The current study demonstrated how linkage analysis could inform genetic association studies and lead to discovery of a rare variant in NRG1 associated with CaD in AAs. We first conducted a dense GWLS for CaD in small nuclear families recruited on the basis of ASPs with either CD and/or OD. The strongest evidence for linkage in our family sample was observed on 8p21.1 (lod =2.9) in AAs. To our knowledge, this region has not been previously reported by linkage studies of any substance dependence disorder. However, chromosome 8p22-p21, which overlaps our linkage signal, has been repeatedly implicated in several neuropsychiatric disorders including schizophrenia, bipolar affective disorder, and major depression (54). Using the SAGE GWAS dataset, we found that rs17664708 located at NRG1 under the linkage peak was associated with CaD in both AAs and EAs. The association was further replicated in an independent AA sample. Our rigorous QC and statistical analysis adjusting for both global and local ancestry argues against the possibility that the significant association between the rs17664708 and CaD is from the effect of population stratification in AAs.
