Gene-Environment Interaction for Cannabis Use Disorders in Blacks and Whites in the U.S.

 描述(申请人提供)：美国黑人和白人大麻使用障碍的基因-环境相互作用。40%-50%的美国成年人使用过大麻，三分之一的吸毒者至少经历过一种大麻使用障碍(CUD)症状，这增加了许多负面结果的风险，包括有问题的物质使用行为(SUB)。最近的数据显示，在非裔美国人(AA)中，CUD的患病率比美国其他所有群体增长得都快。基因-环境相互作用(GxE)研究可以开始解决美国亚病因学中的关键空白：(1)AAS中没有大规模的CUD遗传学研究，这造成了美国对CUD遗传病因学的理解差距。由于等位基因频率和连锁不平衡(LD)的进化差异，AAS具有比白人/欧洲美国人(EA)更大的遗传多样性。因此，比较AAs和EAs的遗传关联研究对于进一步了解AAs的一般情况和在美国是至关重要的。社会环境(创伤、宗教信仰)改变了Subs的遗传风险强度。然而，(2)还没有关于CUD的GxE研究。此外，很少有研究研究AA中SUB的GxE，也没有研究检验AA和EA之间的SUB的GxE效应是否不同，这可能是预期的，因为已知的AA/EA在血统、创伤和宗教暴露的比率和类型以及对SUB的影响方面的差异。(3)GxE对CUD的研究尚未采用结合已知生物学系统的多基因策略的新进展。到目前为止，只有两项关于任何亚组的研究在GxE的背景下使用了多基因策略，主要是因为很少有研究需要足够大的样本，以及对多基因分数不可翻译为特定遗传/神经生物学靶点的担忧。这些担忧通过基于路径的SET测试得到缓解，这种测试聚集了候选生物路径上的遗传变异，以更好地反映CUD的潜在结构。修订后的K01提案勾勒出了我成为一名独立调查员所需的培训，以进行跨学科研究，以确定心理社会因素通过哪些机制改变美国多样化人群中SUB患者的遗传和神经生物学风险。我的研究将在一个具有美国全国代表性的新样本NESARC-III(n=36,309；20%：7,262 AA)中检查创伤和/或宗教信仰是否会改变AA和EA中CUD的遗传风险，其中包括大麻使用频率的基因数据和维度测量，以及DSM-IV和5 CUD。高级培训的三个方面将使我能够实现这些目标：(1)SUB的表型测量，(2)成瘾神经科学，(3)创伤和复原力。建议的活动是雄心勃勃的，但也是可行的，考虑到我的生产力记录，哥伦比亚大学跨学科专家团队(Hasin(主要导师)，Martinez，Koenen)的指导，CUD遗传学的Agrawal博士和Fullilove博士负责任地介绍种族遗传差异，以及K01研究和培训以及R01开发的保护时间(5年)。

 DESCRIPTION (provided by applicant): Gene-Environment Interaction for Cannabis Use Disorders in Blacks and Whites in the US. 40-50% of US adults have used cannabis, and ~1/3 of users experience at least one cannabis use disorder (CUD) symptom which increases risk for many negative outcomes, including problematic substance use behaviors (SUB). Recent data has shown that the prevalence of CUD is growing faster among African- Americans (AA) than all other groups in the US. There are critical gaps in US SUB etiology that gene- environment interaction (GxE) research can begin to address: (1) There are no large-scale genetic studies of CUD in AAs, creating a gap in understanding the genetic etiology of CUD in the US. AAs have greater genetic diversity than Whites/European Americans (EA) due to evolutionary differences in allele frequencies and linkage disequilibrium (LD). Thus, genetic association studies comparing AAs and EAs are critically needed to further understanding in AAs generally, and in the US. Social context (trauma, religiosity) modifies the strength of genetic risk for SUB. However, (2) there are no GxE studies of CUD. Moreover, few studies examine GxE of SUB in AAs, and no study has examined if GxE effects of SUB differ between AAs and EAs, which might be expected due to known AA/EA differences in ancestry, rates and types of exposure to trauma and religiosity, and impact on SUB. (3) GxE research on CUD has yet to employ new developments in polygenic strategies that incorporate known biological systems. To date, only two studies of any SUB used polygenic strategies in the context of GxE, mainly because few studies have sufficiently large samples needed, and concerns about the non-translatability of polygenic scores into specific genetic/neurobiological targets. These concerns are mitigated with pathway-based set tests, which aggregate genetic variants across candidate biological pathways to better reflect the underlying structure of CUD. The revised K01 proposal delineates the training required for me to become an independent investigator conducting interdisciplinary research that identifies the mechanisms via which psychosocial factors modify genetic and neurobiological risk for SUB in the diverse US population. My research will examine if trauma and/or religiosity modifies genetic risk for CUD in both AAs and EAs in a new US nationally representative sample, the NESARC-III (n=36,309; 20%:7,262 AA), which includes genotypic data and dimensional measures of cannabis use frequency, and DSM-IV and 5 CUD. Three areas of advanced training will enable me to carry out these goals: (1) Phenotypic Measurement of SUB, (2) Addictions Neuroscience, and (3) Trauma and Resilience. The proposed activities are ambitious, but feasible, given my record of productivity, mentorship by an interdisciplinary team of experts (Hasin (primary mentor), Martinez, Koenen) at Columbia University, consultation with Dr. Agrawal in CUD Genetics and Dr. Fullilove in the Responsible Presentation of Genetic Differences by Race, and K01 protected time (5 yrs) for research and training, and the development of an R01.