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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.

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Related in: MedlinePlus

Results of the genome-wide association studies of allergic rhinitis, meta-analysis, and GWAS tagging of the coexpression network.
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Figure 3: Results of the genome-wide association studies of allergic rhinitis, meta-analysis, and GWAS tagging of the coexpression network.

Mentions: Because subjects were ethnically diverse, we pooled genotype data from the 7 study centers into three ethnic groups for GWAS: European American, Latino, and African-American/African Caribbean (Figure 1, pink box) and controlled for population stratification within each ethnic group using principal components. Figure 2 shows the results of genome-wide association studies for allergic rhinitis among European Americans, Latinos, and African-American/African-Caribbeans, in addition to the results of the meta-analysis across these ethnic groups. For additional views, Additional file 1: Figure S1 shows the Manhattan plots separately for each ethnic group and for the meta-analysis. There were distinct findings for each ethnic group. Figure 3 summarizes the results for the 22 loci with P value for association ≤ 1 × 10−6 in at least one of the ethnic groups or in the meta-analysis. We show loci meeting this threshold to include loci with suggestive associations (P value ≤ 1 × 10−6) in addition to those genome-wide significant (defined as P value ≤ 5 × 10−8), as loci not meeting strict definitions of genome-wide significance can have biologic relevance [11,12]. Allele frequencies are shown in Additional file 2: Table S1, and a QQ plot for the GWAS meta-analysis is shown in Additional file 3: Figure S2. The genomic inflation factor was 1.06, supporting adequate control for population stratification.


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)

Results of the genome-wide association studies of allergic rhinitis, meta-analysis, and GWAS tagging of the coexpression network.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Results of the genome-wide association studies of allergic rhinitis, meta-analysis, and GWAS tagging of the coexpression network.
Mentions: Because subjects were ethnically diverse, we pooled genotype data from the 7 study centers into three ethnic groups for GWAS: European American, Latino, and African-American/African Caribbean (Figure 1, pink box) and controlled for population stratification within each ethnic group using principal components. Figure 2 shows the results of genome-wide association studies for allergic rhinitis among European Americans, Latinos, and African-American/African-Caribbeans, in addition to the results of the meta-analysis across these ethnic groups. For additional views, Additional file 1: Figure S1 shows the Manhattan plots separately for each ethnic group and for the meta-analysis. There were distinct findings for each ethnic group. Figure 3 summarizes the results for the 22 loci with P value for association ≤ 1 × 10−6 in at least one of the ethnic groups or in the meta-analysis. We show loci meeting this threshold to include loci with suggestive associations (P value ≤ 1 × 10−6) in addition to those genome-wide significant (defined as P value ≤ 5 × 10−8), as loci not meeting strict definitions of genome-wide significance can have biologic relevance [11,12]. Allele frequencies are shown in Additional file 2: Table S1, and a QQ plot for the GWAS meta-analysis is shown in Additional file 3: Figure S2. The genomic inflation factor was 1.06, supporting adequate control for population stratification.

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