Although we used a unique and potentially powerful technique to examine the genetic basis of alcohol misuse, we recognize that alcohol consumption, misuse and dependence are influenced by numerous factors, both genetic and environmental (e.g. availability of alcohol, social norms, laws, psychosocial and personality factors, expectancies, health factors). Further, individuals vary in susceptibility at every stage of alcohol use from initiation to severe dependence, including the continued use after a first drink, the direct subjective and behavioral effects of the drug, withdrawal severity, tolerance and susceptibility to relapse, among others. Genetic factors are likely to influence variability at each of these stages, but different stages may be influenced by different sources of genetic variability. Thus, whereas we have investigated genetic variance related to an intermediate outcome measure of alcohol misuse (as measured by the AUDIT), it remains to be determined exactly how genetic sources of variation influence alcohol consumption. This ambiguity limits our ability to elucidate the underlying molecular mechanisms identified by GWAS of alcohol use and abuse.
