title: The Integration of Epistasis Network and Functional Interactions in a GWAS Implicates RXR Pathway Genes in the Immune Response to Smallpox Vaccine.
abstract: Although many diseases and traits show large heritability, few genetic variants have been found to strongly separate phenotype groups by genotype. Complex regulatory networks of variants and expression of multiple genes lead to small individual-variant effects and difficulty replicating the effect of any single variant in an affected pathway. Interaction network modeling of GWAS identifies effects ignored by univariate models, but population differences may still cause specific genes to not replicate. Integrative network models may help detect indirect effects of variants in the underlying biological pathway. In this study, we used gene-level functional interaction information from the Integrative Multi-species Prediction (IMP) tool to reveal important genes associated with a complex phenotype through evidence from epistasis networks and pathway enrichment. We test this method for augmenting variant-based network analyses with functional interactions by applying it to a smallpox vaccine immune response GWAS. The integrative analysis spotlights the role of genes related to retinoid X receptor alpha (RXRA), which has been implicated in a previous epistasis network analysis of smallpox vaccine.
authors: Tandy School of Computer Science and Department of Mathematics, University of Tulsa, Tulsa, OK, United States of America.
authors: Brett A
authors: BA
authors: McKinney
authors: Tandy School of Computer Science and Department of Mathematics, University of Tulsa, Tulsa, OK, United States of America.
authors: Caleb
authors: C
authors: Lareau
authors: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America.
authors: Ann L
authors: AL
authors: Oberg
authors: Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, United States of America.
authors: Richard B
authors: RB
authors: Kennedy
authors: Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, United States of America.
authors: Inna G
authors: IG
authors: Ovsyannikova
authors: Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, United States of America.
authors: Gregory A
authors: GA
authors: Poland
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D019295:Computational Biology; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D055633:Immune System Phenomena / Q000235:genetics*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D047488:Retinoid X Receptors / Q000235:genetics*; D015398:Signal Transduction; D012899:Smallpox / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control; D012900:Smallpox Vaccine / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: D047488:Retinoid X Receptors; D012900:Smallpox Vaccine