title: Integrative Analysis of Genetic, Genomic, and Phenotypic Data for Ethanol Behaviors: A Network-Based Pipeline for Identifying Mechanisms and Potential Drug Targets.
abstract: Complex behavioral traits, such as alcohol abuse, are caused by an interplay of genetic and environmental factors, producing deleterious functional adaptations in the central nervous system. The long-term behavioral consequences of such changes are of substantial cost to both the individual and society. Substantial progress has been made in the last two decades in understanding elements of brain mechanisms underlying responses to ethanol in animal models and risk factors for alcohol use disorder (AUD) in humans. However, treatments for AUD remain largely ineffective and few medications for this disease state have been licensed. Genome-wide genetic polymorphism analysis (GWAS) in humans, behavioral genetic studies in animal models and brain gene expression studies produced by microarrays or RNA-seq have the potential to produce nonbiased and novel insight into the underlying neurobiology of AUD. However, the complexity of such information, both statistical and informational, has slowed progress toward identifying new targets for intervention in AUD. This chapter describes one approach for integrating behavioral, genetic, and genomic information across animal model and human studies. The goal of this approach is to identify networks of genes functioning in the brain that are most relevant to the underlying mechanisms of a complex disease such as AUD. We illustrate an example of how genomic studies in animal models can be used to produce robust gene networks that have functional implications, and to integrate such animal model genomic data with human genetic studies such as GWAS for AUD. We describe several useful analysis tools for such studies: ComBAT, WGCNA, and EW_dmGWAS. The end result of this analysis is a ranking of gene networks and identification of their cognate hub genes, which might provide eventual targets for future therapeutic development. Furthermore, this combined approach may also improve our understanding of basic mechanisms underlying gene x environmental interactions affecting brain functioning in health and disease.
authors.affiliation: Department of Pharmacology and Toxicology, VCU Alcohol Research Center, Virginia Commonwealth University, 980613, Richmond, VA, 23298, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Bogenpohl
authors.affiliation: Department of Psychiatry, VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Mignogna
authors.affiliation: Department of Human and Molecular Genetics, VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Maren L
authors.initials: ML
authors.lastname: Smith
authors.affiliation: Department of Pharmacology and Toxicology, VCU Alcohol Research Center, Virginia Commonwealth University, 980613, Richmond, VA, 23298, USA. Michael.Miles@vcuhealth.org.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Miles
mesh_terms: D000437:Alcoholism / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D004327:Drinking Behavior; D000431:Ethanol; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods*; D051379:Mice; D010641:Phenotype; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D012984:Software
chemical_list: D000431:Ethanol
keywords: Alcoholism; Bioinformatics; Brain; Ethanol; Gene networks; Genetics; Genomics; Mouse; Use case