Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
Biol Psychiatry. 2011 Sep 15;70(6):519-27. doi: 10.1016/j.biopsych.2011.02.023. Epub 2011 Apr 22.
The liability to addiction has been shown to be highly genetically correlated across drug classes, suggesting nondrug-specific mechanisms.
In 757 subjects, we performed association analysis between 1536 single nucleotide polymorphisms (SNPs) in 106 candidate genes and a drug use disorder diagnosis (DUD).
Associations (p ≤ .0008) were detected with three SNPs in the arginine vasopressin 1A receptor gene, AVPR1A, with a gene-wise p value of 3 × 10(-5). Bioinformatic evidence points to a role for rs11174811 (microRNA binding site disruption) in AVPR1A function. Based on literature implicating AVPR1A in social bonding, we tested spousal satisfaction as a mediator of the association of rs11174811 with the DUD. Spousal satisfaction was significantly associated with DUD in males (p < .0001). The functional AVPR1A SNP, rs11174811, was associated with spousal satisfaction in males (p = .007). Spousal satisfaction was a significant mediator of the relationship between rs11174811 and DUD. We also present replication of the association in males between rs11174811 and substance use in one clinically ascertained (n = 1399) and one epidemiologic sample (n = 2231). The direction of the association is consistent across the clinically-ascertained samples but reversed in the epidemiologic sample. Lastly, we found a significant impact of rs11174811 genotype on AVPR1A expression in a postmortem brain sample.
The findings of this study call for expansion of research into the role of the arginine vasopressin and other neuropeptide system variation in DUD liability.
不同类药物的成瘾性具有高度的遗传相关性，这表明存在非药物特异性机制。
在 757 名受试者中，我们对 106 个候选基因中的 1536 个单核苷酸多态性（SNP）与药物使用障碍诊断（DUD）之间进行了关联分析。
在精氨酸加压素 1A 受体基因（AVPR1A）中发现了三个与 SNP 相关联（p≤0.0008），基因总 p 值为 3×10（-5）。生物信息学证据表明 rs11174811（微 RNA 结合位点破坏）在 AVPR1A 功能中起作用。根据文献表明 AVPR1A 在社交联系中的作用，我们测试了配偶满意度作为 rs11174811 与 DUD 关联的中介。配偶满意度与男性 DUD 显著相关（p<0.0001）。功能性 AVPR1A SNP rs11174811 与男性配偶满意度相关（p=0.007）。配偶满意度是 rs11174811 与 DUD 之间关系的重要中介。我们还在两个临床确定的（n=1399）和一个流行病学样本（n=2231）中复制了 rs11174811 与男性物质使用之间的关联。关联的方向在临床确定的样本中是一致的，但在流行病学样本中是相反的。最后，我们发现 rs11174811 基因型对死后大脑样本中 AVPR1A 表达有显著影响。
本研究的发现呼吁扩大研究精氨酸加压素和其他神经肽系统变异在 DUD 易感性中的作用。
