The observations in this study highlighted several important issues regarding the missing heritability [15] that have not yet been explained by current GWAS. Despite the fact that the 1000 Genomes Project covered almost all SNPs in the human genome, the high frequency deletion (CYP2A6*4) confirmed in our study was not tagged by nearby SNPs (). This finding suggests that the high similarity between sequences around CYP2A6 may have caused recurrent deletion events in multiple ancestors in the Japanese population (see reference [16] for a detailed explanation of the mechanism underlying recurrent deletion events). Although recent studies have claimed that common CNPs may be indirectly explored through genome-wide SNP studies [17], [18], we believe that some common CNPs might have been missed by the current genome-wide SNP studies, and those CNPs may still account for a percentage of the missing heritability.
