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

被引：52

作者：

Bunyavanich, Supinda ^{[1
,2
,3
,4
]}

Schadt, Eric E. ^{[1
,2
]}

Himes, Blanca E. ^{[5
,6
]}

Lasky-Su, Jessica ^{[5
,6
]}

Qiu, Weiliang ^{[5
,6
]}

Lazarus, Ross ^{[5
,6
,23
]}

Ziniti, John P. ^{[5
,6
]}

Cohain, Ariella ^{[1
,2
]}

Linderman, Michael ^{[1
,2
]}

Torgerson, Dara G. ^{[7
,8
]}

Eng, Celeste S. ^{[7
,8
]}

Pino-Yanes, Maria ^{[7
,8
,9
]}

Padhukasahasram, Badri ^{[10
]}

Yang, James J. ^{[11
]}

Mathias, Rasika A. ^{[12
,13
]}

Beaty, Terri H. ^{[12
,13
]}

Li, Xingnan ^{[14
]}

Graves, Penelope ^{[15
,16
]}

Romieu, Isabelle ^{[17
]}

del Rio Navarro, Blanca ^{[18
]}

Salam, M. Towhid ^{[19
]}

Vora, Hita ^{[19
]}

Nicolae, Dan L. ^{[20
]}

Ober, Carole ^{[20
]}

Martinez, Fernando D. ^{[15
,16
]}

Bleecker, Eugene R. ^{[14
]}

Meyers, Deborah A. ^{[14
]}

Gauderman, W. James ^{[19
]}

Gilliland, Frank ^{[19
]}

Burchard, Esteban G. ^{[7
,8
]}

Barnes, Kathleen C. ^{[12
,13
]}

Williams, L. Keoki ^{[10
,21
]}

London, Stephanie J. ^{[22
]}

Zhang, Bin ^{[1
,2
]}

Raby, Benjamin A. ^{[5
,6
]}

Weiss, Scott T. ^{[5
,6
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Dept Pediat, Div Pediat Allergy & Immunol, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA

[5] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Boston, MA USA

[7] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[8] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA USA

[9] Inst Salud Carlos III, IBER Enfermedades Resp, Madrid, Spain

[10] Henry Ford Hlth Syst, Ctr Hlth Policy & Hlth Serv Res, Detroit, MI USA

[11] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI USA

[12] Johns Hopkins Univ, Dept Med, Baltimore, MD USA

[13] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA

[14] Wake Forest Univ, Bowman Gray Sch Med, Ctr Genom, Winston Salem, NC USA

[15] Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA

[16] Univ Arizona, BIO5 Inst, Tucson, AZ USA

[17] Int Agcy Res Canc, Lyon, France

[18] Hosp Infantil Federico Gomez, Mexico City, DF, Mexico

[19] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA

[20] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[21] Henry Ford Hlth Syst, Dept Internal Med, Detroit, MI USA

[22] NIEHS, Dept Hlth & Human Serv, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA

[23] Baker IDI, Med Bioinformat, Melbourne, Australia

来源：

BMC MEDICAL GENOMICS | 2014年 / 7卷

基金：

美国国家卫生研究院;

关键词：

Genome-wide association study; Allergic rhinitis; Coexpression network; Expression single-nucleotide polymorphism; Coexpression module; Pathway; Mitochondria; Hay fever; Allergy; BODY-MASS INDEX; GENE-EXPRESSION; SUSCEPTIBILITY LOCI; RISK-FACTORS; METAANALYSIS; ASTHMA; POPULATION; VARIANTS; SYSTEMS; SENSITIZATION;

D O I：

10.1186/1755-8794-7-48

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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 x 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.

引用

页数：14

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