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

Bunyavanich S, Schadt EE, Himes BE, Lasky-Su J, Qiu W, Lazarus R, Ziniti JP, Cohain A, Linderman M, Torgerson DG, Eng CS, Pino-Yanes M, Padhukasahasram B, Yang JJ, Mathias RA, Beaty TH, Li X, Graves P, Romieu I, Navarro Bdel R, Salam MT, Vora H, Nicolae DL, Ober C, Martinez FD, Bleecker ER, Meyers DA, Gauderman WJ, Gilliland F, Burchard EG, Barnes KC, Williams LK, London SJ, Zhang B, Raby BA, Weiss ST - BMC Med Genomics (2014)

Bottom Line: 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.Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10-72).Our integrated approach can be applied to provide biologic context for GWAS of other diseases.

View Article: PubMed Central - HTML - PubMed

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.

Show MeSH

Related in: MedlinePlus

Study flow for the integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis of allergic rhinitis. CHS = Children’s Health Study, CAMP = Childhood Asthma Management Program, CAG = Chicago Asthma Genetics Study, CSGA = Collaborative Studies on the Genetics of Asthma, SARP = Severe Asthma Research Program, GALA1 = Genetics of Asthma in Latinos, MCCAS = Mexico City Childhood Asthma Study, GRAAD = Genomic Research on Asthma in the African Diaspora and Barbados, SAPPHIRE = Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity. Detailed descriptions of the individual studies have been previously described [25].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4127082&req=5

Figure 1: Study flow for the integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis of allergic rhinitis. CHS = Children’s Health Study, CAMP = Childhood Asthma Management Program, CAG = Chicago Asthma Genetics Study, CSGA = Collaborative Studies on the Genetics of Asthma, SARP = Severe Asthma Research Program, GALA1 = Genetics of Asthma in Latinos, MCCAS = Mexico City Childhood Asthma Study, GRAAD = Genomic Research on Asthma in the African Diaspora and Barbados, SAPPHIRE = Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity. Detailed descriptions of the individual studies have been previously described [25].

Mentions: Our integrated genomic analysis of allergic rhinitis yielded results from GWAS, gene expression profiling, and their integrated analysis (Figure 1). We first describe the results of our GWAS of allergic rhinitis in 5633 ethnically diverse North American subjects, where we identified genome-wide significant loci that were specific to ethnicity (Figure 1, pink box). We then describe the results of our gene expression profiling of immune cells key to allergy (CD4+ lymphocytes [30]), collected from the peripheral blood of selected subjects who had undergone GWAS (Figure 1, blue box). We share the results for the weighted gene coexpression network [31] we constructed to identify modules of genes expressed together. Finally, we describe the integration of our GWAS and gene expression analyses (Figure 1, purple box), where we performed eSNP analysis to assess for the association between genetic variation and gene expression (Figure 1, purple path), assessed GWAS loci for eSNPs (Figure 1, turquoise path), identified coexpression modules tagged by GWAS loci (Figure 1, orange path), and analyzed coexpression modules for enrichment of allergic-rhinitis associated eSNPs (Figure 1, green path) [15]. We then used pathway analysis to further inform on the biological context for our integrated findings.


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

Bunyavanich S, Schadt EE, Himes BE, Lasky-Su J, Qiu W, Lazarus R, Ziniti JP, Cohain A, Linderman M, Torgerson DG, Eng CS, Pino-Yanes M, Padhukasahasram B, Yang JJ, Mathias RA, Beaty TH, Li X, Graves P, Romieu I, Navarro Bdel R, Salam MT, Vora H, Nicolae DL, Ober C, Martinez FD, Bleecker ER, Meyers DA, Gauderman WJ, Gilliland F, Burchard EG, Barnes KC, Williams LK, London SJ, Zhang B, Raby BA, Weiss ST - BMC Med Genomics (2014)

Study flow for the integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis of allergic rhinitis. CHS = Children’s Health Study, CAMP = Childhood Asthma Management Program, CAG = Chicago Asthma Genetics Study, CSGA = Collaborative Studies on the Genetics of Asthma, SARP = Severe Asthma Research Program, GALA1 = Genetics of Asthma in Latinos, MCCAS = Mexico City Childhood Asthma Study, GRAAD = Genomic Research on Asthma in the African Diaspora and Barbados, SAPPHIRE = Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity. Detailed descriptions of the individual studies have been previously described [25].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4127082&req=5

Figure 1: Study flow for the integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis of allergic rhinitis. CHS = Children’s Health Study, CAMP = Childhood Asthma Management Program, CAG = Chicago Asthma Genetics Study, CSGA = Collaborative Studies on the Genetics of Asthma, SARP = Severe Asthma Research Program, GALA1 = Genetics of Asthma in Latinos, MCCAS = Mexico City Childhood Asthma Study, GRAAD = Genomic Research on Asthma in the African Diaspora and Barbados, SAPPHIRE = Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity. Detailed descriptions of the individual studies have been previously described [25].
Mentions: Our integrated genomic analysis of allergic rhinitis yielded results from GWAS, gene expression profiling, and their integrated analysis (Figure 1). We first describe the results of our GWAS of allergic rhinitis in 5633 ethnically diverse North American subjects, where we identified genome-wide significant loci that were specific to ethnicity (Figure 1, pink box). We then describe the results of our gene expression profiling of immune cells key to allergy (CD4+ lymphocytes [30]), collected from the peripheral blood of selected subjects who had undergone GWAS (Figure 1, blue box). We share the results for the weighted gene coexpression network [31] we constructed to identify modules of genes expressed together. Finally, we describe the integration of our GWAS and gene expression analyses (Figure 1, purple box), where we performed eSNP analysis to assess for the association between genetic variation and gene expression (Figure 1, purple path), assessed GWAS loci for eSNPs (Figure 1, turquoise path), identified coexpression modules tagged by GWAS loci (Figure 1, orange path), and analyzed coexpression modules for enrichment of allergic-rhinitis associated eSNPs (Figure 1, green path) [15]. We then used pathway analysis to further inform on the biological context for our integrated findings.

Bottom Line: 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.Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10-72).Our integrated approach can be applied to provide biologic context for GWAS of other diseases.

View Article: PubMed Central - HTML - PubMed

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.

Show MeSH
Related in: MedlinePlus