Genetic architecture of alcohol misuse candidate endophenotypes

描述（由申请人提供）：“酒精滥用候选内表型的遗传结构”研究领域本申请涉及广泛的挑战领域03)生物标志物的发现和验证；专题03-AA-101，酒精使用障碍中间表型标记的鉴定。本研究的策略是通过扩大在两个现有的NIAAA资助项目中收集的数据的类型和数量，探索一种新型的基于fmri的假定的大学生高危饮酒内表型的遗传基础，以产生450个个体的样本，足以进行全基因组关联研究（GWAS）。大学生的不正常饮酒不仅会大大增加他们在大学期间经历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，缺乏针对个人而非群体的风险标记。在目前的一项建议中，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。目前的方案是每年增加140名学生，为期两年，完成一个简短的成像方案，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（fMRI），测量大脑对奖励的反应，其激活模式我们已经表明与酗酒风险相关。我们还将对所有接受影像学检查的受试者进行听觉异常P300事件相关电位评估，并由此得出事件相关振荡（ERO）测量，以检验最近发表的第二种酒精内表型。目前收集了所有受试者的问卷调查和基于实验室的冲动测量；我们已经确定这些归为5个因子域，其中两个与MIDT fMRI激活模式显著相关。最后，将对所有研究对象进行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家族史的受试者来丰富酒精使用障碍高风险个体的样本。高风险的饮酒模式，先前被证明可以预测以后的有害饮酒，将根据几个因素进行量化，这些因素来自于一个安全网站上6个月的数据，这些数据来自于受试者现有的每月饮酒行为自我报告。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。在MIDT和ERO测量期间，BOLD激活的最佳组合将衍生出内表型。fMRI和SNP数据的并行独立成分分析将用于提取fMRI成分模式和SNP关联之间的关系，这纯粹是基于结合高阶统计量的分析。与传统的假设驱动的单变量相关分析相比，该方法允许更广泛的基因型与表型的关联。此外，还将使用传统的方法，需要更大的受试者编号。因此，本研究的主要目标是表征两种酒精使用障碍候选内表型的遗传结构，一种是基于fMRI货币激励延迟任务的异常反应，一种是已知的基于ERO测量，将这两种测量相互比较，并通过正在进行的功能失调酒精使用的纵向测量来验证它们。为什么挑战资助机制是理想的提议的研究？1. 我们的目标是使用创新的方法来确定适合后续验证工作的候选酒精中毒中间表型标记（内表型），这与本RFA的目标相匹配，并代表了该领域的新方向。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高的影响。2. 两年的资助奖是理想的提议的工作。我们可以根据niaaa资助的一项正在进行的大规模研究项目招募受试者，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，这样我们就可以确定合适的个体并获得相关的纵向信息，而无需建立新的基础设施来这样做。我们已经组建了一个具有独特专业知识和过去有效合作的优秀记录的调查小组来进行这些研究。3. 我们计划雇用和培训包括博士后在内的新人员，并利用Illumina Inc.等美国公司采用独特的全基因组技术，这将对刺激经济产生额外的好处。这项挑战拨款申请的目标是在一项正在进行的大学生饮酒大型研究中选择受试者，确定一种新的基于功能mri的酒精滥用内表型，将其与现有的基于电生理的内表型进行比较，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。这种生物标记的识别不仅会增加我们对酒精滥用病理生理学的了解，而且更重要的是识别出患有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.