A 35.8 kilobases haplotype spanning ANKK1 and DRD2 is associated with heroin dependence in Han Chinese males

Ankyrin repeat and kinase domain containing 1 (ANKK1) and dopamine receptor D2 (DRD2) gene polymorphisms have long been considered to contribute to susceptibility to heroin dependence. Despite their adjacent locations, few studies have elucidated the role of the potential interaction between ANKK1 and DRD2 in heroin dependence. In the present study, we performed a systematic analysis of the association between 39 single nucleotide polymorphisms (SNPs) in these two genes and heroin dependence in 593 Chinese subjects. According to our results, polymorphisms of four unreported loci were associated with heroin dependence, among which rs11214598 of ANKK1 were still significant after multiple testing. We also conducted a meta-analysis of the association between a widely studied variant, rs1800497, and heroin dependence as a representative example and obtained a consistent outcome with our results. Notably, a 35.8 kilobases (kb) haplotype spanning ANKK1 and DRD2 was found to be a strong protective factor for heroin dependence. Gene-gene interaction analysis suggested that interactions exist within the ANKK1-DRD2 haplotype block between rs11214598 and rs1800497 in ANKK1 and rs2245805 and rs1079597 in DRD2. Our study highlights the importance of considering haplotypes spanning adjacent genes and the cooperation and interaction of proximal variants or genes in genetic association studies.