BACKGROUND Opioid dependence (OD) is at epidemic levels in the United States. Genetic studies can provide insight into its biology. METHODS We completed an OD genome-wide association study in 3058 opioid-exposed European Americans, 1290 of whom met criteria for a DSM-IV diagnosis of OD. Analysis used DSM-IV criterion count. RESULTS By meta-analysis of four cohorts, Yale-Penn 1 (n = 1388), Yale-Penn 2 (n = 996), Yale-Penn 3 (n = 98), and SAGE (Study of Addiction: Genetics and Environment) (n = 576), we identified a variant on chromosome 15, rs12442183, near RGMA, associated with OD (p = 1.3 × 10-8). The association was also genome-wide significant in Yale-Penn 1 taken individually and nominally significant in two of the other three samples. The finding was further supported in a meta-analysis of all available opioid-exposed African Americans (n = 2014 [1106 meeting DSM-IV OD criteria]; p = 3.0 × 10-3) from three cohorts; there was nominal significance in two of these samples. Thus, of seven subsamples examined in two populations, one was genome-wide significant, and four of six were nominally (or nearly) significant. RGMA encodes repulsive guidance molecule A, which is a central nervous system axon guidance protein. Risk allele rs12442183*T was correlated with higher expression of a specific RGMA transcript variant in frontal cortex (p = 2 × 10-3). After chronic morphine injection, the homologous mouse gene (Rgma) was upregulated in C57BL/6J striatum. Coexpression analysis of 1301 brain samples revealed that RGMA messenger RNA expression was associated with that of four genes implicated in other psychiatric disorders, including GRIN1. CONCLUSIONS This is the first study to demonstrate an association of RGMA with OD. It provides a new lead into our understanding of OD pathophysiology.

中文翻译：

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全基因组关联研究确定了与欧裔美国人阿片类药物依赖相关的 RGMA 调节变体

背景 阿片类药物依赖 (OD) 在美国处于流行水平。遗传研究可以深入了解其生物学。方法 我们在 3058 名暴露于阿片类药物的欧洲裔美国人中完成了 OD 全基因组关联研究，其中 1290 人符合 DSM-IV 诊断 OD 的标准。分析使用 DSM-IV 标准计数。结果 通过对四个队列的荟萃分析，耶鲁大学 1 (n = 1388)、耶鲁大学 2 (n = 996)、耶鲁大学 3 (n = 98) 和 SAGE（成瘾研究：遗传学和环境） （n = 576），我们在 15 号染色体上发现了一个变异，rs12442183，靠近 RGMA，与 OD 相关（p = 1.3 × 10-8）。这种关联在 Yale-Penn 1 中也具有全基因组显着性，并且在其他三个样本中的两个中分别具有显着性和名义上的显着性。对来自三个队列的所有可用的阿片类药物暴露的非裔美国人（n = 2014 [1106 名符合 DSM-IV OD 标准]；p = 3.0 × 10-3）的荟萃分析进一步支持了这一发现；其中两个样本具有名义意义。因此，在两个群体中检查的七个子样本中，一个是全基因组显着的，六个中有四个是名义上（或几乎）显着的。RGMA 编码排斥导向分子 A，它是一种中枢神经系统轴突导向蛋白。风险等位基因 rs12442183*T 与额叶皮层中特定 RGMA 转录变体的更高表达相关 (p = 2 × 10-3)。慢性吗啡注射后，同源小鼠基因 (Rgma) 在 C57BL/6J 纹状体中上调。对 1301 个大脑样本的共表达分析表明，RGMA 信使 RNA 表达与涉及其他精神疾病（包括 GRIN1）的四个基因的表达相关。结论 这是第一个证明 RGMA 与 OD 关联的研究。它为我们对 OD 病理生理学的理解提供了新的线索。