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

项目总结/摘要 美国大规模的流行病学研究表明，酒精使用障碍非常普遍， 与其他精神疾病高度共病，致残，往往得不到治疗。与其他美国 美国原住民的酒精和其他药物依赖率最高， 与特别严重的残疾和死亡率相关。因此，确定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。酒精使用障碍是对环境敏感的复杂遗传疾病 需要复杂的数据策略来揭示潜在风险因素的情况。虽然近年来 我们在对疾病的生物学和遗传学的理解上取得了重大进展， 这些因素如何在个体中相互作用以赋予酒精使用障碍的风险或保护仍然不清楚。 此外，迄今为止通过常规方法在人类基因组中鉴定的遗传因子似乎仅 这只解释了疾病总体遗传率的一小部分。 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， 通过新颖和创新的方法， 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） 来自一个独特的高风险美洲原住民群体和一个欧洲裔美国人群体的数据， 酗酒者大脑的表达数据。该项目将开发分析WGS数据的方法， 与酒精研究有着独特的关联选定的多变量、图形和降维建模工具 将与适用于群体和家系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 疾病和共病疾病。混合模型和聚类方法将被用来揭示 异质遗传影响。将测试不同异质性水平下的差异遗传效应 严格的统计方法。该项目将确定特定人群和祖先的遗传风险因素 和共享的风险因素，并确定其对易感性的差异影响， 酒精使用障碍还将调查内表型，以帮助确定酒精的独特风险因素 使用紊乱的特征。该项目将进一步确定与酒精和成瘾有关的途径和网络， 在酒精中毒的大脑中差异表达，并通过结合基因来建立因果关系的方向。 表达数据与WGS数据，并应用工具变量方法。最后，一个综合系统 将通过进一步利用公共领域的表观基因组图谱和注释数据库来采取方法 建立预测和潜在的因果模型，旨在更“个性化”的预防和干预， 酒精使用障碍在特定的高风险群体和个人。

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.