Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRM1.
Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRM1.
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DOI：
10.1016/j.biopsych.2015.01.003
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发表时间：
2015-10-01
影响因子：
10.6
通讯作者：
Johnson EO
中科院分区：
文献类型：
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作者：
Hancock DB;Levy JL;Gaddis NC;Glasheen C;Saccone NL;Page GP;Hulse GK;Wildenauer D;Kelty EA;Schwab SG;Degenhardt L;Martin NG;Montgomery GW;Attia J;Holliday EG;McEvoy M;Scott RJ;Bierut LJ;Nelson EC;Kral AH;Johnson EO
阿片受体mu 1（OPRM 1）基因多态性，包括功能性单核苷酸多态性（SNP）rs 1799971，与海洛因/其他阿片类药物成瘾无关，尽管它们具有生物学可接受性。我们利用多态性改变正常人脑组织中OPRM 1表达的证据来提名并测试与海洛因成瘾的关联。我们测试了来自BrainCloud队列的224名欧洲裔美国人和非洲裔美国人的103个OPRM 1 SNP与前额叶皮层中OPRM 1 mRNA表达的相关性。然后，我们在城市健康研究和两个复制队列中测试了16个假定的顺式数量性状基因座（cis-eQTL）SNP与海洛因成瘾的相关性，共16，729名欧洲血统的欧洲裔美国人，非洲裔美国人和澳大利亚人。在城市健康研究中，4个假定的顺式eQTL SNP与海洛因成瘾显著相关（最小P=8.9×10−5）：rs 9478495、rs3778150、rs 9384169和rs 562859。位于OPRM 1内含子1的Rs3778150显著复制（P=6.3×10−5）。对所有病例对照队列的荟萃分析得出P=4.3×10 - 8：rs3778150-C等位基因（频率=16%-19%）与海洛因成瘾风险增加相关。重要的是，功能性SNP等位基因rs 1799971-A仅在rs3778150-C存在时与海洛因成瘾相关（rs 1799971-A/rs3778150-C的P=1.48×10−6，rs 1799971-A/rs3778150-T单倍型的P=0.79）。最后，观察到其他6个内含子1 SNP的复制，这些SNP先前与海洛因成瘾有暗示性关联（rs3823010的最小P=2.7×10−8）。我们的研究结果表明，常见的OPRM 1内含子1 SNPs与海洛因成瘾有可复制的关联。rs3778150及其附近SNPs的单倍型结构可能是rs 1799971与海洛因成瘾之间不一致关联的基础。
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. We tested 103 OPRM1 SNPs for association with OPRM1 mRNA expression in prefrontal cortex from 224 European Americans and African Americans of the BrainCloud cohort. We then tested the 16 putative cis-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. 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=0.79 for rs1799971-A/rs3778150-T haplotypes). Lastly, replication was observed for six other intron 1 SNPs which had prior suggestive associations with heroin addiction (smallest P=2.7×10−8 for rs3823010). 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.