NON-DEPENDENT OPIOID MISUSERS AS GWAS CONTROLS

疾控中心最近的一份报告观察到，全美男性和女性的海洛因使用量都有所增加，包括 大多数年龄段和所有收入水平。目前的海洛因流行是在持续的处方阿片类药物之后发生的 滥用流行病帮助推动了海洛因使用的激增。研究以提高对世界经济的理解 因此，阿片类药物使用障碍(OUD)的病理生理学是公共卫生的当务之急。奥德是一种适度可遗传的 (40%-60%)精神障碍；然而，几乎没有重复的遗传学发现被确认。这样做的一个原因是 OUD相关性研究的确切对照样本尚未建立。以候选基因为基础 来自共病和创伤研究(CATS)的数据发现，注意到与OUD的关联结果各不相同 与对照组中的物质暴露基本一致，并与重复良好的研究结果一致 通过比较不依赖的、经常吸烟的人和依赖尼古丁的人，我们进行了一项 猫的全基因组关联研究将对照限制在阿片类药物滥用者身上。最强的 观察到的联合信号是Cornichon家族AMPA受体辅助蛋白3(CNIH3)SNPs。 在另外两个GWAS样本中进行的复制产生了全基因组显著(GWS)元- Rs10799590的分析p值为4.3E-9，这是最强关联的SNP。这些发现，再加上 这一修订后的应用程序中包含的试验性元分析的令人兴奋的结果证明了 与非OUD阿片类药物滥用者(即使是那些适度N的人)的样本进行比较，以识别小说 在与一般人口控制相比不会被检测到的基因座。当前应用程序 建议确定、评估和分型[非洲裔美国人(AA)N=1000和欧洲裔美国人 (EA=1000)阿片类药物滥用史有限但从未达到阿片类药物标准的个人 使用无序(即，非OUD误用者作为对照)。具有OUD(N=400 AA和N=400 EA)的个人也将 接受评估，进行基因分型，并与来自其他来源的OUD病例结合进行GWA。具体的 目标是：目标1)确定、全面评估并从1000个氨基酸和1000个EA中提取DNA 有有限阿片滥用史且从未达到阿片使用障碍标准的个人(OUD) 以及数量较少的具有OUD(400 AA和400 EA)OUD的个人-这是针对大规模 收集非OUD阿片类药物滥用者作为对照。目标2)进行大型分析：1)比较 目前的提案将AA和EA的非OUD阿片类药物滥用扩大到OUD病例的扩大群体，这些病例也 包括先前GWAS型样本，AA(N=2093)和EA(N=6154)；2)进一步扩展 病例和对照样本(AA总数：4366个非OUD病例；1699个非OUD误用对照；EA 总数：10,106个案例；2138个非OUD误用控制案例)。目标3)检查 最初使用阿片类药物和使用阶段的主观反应是否调节或缓和了这种关系 从超级分析到OUD的顶级SNPs之间。

A recent CDC report observed that heroin use has increased in men and women across the U.S., including most age groups and all income levels. The current heroin epidemic follows an ongoing prescription opioid misuse epidemic that has helped drive the spike in heroin use. Research to improve understanding of the pathophysiology of opioid use disorder (OUD) is thus a public health imperative. OUD is a moderately heritable (40-60%) disorder; however, few replicated genetic findings have been identified. One reason for this is that a definitive control sample for association studies of OUD has not been established. Building on candidate gene data findings from the Comorbidity and Trauma Study (CATS) that noted association results for OUD vary substantially with substance exposure in the comparison group, and consistent with well-replicated findings from comparisons of non-dependent, regular smokers to nicotine dependent individuals, we conducted a genome-wide association study (GWAS) in CATS limiting controls to opioid misusers. The strongest association signal observed was for cornichon family AMPA receptor auxiliary protein 3 (CNIH3) SNPs. Replication performed in two additional GWAS samples yielded a genome-wide significant (GWS) meta- analytic p value of 4.3 E-9 for rs10799590, the most strongly associated SNP. These findings, coupled with exciting results from a pilot meta-analysis included in this revised application demonstrate the utility of comparisons to samples of non-OUD opioid misusers (even those with modest N's) to identify novel loci that would not be detected in comparisons to general population controls. The current application proposes to ascertain, assess, and genotype groups [African American (AA) N=1000 and European American (EA) N=1000] of individuals with a limited history of opioid misuse who have never met criteria for an opioid use disorder (i.e., non-OUD misusers as controls). Individuals with OUD (N=400 AA and N=400 EA) will also be assessed, and genotyped and combined with OUD cases from other sources for a GWAS. The specific aims are: Aim 1) To ascertain, comprehensively assess, and obtain DNA from 1000 AA and 1000 EA individuals with a history of limited opioid misuse who have never met criteria for opioid use disorder (OUD) and smaller numbers of individuals with OUD (400 AA and 400 EA) OUD - the first effort targeting large-scale collection of non-OUD opioid misusers to serve as controls. Aim 2) To conduct mega-analyses: 1) comparing the current proposal's AA and EA non-OUD opioid misusers to expanded groups of OUD cases that also include previously GWAS-genotyped samples, AA (N=2093) and EA (N=6154); 2) with further expanded samples of both cases and controls (AA totals: 4366 OUD cases; 1699 non-OUD misuser controls; EA totals: 10,106 OUD cases; 2138 non-OUD misuser controls) from other sources. Aim 3) To examine whether subjective responses to initial opioid use and stages of use mediate or moderate the relationship between top SNPs from the mega-analysis and progression to OUD.