Surfing a genetic association interaction network to identify modulators of antibody response to smallpox vaccine.

Davis NA, Crowe JE, Pajewski NM, McKinney BA
Genes Immun. 2010 11 (8): 630-6

PMID: 20613780 · PMCID: PMC3001955 · DOI:10.1038/gene.2010.37

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.

MeSH Terms (13)

Algorithms Antibody Formation Cytochrome P-450 CYP1A1 Gene Regulatory Networks Genes Genome-Wide Association Study Humans Markov Chains NADPH Oxidases Phenotype Polymorphism, Single Nucleotide Retinoid X Receptor alpha Smallpox Vaccine

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