BMC Med Genomics. 2014 Aug 2;7:48. doi: 10.1186/1755-8794-7-48.
Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.
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.
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).
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.
变应性鼻炎是一种常见疾病，其遗传基础尚未完全阐明。我们报告了变应性鼻炎的综合基因组分析。
我们对 5633 名具有不同种族背景的北美受试者进行了变应性鼻炎的全基因组关联研究（GWAS）。接下来，我们对已进行基因分型的受试者的疾病相关组织（外周血 CD4+淋巴细胞）进行了基因表达谱分析。然后，我们使用表达单核苷酸（eSNP）、共表达网络和途径方法整合 GWAS 和基因表达数据，以确定我们 GWAS 的生物学相关性。
GWAS 揭示了特定种族的发现，其中拉丁裔人群中有 4 个全基因组显著位点，跨种族群体的 GWAS 荟萃分析中有 1 个全基因组显著位点。为了确定这些结果的生物学背景，我们构建了一个共表达网络，以定义具有相似 CD4+基因表达模式的基因模块（共表达模块），这些模块可以作为更广泛基因表达的构建模块。在 22 个 P 值≤1x10-6 的 GWAS 位点中，有 6 个标记了一个特定的共表达模块（4.0 倍富集，P 值为 0.0029），而这个模块也对与变应性鼻炎相关的 eSNP（与基因表达和变应性鼻炎都相关的遗传变异）具有最大的富集（3.4 倍富集，P 值为 2.6×10-24）。因此，综合 GWAS、共表达网络和 eSNP 结果支持了这个共表达模块作为变应性鼻炎模块。通路分析显示，该模块富含线粒体途径（8.6 倍富集，P 值为 4.5×10-72）。
我们的研究结果强调了线粒体途径作为进一步研究变应性鼻炎机制和治疗的靶点。我们的综合方法可以应用于为其他疾病的 GWAS 提供生物学背景。
