Big data analytics for the evaluation of whole genome sequence and transcriptome data in alcohol research

项目摘要/摘要 美国的大规模流行病学研究表明，酒精使用障碍非常普遍， 与其他精神疾病高度并存，致残，而且经常得不到治疗。与美国其他国家相比 美国原住民的酒精和其他药物依赖率是最高的，而且是 与特别严重的残疾和死亡有关。因此，识别特定遗传风险的研究 在美国普通人群中，尤其是在美洲原住民中，酒精使用障碍的因素很高 公共卫生的重要性。酒精使用障碍是一种对环境敏感的复杂遗传性疾病 需要复杂的数据策略才能发现潜在风险因素的条件。虽然最近几年 在我们对疾病的生物学和遗传学的理解上取得了重大进展，确切地说 目前尚不清楚这些因素如何在个体中相互作用，从而增加酒精使用障碍的风险或保护其免受酒精使用障碍的影响。 此外，到目前为止，通过常规方法在人类基因组中识别的遗传因素似乎只有 解释这些疾病总体遗传性的一小部分。 这项研究计划的总体目标是确定复杂的遗传和基因组因素， 通过新颖和创新影响对酒精使用障碍和相关并发症的易感性 量化方法和大数据分析。拟议的研究将利用全基因组序列(WGS) 来自独特的高危美洲原住民和欧洲美国人群体的数据以及基因 酒精中毒人脑的表达数据。该项目将开发分析WGS数据的方法 与酒精研究具有独特的相关性。选定的多元、图形和降维建模工具 将与适用于群体和家庭的基因组数据的混合模型结合使用 剖析酒精使用障碍的多基因基础和酒精使用的共同遗传风险因素的结构 障碍和共病障碍。将使用混合模型和聚类方法来揭示 异质性遗传影响。将测试不同异质性水平上的差异遗传效应。 用严格的统计方法。该项目将确定特定于人群和祖先的遗传风险因素。 和共同的危险因素，并确定它们对易感性的不同影响 酒精使用障碍。还将调查内表型，以帮助确定酒精的独特危险因素 使用障碍特征。该项目将进一步确定与酒精和成瘾相关的途径和网络， 在酒精中毒的大脑中差异表达，并通过结合基因来确定原因的方向 使用WGS数据表达数据，并应用工具变量方法。最后，一个完整的系统 将采取进一步利用公共领域中的表观基因组图和注释数据库的办法 建立预测性和潜在的因果模型，旨在更“个性化”地预防和干预 酒精使用障碍在特定的高危群体和个人。

PROJECT SUMMARY/ABSTRACT Large-scale U.S. epidemiological studies demonstrate that alcohol use disorders are highly prevalent, highly co-morbid with other psychiatric disorders, disabling, and often go untreated. Compared with other U.S. ethnic groups, Native Americans have the highest rates of alcohol and other drug dependence, and it is associated with particularly significant disability and mortality. Thus studies that identify specific genetic risk factors for alcohol use disorders in the general U.S. population, and especially in Native Americans, are of high public health importance. Alcohol use disorders are complex genetic diseases sensitive to environmental conditions that require complex data strategies to uncover the underlying risk factors. Although recent years have seen significant advancement in our understanding in the biology and genetics of the disorders, exactly how these factors interact in an individual to confer risk or protection from alcohol use disorders is still unclear. Further, the genetic factors identified in the human genome thus far by conventional methods appear to only explain a very small fraction of the overall heritability for the disorders. The overall objective of this research program is to identify the complex genetic and genomic factors that affect susceptibility to alcohol use disorders and related comorbidities through novel and innovative quantitative methods and big data analytics. The proposed study will utilize whole-genome sequence (WGS) data from a unique high-risk Native American population and a European American population along with gene expression data of alcoholic human brains. The project will develop methodology to analyze WGS data with unique relevance to alcohol research. Selected multivariate, graphical, and dimension-reduction modeling tools will be used in combination with mixed models suitable for genomic data with both population and family structures to dissect polygenic basis for alcohol use disorders and shared genetic risk factors for alcohol use disorders and comorbid disorders. Mixture models and clustering methods will be employed to uncover heterogeneous genetic influences. Differential genetic effects at various levels of heterogeneity will be tested with rigorous statistical methods. The project will identify population and ancestry-specific genetic risk factors and shared risk factors across populations and determine their differential influences on susceptibility to alcohol use disorders. Endophenotypes will also be investigated to help identify unique risk factors for alcohol use disorder traits. The project will further identify alcohol- and addiction-relevant pathways and networks that are differentially expressed in alcoholic brains, and establish directions of causations by combining gene expression data with WGS data, and applying instrumental variable approaches. Finally, an integrated system approach will be taken by further leveraging epigenomic maps and annotation databases in the public domain to build predictive and potentially causal models aimed at more “personalized” prevention and intervention for alcohol use disorders in specific high-risk groups and individuals.