System Genetics of Alcoholism: Network-based Approaches for Genetic Association

酗酒的系统遗传学：基于网络的遗传关联方法

• 批准号: 8532762
• 负责人: ROHAN Hugh Craig PALMER
• 金额: $ 15.91万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-20 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532762
• 关键词: Accounting; Adult; Affect; Age; Alcohol abuse; Alcohol dependence; Alcoholism; Alcohols; Algorithms; American; Aminobutyric Acids; Architecture; Attenuated; Bioinformatics; Biological; Biology; Biometry; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 5; Collaborations; Complex; Data; Databases; Diagnosis; Diagnostic; Disease; Drug Addiction; EP300 gene; Educational workshop; Emerging Technologies; Environment; Environmental Risk Factor; Ethnic Origin; Event-Related Potentials; Future; Gender; Gene Cluster; Gene Proteins; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genetic Variation; Genome; Genomics; Genotype; Goals; Grant; Graph; Heterogeneity; Individual; Institutes; Joints; K-Series Research Career Programs; Knowledge; Lead; Learning; Link; Major Depressive Disorder; Manuscripts; Mental disorders; Mentors; Mentorship; Methods; Modeling; Molecular; Nature; Network-based; Neural Pathways; Pathway interactions; Pharmacologic Substance; Phenotype; Population; Predisposition; Prevention; Problem Solving; Public Health; Receptor Gene; Recruitment Activity; Research; Research Methodology; Research Training; Resources; Role; Sampling; Sampling Studies; Scientist; Single Nucleotide Polymorphism Map; Statistical Methods; Structure; Sum; Surveys; System; Systems Biology; Techniques; Testing; Training; Variant; alcohol and other drug; alcohol use disorder; alpha synuclein; anti social; attenuation; base; biological systems; career; computer based statistical methods; cost effective; data mining; database of Genotypes and Phenotypes; drinking; endophenotype; gene interaction; genetic association; genetic variant; genetics of alcoholism; genome sequencing; genome wide association study; improved; innovation; meetings; network models; neurophysiology; new technology; novel; novel strategies; programs; public health relevance; relating to nervous system; success; theories; tool

DESCRIPTION (provided by applicant): This Mentored Research Scientist Career Development Award will afford Dr. Rohan Palmer focused training for his programmatic line of research in the genetics of alcohol dependence and related phenotypes (AD). Given that gene identification studies (in particular genomewide association studies) on alcoholism are challenged by the fact that alcoholism is a multifactorial disorder influenced by multiple interacting genes, each with small effect, the public health relevance for deriving new analytical strategies and statistical methods is substantial. The proposed research aligns with the National Institute for Alcohol Abuse and Alcoholism's plan to "Identify genes associated with vulnerability for alcohol dependence by employing new and emerging technologies, on samples from study populations previously recruited for genetic research on alcohol dependence". It is evident that a network-based approach is necessary to describe the joint distribution of genetic effects that comprise specific neural or molecular pathways that underlie alcohol dependence. Genetic samples and phenotypic data available through the Database for Genotype and Phenotypes (dbGAP), as well as collected data from the Center for Antisocial Drug Dependence will be used to provide a cost-effective opportunity to identify gene networks that alter susceptibility to AD, thereby improving our understanding of AD while introducing a novel approach to the field of alcohol genetics. The proposed research assists Dr. Palmer in achieving his career and training goals to: (1) develop proficiency in statistical genetics and systems-based association methods, (2) become adept at using biostatistics tools to identify gene and protein interaction networks, (3) identify variation in evolutionarily robust biological systems by developing novel data mining techniques, (4) develop a program of research aimed at identifying combinations of genetic variation in biological systems affected by alcohol and other drug/pharmaceuticals with the potential for abuse, and (5) establish collaborations to develop high-quality research manuscripts and grants. The specific aims of the proposed research are to: (1) Derive gene network graphs that describe the relationships between genes (i.e., influence graphs) using prior knowledge of genetic association, bioinformatics databases, systems biology, and gene and protein interaction modeling tools; (2) identify sub networks of genes within the influence graphs from Aim 1 (these networks will be identified before and after accounting for several covariates (e.g., major depression, and select environmental factors); and (3) replicate findings from Aim 2 using independent samples with similar phenotypic and genetic data. Training and research goals will be achieved through a combination of didactic coursework, ongoing close mentorship, mentored research, workshops, and collaborative projects. This application will lead to research findings to support planned future R01s, as well as innovative research methods that advance our understanding of gene-biology-phenotype relationships.

描述（由申请人提供）：这个指导研究科学家职业发展奖将为罗汉帕尔默博士提供重点培训，以支持他在酒精依赖和相关表型（AD）遗传学方面的计划性研究。鉴于酒精中毒的基因鉴定研究（特别是全基因组关联研究）受到以下事实的挑战：酒精中毒是一种受多个相互作用的基因影响的多因素疾病，每个基因的影响都很小，因此得出新的分析策略和统计方法的公共卫生相关性是巨大的。这项拟议的研究与国家酒精滥用和酒精中毒研究所的计划相一致，该计划旨在“通过采用新的和新兴的技术，从先前招募用于酒精依赖遗传研究的研究人群中提取样本，确定与酒精依赖脆弱性相关的基因”。很明显，一个基于网络的方法是必要的，以描述联合分布的遗传效应，包括特定的神经或分子通路，酒精依赖的基础。通过基因型和表型数据库（dbGAP）提供的遗传样本和表型数据，以及从反社会药物依赖中心收集的数据将用于提供一个具有成本效益的机会，以确定改变AD易感性的基因网络，从而提高我们对AD的理解，同时引入酒精遗传学领域的新方法。拟议的研究有助于帕尔默博士实现他的职业和培训目标：（1）熟练掌握统计遗传学和基于系统的关联方法，（2）熟练使用生物统计学工具来识别基因和蛋白质相互作用网络，（3）通过开发新的数据挖掘技术来识别进化稳健的生物系统中的变异，（4）制定一项研究计划，旨在确定受酒精和其他药物/药物影响的生物系统中具有滥用潜力的遗传变异组合，以及（5）建立合作，以开发高质量的研究手稿和赠款。所提出的研究的具体目标是：（1）导出描述基因之间关系的基因网络图（即，影响图）;（2）识别来自Aim 1的影响图内的基因的子网络（这些网络将在考虑几个协变量之前和之后被识别（例如，重性抑郁症，并选择环境因素）;（3）使用具有相似表型和遗传数据的独立样本重复Aim 2的发现。培训和研究目标将通过教学课程，正在进行的密切指导，指导研究，研讨会和合作项目的组合来实现。该应用程序将导致研究结果，以支持计划的未来R 01，以及创新的研究方法，促进我们对基因-生物学-表型关系的理解。