Evidence of CNIH3 involvement in opioid dependence.
Evidence of CNIH3 involvement in opioid dependence.
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DOI：
10.1038/mp.2015.102
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发表时间：
2016-05
影响因子：
11
通讯作者：
Montgomery GW
中科院分区：
文献类型：
--
作者：
Nelson EC;Agrawal A;Heath AC;Bogdan R;Sherva R;Zhang B;Al-Hasani R;Bruchas MR;Chou YL;Demers CH;Carey CE;Conley ED;Fakira AK;Farrer LA;Goate A;Gordon S;Henders AK;Hesselbrock V;Kapoor M;Lynskey MT;Madden PA;Moron JA;Rice JP;Saccone NL;Schwab SG;Shand FL;Todorov AA;Wallace L;Wang T;Wray NR;Zhou X;Degenhardt L;Martin NG;Hariri AR;Kranzler HR;Gelernter J;Bierut LJ;Clark DJ;Montgomery GW
阿片类药物依赖是一种严重的成瘾性疾病和主要的社会问题，已被证明具有中度遗传性。我们在Comorrhage和创伤研究数据中进行了一项全基因组关联研究，比较了阿片类药物依赖性每日注射者（N=1167）与从未进展至每日注射的阿片类药物滥用者（N=161）。CNIH 3 SNPs观察到的最强关联在两个独立样本中得到证实，即耶鲁-宾夕法尼亚大学阿片类药物，可卡因和酒精依赖的遗传研究和成瘾研究：遗传学和环境，其中都包含非依赖性阿片类药物滥用者和阿片类药物依赖者。Meta分析发现5个全基因组显著的CNIH 3 SNP。rs 10799590的A等位基因是最高度相关的SNP，具有强保护性[p=4.30E-9; OR 0.64（95%CI 0.55 - 0.74）]。表观遗传学注释预测该SNP在胎儿脑中是功能性的。来自杜克神经遗传学研究（N=312）的神经影像学数据提供了该SNP体内功能的证据; rs 10799590 A等位基因携带者显示出显著更大的右杏仁核对威胁相关面部表情的习惯性，这是一种与精神病理学恢复力相关的表型。计算遗传分析的身体依赖吗啡在23个小鼠品系产生显着的相关性单倍型CNIH 3和功能相关基因。这些一致的发现支持CNIH 3参与阿片类药物依赖的病理生理学，补充了涉及AMPA谷氨酸系统的先前研究。
Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 SNPs, were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine, and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid dependent individuals. Meta-analyses found 5 genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective [p=4.30E-9; OR 0.64 (95%CI 0.55 – 0.74)]. Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP’s in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally-related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence complementing prior studies implicating the AMPA glutamate system.