There are additional limitations pertaining to the case samples used in this study. Drug addicted individuals were obtained from various NIDA genetics study populations, each of which has different inclusion and exclusion criteria for drug addicted participants. This may have lead to subtle differences between the case populations; however, it should be noted that all drug addicted individuals genotyped in this study do meet DSM-IV criteria for opioid or cocaine addiction. Furthermore, while the NHLBI-ESP removes all exomes from their database which demonstrate first to third degree relatedness, the cases used in this study were not analyzed for cryptic relatedness and this may have impacted the frequency of rare variants reported in this study. Population stratification may also have affected the associations reported in this study as differences in population substructure were not controlled for between the cases and the NHLBI-ESP population. Without access to the raw genotype data for the NHLBI-ESP population it is not possible to test for differences in population admixture between the cases and controls and this should be recognized as a limitation of this study.
