Though the GWAS based approach has been successful for nicotine dependence and other complex traits, a significant fraction of the genetic variance remains unexplained (Frazer et al., 2009). The heritability of addiction is approximately 50%, yet the confirmed genetic contributions to nicotine dependence (through the nicotinic receptors and nicotine metabolizing genes) and alcohol dependence (through alcohol metabolizing genes) explain only a small fraction of this heritability. There are two main explanations for the missing variance: rare variation not queried on the current GWAS chips, and many genes of small effect. It is likely that both of these reasons contribute to the missing genetic variance.
