We acknowledge several limitations to our study. First, our discovery sample, which was ascertained through sibling pairs concordant for CD or opioid dependence, is probably enriched for genetic factors for CD and CIP compared with subjects exposed to cocaine in the general population. To overcome this issue and the problem that association findings in discovery samples tend to overestimate the effect size of the genetic risk factor,51 we replicated our results in independent EA and AA case-control samples. Although results with individual SNPs were uneven across study samples, haplotype analysis showed significant association with the same allele of 1 SNP (SNP 9, rs9387522) in both EA and both AA data sets. Second, genetic association studies are vulnerable to false-positive results owing to population stratification and to false-negative results owing to misclassification of subjects or power. Our use of family-based controls in the discovery phase and the assignment of nearly all subjects to genetically matched groups based on analysis of many markers distributed across the genome lessened the potential for stratification. Furthermore, all of the approximately 4000 subjects included in this
