong linkage signal (Straub, et al., 1999). However, in further analysis the authors identified a number of regions in which multiple consecutive positive markers could be found, and the authors concluded that the difficulty was identifying signals from genes that each likely had a small effect and contributed heterogeneously to the phenotype. The stringency of the statistical criteria applied to the analysis, discussed in more detail below, may have been a critical factor in the limited number of positive effects identified in these studies. Indeed, a genome-wide linkage scan for opioid dependence identified only weak linkage signals (Gelernter, et al., 2006), and a genome-wide linkage scan for nicotine dependence identified only one “genome-wide” result that was significant (Gelernter, et al., 2007). As will be discussed below, there are statistical issues with regard to “genome-wide” significance, but because linkage involves fewer recombination events, it may lack the resolution necessary for these studies.
