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

美国黑人和白人大麻使用障碍的基因与环境相互作用

• 批准号: 9093722
• 负责人: Jacquelyn Leigh Meyers
• 金额: $ 11.65万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9093722
• 关键词: Accounting; Address; Adult; African American; Alcohol or Other Drugs use; Alcohols; American; Area; Automobile Driving; Behavior; Biological; Cannabinoids; Cannabis; Consultations; DSM-IV; Data; Dependence; Development; Dopamine; Environmental Exposure; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Ethnic group; Etiology; European; Event; Exposure to; Frequencies; Gene Frequency; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Genotype; Geographic state; Glycine; Goals; Health; Heterogeneity; Interdisciplinary Study; Lead; Life; Linkage Disequilibrium; Measurement; Measures; Medical; Mentors; Mentorship; Modification; N-Methylaspartate; National Institute of Drug Abuse; Neurobiology; Neurosciences; Outcome; Pathway interactions; Pattern; Periodontal Diseases; Phenotype; Policies; Population; Prevalence; Preventive Intervention; Productivity; Psychology; Psychosocial Factor; Psychotic Disorders; Reporting; Research; Research Personnel; Research Training; Risk; Role; Sampling; Social Environment; Stress and Coping; Structure; Surveys; Symptoms; System; Testing; Time; Training; Trauma; Universities; addiction; base; biological systems; experience; gamma-Aminobutyric Acid; gene environment interaction; genetic association; genetic variant; illicit drug use; marijuana use; marijuana use disorder; marijuana user; meetings; neuropsychological; psychologic; racial and ethnic; racial difference; racial diversity; resilience; response; social; traumatic event

 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.

 描述（由申请人提供）：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，约1/3的使用者经历过至少一种大麻使用障碍（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（CUP）。最近的数据显示，CUD的患病率在非裔美国人（AA）中的增长速度比美国所有其他群体都快。基因-环境相互作用（GxE）研究可以开始解决美国CUD病因学中存在的关键空白：（1）在AA中没有大规模的CUD遗传学研究，在理解美国CUD遗传病因学方面存在空白。由于等位基因频率和连锁不平衡（LD）的进化差异，AA比白人/欧洲裔美国人（EA）具有更大的遗传多样性。因此，遗传关联研究比较AA和EA是非常必要的，以进一步了解一般的AA，在美国。社会背景（创伤，宗教信仰）改变了遗传风险的强度。然而，（2）没有关于CUD的GxE研究。此外，很少有研究检查AAs中的GxE，也没有研究检查AAs和EA之间的GxE效应是否不同，这可能是由于已知的AA/EA在血统、创伤和宗教信仰暴露率和类型以及对GxE的影响方面的差异。(3)关于CUD的GxE研究尚未采用结合已知生物系统的多基因策略的新进展。到目前为止，只有两项研究的任何一个使用多基因策略的背景下，GxE，主要是因为很少有研究有足够大的样本需要，并关注多基因评分到特定的遗传/神经生物学目标的不可翻译性。这些担忧通过基于通路的集合测试得到缓解，该测试聚集了候选生物通路中的遗传变异，以更好地反映CUD的潜在结构。修订后的K 01提案描述了我成为一名独立调查员所需的培训，该调查员进行跨学科研究，确定了心理社会因素在不同美国人群中修改遗传和神经生物学风险的机制。我的研究将检查创伤和/或宗教信仰是否会改变新的美国全国代表性样本中AA和EA的CUD遗传风险，NESARC-III（n= 36，309; 20%：7，262 AA），其中包括大麻使用频率的基因型数据和维度测量，以及DSM-IV和5 CUD。三个领域的高级培训将使我能够实现这些目标：（1）成瘾的表型测量，（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，但可行的，考虑到我的生产力记录，在哥伦比亚大学的跨学科专家团队（Hasin（主要导师），Martinez，Koenen）的指导下，与Agrawal博士在CUD遗传学和Fullilove博士在种族遗传差异的负责任介绍中进行磋商，以及K 01保护时间（5年）用于研究和培训，以及R 01的开发。