Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis
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
BMC Medical Genomics 2014, 7:48 doi:10.1186/1755-8794-7-48Published: 2 August 2014
Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.
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.
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).
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.