title: Surfing a genetic association interaction network to identify modulators of antibody response to smallpox vaccine.
abstract: The variation in antibody response to vaccination likely involves small contributions of numerous genetic variants, such as single-nucleotide polymorphisms (SNPs), which interact in gene networks and pathways. To accumulate the bits of genetic information relevant to the phenotype that are distributed throughout the interaction network, we develop a network eigenvector centrality algorithm (SNPrank) that is sensitive to the weak main effects, gene-gene interactions and small higher-order interactions through hub effects. Analogous to Google PageRank, we interpret the algorithm as the simulation of a random SNP surfer (RSS) that accumulates bits of information in the network through a dynamic probabilistic Markov chain. The transition matrix for the RSS is based on a data-driven genetic association interaction network (GAIN), the nodes of which are SNPs weighted by the main-effect strength and edges weighted by the gene-gene interaction strength. We apply SNPrank to a GAIN analysis of a candidate-gene association study on human immune response to smallpox vaccine. SNPrank implicates a SNP in the retinoid X receptor α (RXRA) gene through a network interaction effect on antibody response. This vitamin A- and D-signaling mediator has been previously implicated in human immune responses, although it would be neglected in a standard analysis because its significance is unremarkable outside the context of its network centrality. This work suggests SNPrank to be a powerful method for identifying network effects in genetic association data and reveals a potential vitamin regulation network association with antibody response.
authors.affiliation: Department of Mathematical and Computer Sciences, University of Tulsa, Tulsa, OK 74104, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Davis
authors.forename: J E
authors.initials: JE
authors.lastname: Crowe
authors.forename: N M
authors.initials: NM
authors.lastname: Pajewski
authors.forename: B A
authors.initials: BA
authors.lastname: McKinney
mesh_terms: D000465:Algorithms; D000917:Antibody Formation / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D053263:Gene Regulatory Networks; D005796:Genes; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008390:Markov Chains; D019255:NADPH Oxidases / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D047490:Retinoid X Receptor alpha / Q000235:genetics; D012900:Smallpox Vaccine / Q000235:genetics / Q000276:immunology*
chemical_list: D047490:Retinoid X Receptor alpha; D012900:Smallpox Vaccine; D019363:Cytochrome P-450 CYP1A1; D019255:NADPH Oxidases; C527764:NCF2 protein, human