Integrative pathway genomics of lung function and airflow obstruction
Integrative pathway genomics of lung function and airflow obstruction
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DOI：
10.1093/hmg/ddv378
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发表时间：
2015-12-01
影响因子：
3.5
通讯作者：
London, Stephanie J.
中科院分区：
文献类型：
--
作者：
Gharib, Sina A.;Loth, Daan W.;London, Stephanie J.
慢性呼吸系统疾病是造成全球疾病负担的重要因素。全基因组关联研究（GWASs）肺功能的措施已经确定了几个性状相关的基因座，但只能解释一个小部分的表型变异。我们假设，将基于途径的方法与肺功能和气流阻塞的GWAS相结合，将确定影响这些特征的更广泛的基因和过程。我们进行了两次独立的肺功能GWAS，并将基因集富集分析应用于其中一项研究，并使用第二次GWAS验证了结果。我们确定了131个与肺功能相关的显著富集的基因集，并将它们聚类为参与不同过程的较大生物模块，包括发育，免疫，细胞信号传导，增殖和花生四烯酸。我们发现基因集的富集不是由GWAS显著的变体或位点驱动的，而是由那些具有较低严格关联P值的变体或位点驱动的。接下来，我们将途径富集分析应用于气流阻塞的荟萃分析GWAS。我们确定了几个与肺功能相关的生物模块在功能上重叠。然而，也注意到差异，包括细胞外基质（ECM）过程的富集，特别是在气流阻塞研究中。ECM模块的网络分析暗示候选基因基质金属蛋白酶10（MMP 10）作为推定的疾病靶点。我们使用基因敲除小鼠模型来功能性地验证MMP 10在影响肺对香烟烟雾诱导的肺气肿的易感性中的作用。通过整合通路分析和基于人群的基因组学，我们揭示了肺功能特征的生物学过程，并确定了阻塞性肺疾病的候选基因。
Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10' s role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.