Abstract
BACKGROUND: Each gene in the chromosome 11q23 cluster of NCAM1, TTC12, ANKK1, and DRD2 is functionally linked to dopamine in brain. Many association studies of DRD2 and substance dependence (SD), including alcohol dependence (AD) and drug dependence (DD), have been reported; the results have been inconsistent. Recent association studies have considered this cluster more comprehensively, examining the association of SD with several risk variants mapped to the other genes in the cluster. Because comorbid AD with DD (AD+DD) is common, we hypothesized that heterogeneity of the SD diagnoses studied might have contributed to the inconsistency of prior results. METHODS: We conducted 2 separate association studies of AD+DD and AD without DD (AD-only) in 1,090 European-Americans using family-based and case-control designs and 43 single nucleotide polymorphisms mapped to this cluster. We used a generalized linear model and haplotype score tests for the case-control sample, and the family-based association test for the family sample. RESULTS: For AD+DD, the risk regions centered on TTC12 exon 3 [optimal individual haplotype simulated p (p(oihs)) = 0.000015], and another extended from ANKK1 exon 8 to DRD2;C957T (p(oihs) = 0.0028), in both samples. NCAM1 exon 12 markers showed global significance in both designs, but were significant for specific haplotypes (p(oihs) = 0.0029) only for the family sample. For AD-only, NCAM1 intron 14 to 18 and the junction of ANKK1 and DRD2 were associated globally. Population stratification was excluded as the basis for these results. Linkage disequilibrium contrast tests supported selection at TTC12 exon 3 and ANKK1 exon 2. CONCLUSIONS: We conclude that variants in TTC12 exon 3, NCAM1 exon 12, and the two 3'-ends of ANKK1 and DRD2 co-regulate risk for comorbid AD and DD.