Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis.
Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis.
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DOI：
10.1186/1755-8794-7-48
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发表时间：
2014-08-02
影响因子：
2.7
通讯作者：
Weiss ST
中科院分区：
文献类型：
--
作者：
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
变应性鼻炎是一种常见病，其遗传基础尚不完全清楚。我们报告一个综合的基因组分析变应性鼻炎。我们在5633名不同种族的北美受试者中进行了过敏性鼻炎的全基因组关联研究（GWAS）。接下来，我们分析了从已进行基因分型的受试者中收集的疾病相关组织（外周血CD4+淋巴细胞）中的基因表达。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，以确定我们的GWAS的生物相关性。GWAS揭示了种族特异性结果，在拉丁美洲人中有4个全基因组显著位点，在跨种族的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，以定义具有类似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体。在22个GWAS基因座中，P值≤ 1x10−6的6个标记了一个特定的共表达模块（4.0倍富集，P值0.0029），该模块也对过敏性鼻炎相关的eSNP（与基因表达和过敏性鼻炎相关的遗传变异）具有最大的富集（3.4倍富集，P值2.6 × 10−24）。因此，整合的GWAS、共表达网络和eSNP结果支持该共表达模块作为过敏性鼻炎模块。途径分析显示，该模块富集了线粒体途径（8.6倍富集，P值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目标。我们的综合方法可用于为其他疾病的GWAS提供生物学背景。
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.
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