Clarke Toni-Kim, Weiss Amy R D, Ferarro Thomas N, Kampman Kyle M, Dackis Charles A, Pettinati Helen M, O'brien Charles P, Oslin David W, Lohoff Falk W, Berrettini Wade H
Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA.
Ann Hum Genet. 2014 Jan;78(1):33-9. doi: 10.1111/ahg.12046. Epub 2013 Nov 25.
The risk for drug addiction is partially heritable. Genes of the dopamine system are likely candidates to harbour risk variants, as dopamine neurotransmission is involved in mediating the rewarding effects of drugs of abuse. One functional single nucleotide polymorphism in dopamine receptor D2 (DRD2), rs1076560, is involved in regulating splicing of the gene and alters the ratio of DRD2 isoforms located pre- and postsynaptically. rs1076560 has been previously associated with cocaine abuse and we set out to confirm this association in a sample of European American (EA) (n = 336) and African American (AA) (n = 1034) cocaine addicts and EA (n = 656) and AA (n = 668) controls. We also analysed the role of rs1076560 in opioid dependence by genotyping EA (n = 1041) and AA (n = 284) opioid addicts. rs1076560 was found to be nominally associated with opioid dependence in EAs (p = 0.02, OR = 1.27) and AAs (p = 0.03, OR = 1.43). When both opioid-addicted ancestral samples were combined, rs1076560 was significantly associated with increased risk for drug dependence (p = 0.0038, OR = 1.29). This association remained significant after correction for multiple testing. No association was found with cocaine dependence. These data demonstrate the importance of dopamine gene variants in the risk for opioid dependence and highlight a functional polymorphism that warrants further study.
药物成瘾风险具有部分遗传性。多巴胺系统的基因很可能携带着风险变异,因为多巴胺神经传递参与介导滥用药物的奖赏效应。多巴胺受体D2(DRD2)中的一个功能性单核苷酸多态性rs1076560,参与调节该基因的剪接,并改变突触前和突触后DRD2亚型的比例。rs1076560先前已与可卡因滥用相关联,我们着手在一组欧美裔(EA)(n = 336)和非裔美国人(AA)(n = 1034)可卡因成瘾者以及EA(n = 656)和AA(n = 668)对照组中证实这种关联。我们还通过对EA(n = 1041)和AA(n = 284)阿片类成瘾者进行基因分型,分析了rs1076560在阿片类药物依赖中的作用。结果发现,rs1076560在欧美裔(p = 0.02,OR = 1.27)和非裔美国人(p = 0.03,OR = 1.43)中与阿片类药物依赖存在名义上的关联。当将两个阿片类成瘾的祖先样本合并时,rs1076560与药物依赖风险增加显著相关(p = 0.0038,OR = 1.29)。在进行多重检验校正后,这种关联仍然显著。未发现与可卡因依赖有关联。这些数据证明了多巴胺基因变异在阿片类药物依赖风险中的重要性,并突出了一个值得进一步研究的功能性多态性。