GWAS for drug dependence traits have identified several significant risk alleles, but replication studies in different ancestry groups often fail to reproduce these outcomes [12,13]. In the present study, we tested the effect of genetic background (variants located in the surrounding regions or in functional partners) on the significantly-associated variants. Our results provided significant evidence that local ancestry differences can partially explain the ancestry difference observed in GWAS. Specifically, we observed that when adjusting for these local ancestry-related variants, the differences between African–Americans and European–Americans tend to diminish.