Integrative information theoretic network analysis for genome-wide association study of aspirin exacerbated respiratory disease in Korean population

Sehee Wang, Hyun-hwan Jeong, Dokyoon Kim, Kyubum Wee, Hae-Sim Park, Seung-Hyun Kim, Kyung-Ah Sohn

Aspirin Exacerbated Respiratory Disease (AERD) is a chronic medical condition that encompasses asthma, nasal polyposis, and hypersensitivity to aspirin and other non-steroidal anti-inflammatory drugs. Several previous studies have shown that part of the genetic effects of the disease may be induced by the interaction of multiple genetic variants. However, heavy computational cost as well as the complexity of the underlying biological mechanism has prevented a thorough investigation of epistatic interactions and thus most previous studies have typically considered only a small number of genetic variants at a time. In this study, we propose a gene network based analysis framework to identify genetic risk factors from a genome-wide association study dataset. We first derive multiple single nucleotide polymorphisms (SNP)-based epistasis networks that consider marginal and epistatic effects by using different information theoretic measures. Each SNP epistasis network is converted into a gene-gene interaction network, and the resulting gene networks are combined as one for downstream analysis. The integrated network is validated on existing knowledgebase of DisGeNET for known gene-disease associations and GeneMANIA for biological function prediction. We demonstrated our proposed method on a Korean GWAS dataset, which has genotype information of 440,094 SNPs for 188 cases and 247 controls. The topological properties of the generated networks are examined for scale-freeness, and we further performed various statistical analyses in the Allergy and Asthma Portal (AAP) using the selected genes from our integrated network. Our result reveals that there are several gene modules in the network that are of biological significance and have evidence for controlling susceptibility and being related to the treatment of AERD.