Until recently, candidate gene studies and GWAS focused on common variation. However, three additional sources of genomic variation have the potential to further explain heritability in addiction. First, copy number variants—large segments of DNA that are deleted or duplicated producing considerable structural instability—need to be explored for addictions. Recent research has shown associations between rare copy number variants (mostly deletions) and several psychiatric disorders, including schizophrenia, autism and Parkinson disease (see Stankiewicz and Lupski130 for a review). Second, as discussed above, rare variants are inadequately captured on commercial GWAS arrays. Deeper sequencing of the human genome presents the opportunity to identify such rare SNPs (<1% minor allele frequency). Although this is being facilitated by the 1000 Genomes Project,131 the identification of disease-specific rare variants requires next-generation sequencing in samples ascertained for addiction. Finally, epigenetic modifications are implicated as contributors to and consequence of chronic substance use. Animal research shows that repeated drug use alters gene expression profiles in the brain reward system, through epigenetic mechanisms such as histone acetylation and methylation change (see Renthal and Nestler,132 Maze and Nestler133 and
