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

      Abstract

      Background

      No opioid receptor, mu 1 (OPRM1) gene polymorphisms, including the functional single nucleotide polymorphism (SNP) rs1799971, have been conclusively associated with heroin/other opioid addiction, despite their biological plausibility. We used evidence of polymorphisms altering OPRM1 expression in normal human brain tissue to nominate and then test associations with heroin addiction.

      Methods

      We tested 103 OPRM1 SNPs for association with OPRM1 messenger RNA expression in prefrontal cortex from 224 European Americans and African Americans of the BrainCloud cohort. We then tested the 16 putative cis-expression quantitative trait loci (cis-eQTL) SNPs for association with heroin addiction in the Urban Health Study and two replication cohorts, totaling 16,729 European Americans, African Americans, and Australians of European ancestry.

      Results

      Four putative cis-eQTL SNPs were significantly associated with heroin addiction in the Urban Health Study (smallest p = 8.9 × 10−5): rs9478495, rs3778150, rs9384169, and rs562859. Rs3778150, located in OPRM1 intron 1, was significantly replicated (p = 6.3 × 10−5). Meta-analysis across all case-control cohorts resulted in p = 4.3 × 10−8: the rs3778150-C allele (frequency = 16%–19%) being associated with increased heroin addiction risk. Importantly, the functional SNP allele rs1799971-A was associated with heroin addiction only in the presence of rs3778150-C (p = 1.48 × 10−6 for rs1799971-A/rs3778150-C and p = .79 for rs1799971-A/rs3778150-T haplotypes). Lastly, replication was observed for six other intron 1 SNPs that had prior suggestive associations with heroin addiction (smallest p = 2.7 × 10−8 for rs3823010).

      Conclusions

      Our findings show that common OPRM1 intron 1 SNPs have replicable associations with heroin addiction. The haplotype structure of rs3778150 and nearby SNPs may underlie the inconsistent associations between rs1799971 and heroin addiction.

      Keywords

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      Linked Article

      • Mu Opioid Receptor Genetic Variation and Heroin Addiction
        Biological PsychiatryVol. 78Issue 7
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          The article by Hancock et al. (1) examines the functional significance of single nucleotide polymorphisms (SNPs) in the mu opioid receptor (OPRM1) gene as it pertains to associations with heroin addiction. In this work, cis-expression quantitative trait analyses in control, nonaddicted postmortem samples (BrainCloud participants) were employed to reduce an initial sample of 103 SNPs to 16 that were found to be associated with changes in messenger RNA expression and presented functional significance.
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