In recent years, intermediate phenotypes have been proposed as an alternative to traditional phenotype measures. These include neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive and neuropsychological correlates that are heritable and quantifiable and are thought to more closely manifest etiologies of addictions. The relationship between genes and clinically observable symptomologies of addiction is highly complex, and intermediate phenotypes are thought to capture information on mediating variables within this chain of events. Because they are objective measures, and are potentially less complex compared to the diagnostic criteria for addiction, with wide-ranging symptomologies and clinical courses and a dependency on environmental exposures, intermediate phenotypes may be more representative of gene action. Electrophysiological measures, as well as structural and functional imaging data in so-called “imaging genetics” studies, have been used to investigate brain alterations associated with alcohol dependence in relation to genetic variations in GABRA2 and CHRM2 (reviewed in (24), Supplementary Table 1), COMT and mGluR3 (25), and DRD4 and OPRM1 (26).
