Given these multiple findings in CHRN genes, an important question is the proportion of phenotypic variance explained by these loci. Although large-scale association studies of complex diseases are reproducibly identifying common genetic “risk” variants, typically these variants have small effect sizes and account for only a small fraction of the heritability or phenotypic variance known to exist (Goldstein, 2009, Hirschhorn, 2009, Kraft & Hunter, 2009, Maher, 2008). In our sample, the variation explained by the chromosome 15q25 SNPs rs16969968, rs578776 and rs588765 is 1.9% in both EAs and AAs. With the addition of 6 SNPs representing the top associated CHRN genes in the full sample, the variation explained in each sample increases dramatically to 4.9% in EAs and 7.3% in AAs (Table 4). As with many other complex diseases, these associated SNPs account for only a modest fraction of the trait variation. However, the important message is that we see a substantial additional contribution from variants in the other nicotinic receptor genes beyond CHRNA5-CHRNA3-CHRNB4. This is striking given that CHRNA5-CHRNA3-CHRNB4 loci such as rs16969968 are genome-wide significant in multiple studies of European-descent subjects, while of the SNPs reported here, none even approach genome-wide significance.
