Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRM1.
- Authors
- Hancock, Dana B; Levy, Joshua L; Gaddis, Nathan C; Glasheen, Cristie; Saccone, Nancy L; Page, Grier P; Hulse, Gary K; Wildenauer, Dieter; Kelty, Erin A; Schwab, Sibylle G; Degenhardt, Louisa; Martin, Nicholas G; Montgomery, Grant W; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Bierut, Laura J; Nelson, Elliot C; Kral, Alex H; Johnson, Eric O
- Year
- 2015
- Journal
- Biological psychiatry
- PMID
- 25744370
- DOI
- 10.1016/j.biopsych.2015.01.003
- PMCID
- PMC4519434
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.
Overview of study design.
LLM interpretation
This figure is a flow diagram illustrating the study design for identifying SNP associations with heroin addiction. The process begins with cis-eQTL mapping of 103 SNPs in the *OPRM1* gene region, followed by association testing of 16 SNPs in the Urban Health Study (N=10,757) and replicability testing of 4 SNPs across two independent cohorts (N=5,972). The diagram specifies statistical thresholds for each stage, including p-values of <0.05, <0.005, and <0.0125.
Forest plot of association results for the rs3778150-C allele. Results are shown across all heroin addiction case-control cohorts (Urban Health Study [UHS], CIDR – Gelernter Study, and Australian Heroin Dependence Study) and ancestry groups (European Americans, African Americans, Australians of European ancestry).
LLM interpretation
This forest plot displays the association between the rs3778150-C allele and heroin addiction across four groups: European Americans (UHS), African Americans (UHS), African Americans (CIDR-Gelernter), and Australians (Australian Heroin Dep.). The x-axis represents the Odds Ratio, with most groups showing an increased risk (OR > 1.0), though the CIDR-Gelernter cohort has a wider confidence interval crossing the null line. A meta-analysis p-value of $4.3 \times 10^{-8}$ is indicated at the top of the figure.
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