Alcohol-induced flushing is a protective alcohol-related endophenotype influenced by alleles mediating variation in alcohol metabolism. Low response to alcohol is an endophenotype predictive of alcoholism risk.48–50 In humans, level of response is due mainly to pharmacodynamic variation in response51 rather than variation in metabolism. Low response to alcohol has been associated with genetic variation in the serotonin transporter gene (SLC6A4) and in the gene encoding the subunit a6 of the γ-aminobutyric acid receptor A (GABRA6).52 Other addiction-relevant intermediate phenotypes include electrophysiologic, neuropsychological, neuroendocrinologic, and, more recently, neuroimaging measures. Neuroimaging accesses neuronal mechanisms underlying emotion, reward, and craving and has thereby enabled linkage of genes to neuronal networks relevant in addiction (for review see Ref.53). For example, amygdala activation after exposure to emotional imagery and stressful stimuli captures interindividual differences in emotional response.54 As discussed in the text that follows, amygdala activation is influenced by SLC6A4 and MAOA. On the other hand, task-elicited activation of the prefrontal cortex accesses prefrontal cognitive function that is impaired in several psychiatric diseases including addictions and has been linked to genetic variation within COMT and
