Admixture mapping has led to the discovery of many genes associated with differential disease risk by ancestry, highlighting the importance of ancestry-based approaches to association studies. However, the potential of admixture mapping in deciphering the interplay between genes and environment exposures has been seldom explored. Here we performed a genome-wide screening of local ancestry-smoking interactions for five spirometric lung function phenotypes in 3300 African Americans from the COPDGene study. To account for population structure and outcome heterogeneity across exposure groups, we developed a multi-component linear mixed model for mapping gene-environment interactions and empirically showed its robustness and increased power. When applied to the COPDGene study, our approach identified two 11p15.2-3 and 2q37 loci, exhibiting local ancestry-smoking interactions at genome-wide significant level, which would have been missed by standard single-nucleotide polymorphism analyses. These two loci harbor the PARVA and RAB17 genes previously recognized to be involved in smoking behavior. Overall, our study provides the first evidence for potential synergistic effects between African ancestry and smoking on pulmonary function, and underlines the importance of ethnic diversity in genetic studies.

中文翻译：

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混合模型混合物映射可确定非裔美国人的吸烟依赖性肺功能基因座。

混合作图已导致许多与祖先差异性疾病风险相关的基因的发现，突显了基于祖先的方法进行关联研究的重要性。然而，很少探讨混合映射在破译基因与环境暴露之间相互作用方面的潜力。在这里，我们从COPDGene研究中对3300名非洲裔美国人的五种肺活量肺功能表型进行了全基因组范围的局部祖先-吸烟相互作用的筛选。为了说明各个暴露人群之间的种群结构和结果异质性，我们开发了一种多组分线性混合模型来绘制基因与环境之间的相互作用，并通过经验证明了其鲁棒性和增强的功效。当应用于COPDGene研究时，我们的方法确定了两个11p15.2-3和2q37基因座，在全基因组显着水平上显示出本地祖先-吸烟相互作用，而标准单核苷酸多态性分析可能会忽略这些相互作用。这两个基因座包含先前公认参与吸烟行为的PARVA和RAB17基因。总体而言，我们的研究为非洲血统和吸烟之间对肺功能的潜在协同作用提供了第一个证据，并强调了种族多样性在遗传研究中的重要性。