Risk factors for heavy drinking operate primarily through intermediate characteristics that relate to environmental events and genetic influences to impact on the development of heavy drinking and alcohol use disorders (AUDs) [1–5]. One such preexisting phenotype is the low level of response (LR) to alcohol, where individuals who require higher doses of alcohol to achieve an effect (reflecting a lower sensitivity or more rapid intra-session tolerance) are more likely to develop AUDs than those who react more intensely to ethanol [6–9]. This trait can be measured as less alcohol-related change in positive (e.g., feeling high) and negative (e.g., feeling dizzy) subjective feelings of intoxication, hormones, and EEG measures at a given blood alcohol concentration (BAC), or as less effect per drink on a retrospective questionnaire [4, 10–16]. A low LR is seen in ~40% of the children of alcoholics, but only ~10% of controls, and the heritability of this trait is 40%-60% [3, 5, 10]. Low LR predicts later heavy drinking, but has little overlap with other genetically-influenced risk factors (e.g., alcohol metabolizing enzymes and impulsivity [3,11].
