Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis

Supinda Bunyavanich, Eric E. Schadt, Blanca E. Himes, Jessica Lasky-Su, Weiliang Qiu, Ross Lazarus, John P. Ziniti, Ariella Cohain, Michael Linderman, Dara G. Torgerson, Celeste S. Eng, Maria Pino-Yanes, Badri Padhukasahasram, James J. Yang, Rasika A. Mathias, Terri H. Beaty, Xingnan Li, Penelope Graves, Isabelle Romieu, Blanca Del Rio NavarroM. Towhid Salam, Hita Vora, Dan L. Nicolae, Carole Ober, Fernando D. Martinez, Eugene R. Bleecker, Deborah A. Meyers, W. James Gauderman, Frank Gilliland, Esteban G. Burchard, Kathleen C. Barnes, L. Keoki Williams, Stephanie J. London, Bin Zhang, Benjamin A. Raby, Scott T. Weiss

Research output: Contribution to journalArticle

Abstract

Background: Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis. Methods. We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS. Results: GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10-6tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10-24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10-72). Conclusions: Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.

Original languageEnglish (US)
Article number48
JournalBMC Medical Genomics
Volume7
Issue number1
DOIs
StatePublished - Aug 2 2014

Keywords

  • Allergic rhinitis
  • Allergy
  • Coexpression module
  • Coexpression network
  • Expression single-nucleotide polymorphism
  • Genome-wide association study
  • Hay fever
  • Mitochondria
  • Pathway

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Bunyavanich, S., Schadt, E. E., Himes, B. E., Lasky-Su, J., Qiu, W., Lazarus, R., Ziniti, J. P., Cohain, A., Linderman, M., Torgerson, D. G., Eng, C. S., Pino-Yanes, M., Padhukasahasram, B., Yang, J. J., Mathias, R. A., Beaty, T. H., Li, X., Graves, P., Romieu, I., ... Weiss, S. T. (2014). Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis. BMC Medical Genomics, 7(1), [48]. https://doi.org/10.1186/1755-8794-7-48