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

基本信息

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
项目类别：
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

项目摘要

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）：这项受过指导的研究科学家职业发展奖将为Rohan Palmer博士提供专注于他在酒精依赖及相关表型（AD）遗传学的计划研究方面的培训。鉴于基因鉴定研究（特别是全基因组关联研究）对酒精中毒是一种多因素疾病的挑战，即受多种相互作用基因影响的多因素疾病，每个相互作用效果很小，公共卫生与得出新的分析策略和统计方法的相关性是实质性的。。拟议的研究与美国国家酒精滥用和酒精中毒研究所的计划保持一致，该计划“通过采用新的和新兴的技术来识别与酒精依赖脆弱性相关的基因，这是对以前从事遗传研究的研究人群的样本来确定对酒精依赖的研究人群的样本”。显然，基于网络的方法是描述构成依赖酒精依赖性的特定神经或分子途径的遗传效应的联合分布。通过数据库可用于基因型和表型（DBGAP）以及来自反社会药物依赖中心的收集数据，将使用遗传样本和表型数据，用于提供具有成本效益的机会，以识别改变AD易感性的基因网络，从而改变AD的易感性提高我们对AD的理解，同时引入一种新颖的酒精遗传学方法。拟议的研究协助帕尔默博士实现了自己的职业和培训目标：（1）发展统计遗传学和基于系统的关联方法的熟练程度，（2）善于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（3）（3 ）通过开发新型的数据挖掘技术来确定进化强大的生物系统的变化，（4）制定了一项研究计划，旨在识别受酒精和其他药物/药物影响滥用潜力的生物系统遗传变异的组合，5 ）建立合作以开发高质量的研究手稿和赠款。拟议研究的具体目的是：（1）得出使用遗传关联，生物信息学数据库，系统生物学以及基因和蛋白质相互作用建模工具的先验知识，描述基因（即影响图）之间关系的基因网络图；（2）从AIM 1中确定影响图内基因的子网络（这些网络将在考虑到多个协变量（例如，重度抑郁症和精选环境因素）之前和之后确定；（3）使用AIM 2复制AIM 2的发现。具有类似表型和遗传数据的独立样本将通过教学课程，持续的近距离指导，指导研究，研讨会和协作项目来实现。以及创新的研究方法，可以提高我们对基因生物学 - 表型关系的理解。