@article{b6c66a143be84d96a6f01da7ed035ede,
title = "Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis",
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.",
keywords = "Allergic rhinitis, Allergy, Coexpression module, Coexpression network, Expression single-nucleotide polymorphism, Genome-wide association study, Hay fever, Mitochondria, Pathway",
author = "Supinda Bunyavanich and Schadt, {Eric E.} and Himes, {Blanca E.} and Jessica Lasky-Su and Weiliang Qiu and Ross Lazarus and Ziniti, {John P.} and Ariella Cohain and Michael Linderman and Torgerson, {Dara G.} and Eng, {Celeste S.} and Maria Pino-Yanes and Badri Padhukasahasram and Yang, {James J.} and Mathias, {Rasika A.} and Beaty, {Terri H.} and Xingnan Li and Penelope Graves and Isabelle Romieu and Navarro, {Blanca Del Rio} and Salam, {M. Towhid} and Hita Vora and Nicolae, {Dan L.} and Carole Ober and Martinez, {Fernando D.} and Bleecker, {Eugene R.} and Meyers, {Deborah A.} and Gauderman, {W. James} and Frank Gilliland and Burchard, {Esteban G.} and Barnes, {Kathleen C.} and Williams, {L. Keoki} and London, {Stephanie J.} and Bin Zhang and Raby, {Benjamin A.} and Weiss, {Scott T.}",
note = "Funding Information: We thank all the participants who made this study possible. We appreciate contributions from Brooke Schuemann, Barbara Klanderman, PhD, Jody S. Sylvia, Ute Geigenmuller, PhD, Roxanne Kelly, M.B.A., Jose Rodriguez Santana, M.D, William Rodriguez Cintron, M.D., Rocio Chapela, M.D., Jean Ford, M.D., Shannon Thyne, M.D., and Pedro C. Avila, M.D. This work was supported by grants from the National Institutes of Allergy and Infectious Disease (K08AI093538 to S.B.; AI070503 to C.O.; AI079139 and AI061774 to L.K.W.; and AI077439 to E.G.B.), the National Heart, Lung, and Blood Institute (HL101651 to C.O. and D.L.N.; HL087665 to D.L.N.; HL085197, HL087665, HL072414, and HL49596 to C.O.; HL064307 and HL064313 to F.D.M.; HL075419, HL65899, HL083069, HL066289, HL087680, HL101543, and HL101651 to S.T.W.; HL079055 to L.K.W.; HL087699, to K.C.B.; HL061768, HL076647, P30ES007048, P01ES011627 to F.D.G.; HL087680 to W.J.G.; HL078885 and HL088133 to E.G.B.; HL087665 to D.A.M.; and HL069167 to E.R.B), the National Institute of Diabetes and Digestive and Kidney Diseases to L.K.W. (DK064695); the National Institutes of Environmental Health Sciences (ES020801 and ES022719 to W.J.G.; ES007048, ES009581, R826708, RD831861, and ES011627 to F.D.G.; ES015794 to E.G.B.; and the Division of Intramural Research, Z01 ES049019 to S.J.L.) of the National Institutes of Health. Also supported by the American Asthma Foundation and the Fund for Henry Ford Hospital (to L.K. W.), Mary Beryl Patch Turnbull Scholar Program (to K.C.B.); the Flight Attendant Medical Research Institute (FAMRI), RWJF Amos Medical Faculty Development Award, the American Asthma Foundation, the Sandler Foundation (to E.G.B.), and Fundaci{\'o}n Ram{\'o}n Areces (to M.P.Y.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2014 Bunyavanich et al.; licensee BioMed Central Ltd.",
year = "2014",
month = aug,
day = "2",
doi = "10.1186/1755-8794-7-48",
language = "English (US)",
volume = "7",
journal = "BMC Medical Genomics",
issn = "1755-8794",
publisher = "BioMed Central",
number = "1",
}