Case-control association analysis of polymorphisms in the δ-opioid receptor, OPRD1, with cocaine and opioid addicted populations

Abstract

Background: Addiction susceptibility and treatment responsiveness are greatly influenced by genetic factors. Sequence variation in genes involved in the mechanisms of drug action have the potential to influence addiction risk and treatment outcome. The opioid receptor system is involved in mediating the rewarding effects of cocaine and opioids. The μ-opioid receptor (MOR) has traditionally been considered the primary target for opioid addiction. The MOR, however, interacts with and is regulated by many known MOR interacting proteins (MORIPs), including the δ-opioid receptor (DOR).

Methods: The present study evaluated the contribution of OPRD1, the gene encoding the DOR, to the risk of addiction to opioids and cocaine. The association of OPRD1 polymorphisms with both opioid addiction (OA) and cocaine addiction (CA) was analyzed in African American (OA n=336, CA n=503) and European American (OA n=1007, CA n=336) populations.

Results: The primary finding of this study is an association of rs678849 with cocaine addiction in African Americans (allelic p=0.0086). For replication purposes, this SNP was analyzed in a larger independent population of cocaine addicted African Americans and controls and the association was confirmed (allelic p=4.53 × 10(-5); n=993). By performing a meta-analysis on the expanded populations, the statistical evidence for an association was substantially increased (allelic p=8.5 × 10(-7)) (p-values non-FDR corrected).

Conclusion: The present study suggests that polymorphisms in OPRD1 are relevant for cocaine addiction in the African American population and provides additional support for a broad role for OPRD1 variants in drug dependence.

Figure 1

LD between OPRD1 SNPs genotyped in HapMap CEU population and ASW population (www.hapmap.org). A: HapMap data release 28, phase II and III, August 10. In the CEU population, 7 SNPs capture 85% of SNPs in OPRD1 with a minor allele frequency cut-off of 10% and an r² of 0.8. (rs2234918 not included in LD analysis as HapMap data not available). B: HapMap data phase III/rel#2 Feb09. In the ASW population, 7 SNPs capture 33% of SNPs in OPRD1 with a minor allele frequency cut-off of 10% and an r² of 0.8. (rs2234918 and rs533123 not included in LD analysis as HapMap data not available). Numbers inside the squares represent D’ and the shading is representative of r². When no number is displayed D’ =1.