No large-scale genome- or exome-wide study of rare variation has been conducted to date. The vast majority of existing addiction-related rare variant studies have used targeted sequencing of putative addiction-associated loci to discover and test for association in relatively small samples. Existing research has led to intriguing leads, including rare variant associations in loci that span nicotinic receptor gene clusters(12–21) and alcohol metabolism genes(22–24) for nicotine and alcohol dependence, respectively. This strategy has also produced rare variant associations in novel loci. In one case, gene-level association tests were used to find an association with rare variants in SERINC2(24). In another case, a burden test across PTP4A1, PHF3, and EYS showed association with alcohol dependence(25). Unfortunately, these genes are not obviously involved in etiological processes related to addiction, and replications have not been reported to date.
