This large, family study of AA and EA individuals utilized a multi-pronged approach (Figure 1) to dissect the genetic underpinnings of alcohol dependence (DSM-IV AD). In addition to the primary phenotype of DSM-IV diagnosis of AD, and severity as captured by the AD criterion count, it is, to our knowledge, the largest GWAS of each DSM-IV AD criterion. We detected five regions with variants meeting traditional GWS criteria, of which four were novel (chromosomes 1, 2, 8, and 15). Notably, the chromosome 8 signal was replicated in an independent dataset, as was the well-known association with rs1229984 in ADH1B. Even when excluding the larger effect size associated with rs1229984, PRS derived from the EA GWAS predicted 0.61-1.82% of the variation in AD in independent datasets, underscoring significant polygenicity underlying liability to the disorder. Analyses of two reward-related neural phenotypes also showed associations with two GWS variants.
