In summary, collective findings from GWAS among the African and European ancestry populations implicate chromosome 15q25 region as the most significant for smoking quantity. However, for both populations, SNPs in this region are associated with very small changes in smoking quantity and explain a small proportion of the variance, which suggests that conventional GWAS approaches may not be adequate to discover the likely hundreds of variants contributing small increments in risks of the additive genetic effects for heritable traits or so-called ‘missing heritability' of complex diseases.59 The use of more refined, specific and harmonized phenotypes capturing the complex behavior of SI, trajectories of progression and cessation, and environmental effect-modifiers are also needed to detect the genetic architecture of smoking behavior in different ancestral populations. Larger studies utilizing next-generation SNP arrays, whole-exome or whole-genome sequencing will be required to investigate lower-frequency variation, which may contribute to unexplained heritability for common traits.60
