Open Access Highly Accessed Research article

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

Supinda Bunyavanich12*, Eric E Schadt1, Blanca E Himes3, Jessica Lasky-Su3, Weiliang Qiu3, Ross Lazarus173, John P Ziniti3, Ariella Cohain1, Michael Linderman1, Dara G Torgerson4, Celeste S Eng4, Maria Pino-Yanes45, Badri Padhukasahasram6, James J Yang7, Rasika A Mathias8, Terri H Beaty8, Xingnan Li9, Penelope Graves10, Isabelle Romieu11, Blanca del Rio Navarro12, M Towhid Salam13, Hita Vora13, Dan L Nicolae14, Carole Ober14, Fernando D Martinez10, Eugene R Bleecker9, Deborah A Meyers9, W James Gauderman13, Frank Gilliland13, Esteban G Burchard4, Kathleen C Barnes8, L Keoki Williams156, Stephanie J London16, Bin Zhang1, Benjamin A Raby3 and Scott T Weiss3

Author Affiliations

1 Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029 New York, NY, USA

2 Division of Pediatric Allergy and Immunology, Department of Pediatrics, and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

3 Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA

4 Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA

5 IBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain

6 Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA

7 Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA

8 Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD, USA

9 Center for Genomics, Wake Forest University School of Medicine, Winston Salem, NC, USA

10 Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, AZ, USA

11 International Agency for Research on Cancer, Lyon, France

12 Hospital Infantil Federico Gómez, México City, Mexico

13 Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA

14 Department of Human Genetics, University of Chicago, Chicago, IL, USA

15 Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA

16 Division of Intramural Research, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle, Park, NC, USA

17 Medical Bioinformatics, Baker IDI, Melbourne, Australia

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BMC Medical Genomics 2014, 7:48  doi:10.1186/1755-8794-7-48

Published: 2 August 2014

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 ≤ 1x10−6 tagged 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.

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