Our study differs from most published GWAS in its use of complex multi-dimensional phenotypes rather than a binary diagnosis such as drug dependence or abuse. We obtained responses on three questionnaires, administered over six time points, in three sessions, after placebo or one of two doses of drug. Such multi-dimensional “intermediate phenotypes” have many advantages over binary diagnoses. Drug abuse is a heterogeneous phenotype that consists of a series of stages, each influenced by a variety of environmental and genetic factors [21]. In contrast, intermediate phenotypes can be measured under carefully controlled conditions, e.g., laboratory conditions, and may be directly linked to genetic variants and resulting from specific biological processes. For this reason, intermediate phenotypes are hypothesized to show stronger genetic associations than binary diagnoses, potentially allowing for smaller sample sizes [22]. For example, a GWAS of electroencephalogram (EEG), which is an intermediate phenotype for brain-related clinical endpoints, reported genome-wide significant associations using just 322 participants [23]. Furthermore, acute responses to pharmacological perturbations often yield alleles of relatively large effects [24]. Association studies of the response to cisplatin [25], warfarin
