Genetic architecture of alcohol misuse candidate endophenotypes

描述（由申请人提供）：“酒精滥用候选内在表型的遗传结构”研究领域该申请解决了广泛的挑战领域03）生物标志物发现和验证;具体挑战主题03-AA-101，酒精使用障碍中间表型标志物的鉴定。本研究的策略是探索一种基于fMRI的新型推定内表型的遗传基础，用于大学生高风险饮酒，通过扩大现有的两个资助NIAAA赠款中收集的数据的类型和数量，以产生450个个体的样本，足以进行全基因组关联研究（GWAS）。大学生的功能失调性饮酒不仅显著增加了他们在大学期间遇到酒精相关问题的几率，而且也是十年后酒精滥用和依赖的重要风险因素。然而，缺乏针对个人而不是群体的风险标记。在目前的一项提案中，每年评估的750名大学生中有130人接受结构和功能磁共振成像。目前的提案每年增加140名学生，为期两年，完成一个简短的成像协议，包括在货币激励延迟任务（MIDT）期间的结构序列和功能磁共振成像，该任务测量大脑对奖励的反应，我们已经显示其激活模式与酗酒风险相关。我们还将获得所有接受成像的受试者的听觉奇球P300事件相关电位评估，并从中获得事件相关振荡（ERO）措施，以检查最近发表的第二种酒精内表型。目前收集所有受试者的问卷调查和实验室为基础的冲动性措施，我们已经确定，这些属于5个因素域，其中两个显着相关的MIDT功能磁共振成像激活模式。最后，将为所有研究受试者增加GWAS的DNA采集和基因分型。我们将通过选择30%的父亲和至少1名其他近亲有酒精滥用阳性家族史的受试者来丰富酒精使用障碍高风险个体的样本。先前被证明可以预测晚年有害饮酒的高风险饮酒模式将基于几个元素进行量化，这些元素来自受试者在安全网站上现有的每月饮酒行为自我报告的6个月数据。这些包括目前收集的饮酒量和频率的测量，加上对酒精反应的自我报告，酒精相关的不良后果和大学成绩的客观测量。内表型将从MIDT和ERO测量期间BOLD激活的最佳组合导出。将使用fMRI和SNP数据的并行独立成分分析来提取纯粹基于结合高阶统计的分析的fMRI成分和SNP关联的模式之间的关系。该方法允许更广泛的关联基因型与表型比传统的假设驱动的单变量相关分析。此外，还将使用需要更多受试者数量的传统方法。因此，所提出的研究的主要目标是描述两种酒精使用障碍候选人内表型的遗传结构，一种是基于功能磁共振成像货币激励延迟任务的异常反应，一种是基于ERO措施的已知方法，将这两种措施相互比较，并验证它们对功能失调的酒精使用的纵向措施。为什么挑战奖助金机制是拟议研究的理想选择？1.我们的目标是使用创新的方法来确定候选的中间表型标记物（内表型）的酗酒，是适合随后的验证工作相匹配的目标，这RFA，并代表了该领域的一个新方向。目前还没有可靠的酒精中毒生物标志物，因此，对这种可以预测疾病风险的中间表型的研究具有很大的影响。2.一个为期两年的赠款奖励是理想的拟议工作。我们可以将拟议研究的受试者招募基于一个正在进行的大规模NIAAA资助的研究项目，该项目已经确定了受试者，并为另一个目的详细描述了他们的特征，使我们能够识别合适的个人并获得相关的纵向信息，而不必建立新的基础设施。我们已经组建了一个具有独特专业知识的研究人员团队，并在过去的有效合作中保持了良好的记录，以进行这些研究。3.我们计划雇用和培训包括博士后学生在内的新人员，并利用美国公司（如Illumina Inc.）的独特全基因组技术。这将带来刺激经济的额外好处。这项挑战资助申请的目标是确定一种新的功能性基于MRI的酒精滥用的内表型，这些受试者是从一项正在进行的大规模大学生饮酒研究中选择的，将其与现有的基于电生理学的内表型进行比较，并使用全基因组关联研究设计确定这些内表型的遗传基础。识别这些生物标志物不仅会增加我们对酒精滥用的病理生理学的了解，更重要的是识别出这种疾病的高风险个体。

DESCRIPTION (provided by applicant): "Genetic architecture of alcohol misuse candidate endophenotypes" Research Area This application addresses broad Challenge Area 03) Biomarker Discovery and Validation; specific Challenge Topic 03-AA-101,Identification of Intermediate Phenotypic Markers of Alcohol Use Disorders. The strategy of this study to explore the genetic underpinnings of a novel fMRI-based putative endophenotype for high-risk drinking in college students, by expanding the type and amount of data being collected in two existing, funded NIAAA grants, to yield a sample of 450 individuals, sufficiently powered to perform a genome-wide association study (GWAS). Dysfunctional drinking in college students significantly raises the odds for their experiencing not only alcohol-related problems in college but is also a significant risk factor for alcohol abuse and dependence a decade later. Risk markers for individuals rather than populations are lacking however. In one of the current proposals, 130 of 750 total college students assessed per year undergo structural and fMRI imaging. The current proposal has an additional 140 students per year for two years, complete an abbreviated imaging protocol, consisting of a structural sequence and fMRI during a Monetary Incentive Delay Task (MIDT) that measures the brain's response to reward and whose activation patterns we have shown are associated with alcoholism risk. We will also obtain an auditory oddball P300 event related potential assessment in all subjects undergoing imaging and derive event-related oscillation (ERO) measures from this to examine a recently published second alcohol endophenotype. Both questionnaire- and laboratory-based impulsivity measures are currently collected on all subjects; we have determined that these fall into 5 factor domains, two of which are significantly correlated with the MIDT fMRI activation patterns. Finally, DNA collection and genotyping for GWAS will be added for all study subjects. We will enrich the sample for individuals at higher risk for alcohol use disorders by choosing 30% of our subjects with a positive family history of alcohol abuse in father and at least 1 other close relative. High-risk drinking patterns, previously shown to predict later- life harmful drinking will be quantified based on several elements, derived from 6-month data on subjects' existing monthly self-reports of drinking behavior on a secure website. These include currently collected measures of quantity and frequency of drinking, plus self- reports of response to alcohol, adverse alcohol-related consequences and objective measures of college grades. Endophenotypes will be derived from the best combination of BOLD activation during the MIDT and ERO measures. Parallel independent component analysis of the fMRI and SNP data will be used to extract relations between patterns of fMRI components and SNP associations purely based on an analysis incorporating higher order statistics. The method allows for broader associations of genotypes with phenotypes than traditional hypothesis-driven univariate correlational analyses. Traditional methods requiring greater subject numbers will be used in addition. Thus, the major goal of the proposed research is to characterize the genetic architecture of two alcohol use disorder candidate endophenotypes, one novel based on abnormal responses on an fMRI monetary incentive delay task, one known and based on ERO measures, to compare these two measures to each other and to validate them against ongoing longitudinal measures the dysfunctional alcohol use. Why is a Challenge grant mechanism ideal for the proposed research? 1. Our goal of using innovative approaches to identify candidate intermediate phenotypic markers (endophenotypes) for alcoholism that are suitable for subsequent validation efforts matches the goals of this RFA and represents a new direction in the field. There are currently no reliable biomarkers for alcoholism so that the proposed search for such intermediate phenotypes that can predict disease risk is of high impact. 2. A two-year grant award is ideal for the proposed work. We can base subject recruitment for the proposed study on an ongoing large-scale NIAAA-funded research project that is already identifying subjects and characterizing them in detail for another purpose, in a manner that allows us to identify suitable individuals and obtain relevant longitudinal information, without having to build a new infrastructure to do so. We have assembled a team of investigators with unique expertise and an excellent record of effective past collaborations to pursue these studies. 3. We plan to hire and train new personnel including postdoctoral students and to employ unique genome- wide technology using US-based companies such as Illumina Inc. that will have the added benefit of stimulating the economy. The goal of this Challenge grant application is to identify a novel functional MRI-based endophenotype of alcohol misuse in subjects who are chosen from a large ongoing study of drinking in college students, to compare it with an existing electrophysiologically-based endophenotype and to determine the genetic underpinnings of these endophenotypes using a genome wide association study design. The identification of such biological markers will not only increase our knowledge of the pathophysiology of alcohol misuse, but more importantly identify individuals at high risk for the disorder.