Although the GWASs approach has been successful for many illnesses, much of the genetic variation underlying the development of alcohol dependence remains undiscovered. Thus, although the heritability of alcohol dependence approaches 50 percent, the explained genetic variance to date is less than 1 percent, which raises the question “Where is the missing genetic variance?” Three main explanations have been given for the missing variance in the genetic risk for alcohol dependence: (1) many genes of small effect may be involved that do not yet surpass the stringent threshold for genome-wide significance; (2) rare variations—that is, SNPs that only occur in less than 1 percent of the population—exist that are not included on standard chips and hence not captured by GWASs genotyping; and (3) other mechanisms, including the interplay of genes and environments, may contribute that are not detected in current analyses.
