Similar to prior scoring endeavors (e.g., International Schizophrenia Consortium, 2009; Evans et al., 2009), we made use of a large sample enriched for our phenotypes of interest to conduct intra-sample cross-validation. Because of the amount of evidence implicating the dopamine system in substance use generally, and cocaine dependence specifically, we focused our analyses on this system. The intention behind focusing on a specific neurotransmitter system was to reduce the likelihood of including “noise” SNPs, increasing our ability to identify a valid scoring set of SNPs. Similarly, the construction of a poly-SNP genetic “risk” score is well-aligned with current theories of genetic contributions to complex phenotypes, such as substance dependence, in which numerous genetic variants are likely to each have a relatively small effect on the observed phenotype (e.g., Plomin et al., 2009).
