Genomewide association studies (GWAS) have had limited success at identifying risk genes for complex traits (Chambers et al., 2001). With the noteworthy exception of nicotine dependence (ND), published GWAS for drug dependence traits (excluding alcohol dependence) have for the most part not produced compelling results (Liu et al., 2010). The reservoir of the unexplained heritable risk for most complex traits is an area of much discussion. Clearly, some of this reservoir is composed of rare variants (RVs), either too infrequent, or of too recent origin, or both, to be detected by GWAS. It is unlikely that the full set of RVs will be sufficient to account for all or even most of the “missing” heritability, but RVs have been shown to account for at least some of the risk in a growing set of complex traits, including inflammatory bowel disease (Rivas et al., 2011), autism (Sanders et al., 2012), schizophrenia (Girard et al., 2011), impulsivity (Bevilacqua et al., 2010), and nicotine dependence (Xie et al., 2011). Next-generation high throughput sequencing technologies have recently rendered deep sequencing projects more feasible. However,
