Substance dependence is a complex behavior influenced by both genetic and environmental factors. The role of genetics in substance dependence is well established in twin and family studies. Unfortunately, molecular genetic studies have had limited success identifying individual genetic variants that are common across multiple substances of abuse (1-10). First, the primary conclusions from molecular genetic studies are that common single nucleotide polymorphisms (SNPs) modestly contribute to substance dependence phenotypes (e.g., rs1614972 in the alcohol dehydrogenase gene (ADH1C) was the only replicable SNP in a recent alcoholism genome-wide association study (GWAS) (11), and variants in the CHRNA5-A3-B4 gene cluster have been repeated linked to tobacco addiction/dependence (12, 13)). Second, multiple genetic polymorphisms influence substance dependence. In part to address the possibility that most variants truly associated with complex traits have effect sizes too small to detect individually using GWAS studies, Yang et al. (14) developed a new method, Genome-wide Complex Trait Analysis (GCTA), that focuses on the estimation of the phenotypic variance explained by genome-wide similarity at genotyped single nucleotide polymorphism (SNPs). Rather than testing each SNP individually, GCTA decomposes
