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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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eSNP enrichment and pathway analysis of coexpression modules tagged by GWAS loci.
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Figure 5: eSNP enrichment and pathway analysis of coexpression modules tagged by GWAS loci.

Mentions: In this instance, we identified the brown module as giving rise to the greatest enrichments of allergic-rhinitis-associated eSNPs (3.4-fold enrichment; FDR-adjusted Fisher’s Exact Test P value 2.6 × 10−24) (Figure 5), thus providing statistical support for involvement of the brown module in allergic rhinitis. Pathway analysis revealed that the brown module was enriched for mitochondrial pathways (8.6-fold enrichment, FDR-adjusted Fisher Exact Test P value = 4.5 × 10−72) (Figure 5 and Figure 4B). The red and midnight blue modules were also enriched for allergic rhinitis–associated eSNPs, and both these modules were enriched for mitochondrial pathways as well (Figure 5). The pink module, enriched for the GO term intracellular organelle lumen, functionally overlaps with mitochondrial pathway. Thus, the candidate allergic rhinitis-associated modules were all significantly enriched for allergic rhinitis-associated eSNPs, and pathway analysis results for at least half of these modules highlighted mitochondrial pathways as linked to allergic rhinitis. Results from randomized networks did not yield meaningful results (Additional file 13: Supplementary Results 2, Additional file 14: Figure S7).


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)

eSNP enrichment and pathway analysis of coexpression modules tagged by GWAS loci.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: eSNP enrichment and pathway analysis of coexpression modules tagged by GWAS loci.
Mentions: In this instance, we identified the brown module as giving rise to the greatest enrichments of allergic-rhinitis-associated eSNPs (3.4-fold enrichment; FDR-adjusted Fisher’s Exact Test P value 2.6 × 10−24) (Figure 5), thus providing statistical support for involvement of the brown module in allergic rhinitis. Pathway analysis revealed that the brown module was enriched for mitochondrial pathways (8.6-fold enrichment, FDR-adjusted Fisher Exact Test P value = 4.5 × 10−72) (Figure 5 and Figure 4B). The red and midnight blue modules were also enriched for allergic rhinitis–associated eSNPs, and both these modules were enriched for mitochondrial pathways as well (Figure 5). The pink module, enriched for the GO term intracellular organelle lumen, functionally overlaps with mitochondrial pathway. Thus, the candidate allergic rhinitis-associated modules were all significantly enriched for allergic rhinitis-associated eSNPs, and pathway analysis results for at least half of these modules highlighted mitochondrial pathways as linked to allergic rhinitis. Results from randomized networks did not yield meaningful results (Additional file 13: Supplementary Results 2, Additional file 14: Figure S7).

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