Association ofOPRD1polymorphisms with heroin dependence in a large case-control series

Abstract

Genes encoding the opioid receptors (OPRM1, OPRD1, and OPRK1) are obvious candidates for involvement in risk for heroin dependence. Prior association studies commonly had samples of modest size, included limited single nucleotide polymorphism (SNP) coverage of these genes, and yielded inconsistent results. Participants for the current investigation included 1459 heroin dependent cases ascertained from maintenance clinics in New South Wales, Australia, 1495 unrelated individuals selected from an Australian sample of twins and siblings as not meeting DSM-IV criteria for lifetime alcohol or illicit drug dependence (non-dependent controls), and 531 controls ascertained from economically-disadvantaged neighborhoods in proximity to the maintenance clinics. A total of 136 OPRM1, OPRD1, and OPRK1 SNPs were genotyped in this sample. After controlling for admixture with principal components analysis, our comparison of cases to non-dependent controls found 4 OPRD1 SNPs in fairly high linkage disequilibrium for which adjusted p values remained significant (e.g., rs2236857; OR 1.25; p=2.95 × 10−4) replicating a previously reported association. A post-hoc analysis revealed that the two-SNP (rs2236857 and rs581111) GA haplotype in OPRD1 is associated with greater risk (OR 1.68; p=1.41 × 10−5). No OPRM1 or OPRK1 SNPs reached more than nominal significance. Comparisons of cases to neighborhood controls reached only nominal significance. Our results replicate a prior report providing strong evidence implicating OPRD1 SNPs and, in particular, the two SNP (rs2236857 and rs581111) GA haplotype in liability for heroin dependence. Support was not found for similar association involving either OPRM1 or OPRK1 SNPs.

An Intronic Variant in OPRD1 Predicts Treatment Outcome for Opioid Dependence in African-Americans

“…Three common intronic SNPs (rs2236861, rs2236857, and rs3766951) were nominally associated with heroin dependence in EuropeanAmericans, although these associations were not significant after correction for multiple testing (Levran et al, 2008). In an Australian cohort, rs2236857 was again associated with heroin dependence, along with a haplotype block consisting of rs2236857 and rs581111 (Nelson et al, 2012). In addition to these associations with opioid dependence, an intronic variant of OPRD1 (rs678849) has also been associated with cocaine dependence in African-Americans (Crist et al, 2012).…”

Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRM1

“…We henceforth refer to them as the Australian Heroin Dependence Study. A subset of this case-control cohort and descriptions of the study design have been previously described (10). Our final analysis dataset totaled 5,120 Australians of European ancestry (1,976 cases and 3,144 controls, see Table S2 and Supplemental Methods).…”

“…Genetic vulnerability is recognized as a major risk factor contributing to heroin and other opioid addiction, as evidenced by twin studies showing that genetic factors account for 40% to 60% of the population variability (3-6). A few genome-wide association (7-9) and numerous candidate gene studies (10-19) in humans have implicated genes encoding opioid receptors ( OPRM1, OPRD1 , and OPRK1 ), potassium channels ( KCNG1 and KCNG2 ), and others as contributing to heroin/opioid addiction phenotypes. In supporting the biological plausibility of the candidate genes, particularly genes in the opioid system (20), knockout mouse models have been used to study behavioral effects resulting from genetic perturbations.…”

“…However, rs1799971 associations with heroin and other drug addictions (13-17) have been modest and often inconsistent. Additional OPRM1 single nucleotide polymorphisms (SNPs) have been tested for association with heroin/opioid addiction (10, 12, 13, 18, 19), but none of the findings have been independently replicated.…”

Bioinformatics and Evolution of Vertebrate Nociceptin and Opioid Receptors

“…Altering the expression of genes, by adaptive evolution in noncoding DNA, is a viable outlet for Darwinian or positive selection (Gu & Gu, 2003;Jordan, Marino-Ramirez, & Koonin, 2005). There are fewer studies of the hKOR polymorphism (Gerra et al, 2007;LaForge et al, 2000;Saito et al, 2003;Yuferov et al, 2004), hDOR (Beer et al, 2013;Kobayashi et al, 2006;Nelson et al, 2012;Zhang et al, 2010), and less than a handful of studies examining SNPs in hORL (Huang, Young, Pletcher, Heilig, & Wahlestedt, 2008;Ito, Xie, Maruyama, & Palmer, 2000;Xuei et al, 2008).…”