Departments of Human Genetics, University of Chicago, Chicago, IL, USA.
Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
Genome Med. 2021 Oct 10;13(1):157. doi: 10.1186/s13073-021-00967-y.
Genome-wide association studies (GWASs) have identified thousands of variants associated with asthma and other complex diseases. However, the functional effects of most of these variants are unknown. Moreover, GWASs do not provide context-specific information on cell types or environmental factors that affect specific disease risks and outcomes. To address these limitations, we used an upper airway epithelial cell (AEC) culture model to assess transcriptional and epigenetic responses to rhinovirus (RV), an asthma-promoting pathogen, and provide context-specific functional annotations to variants discovered in GWASs of asthma.
Genome-wide genetic, gene expression, and DNA methylation data in vehicle- and RV-treated upper AECs were collected from 104 individuals who had a diagnosis of airway disease (n=66) or were healthy participants (n=38). We mapped cis expression and methylation quantitative trait loci (cis-eQTLs and cis-meQTLs, respectively) in each treatment condition (RV and vehicle) in AECs from these individuals. A Bayesian test for colocalization between AEC molecular QTLs and adult onset asthma and childhood onset asthma GWAS SNPs, and a multi-ethnic GWAS of asthma, was used to assign the function to variants associated with asthma. We used Mendelian randomization to demonstrate DNA methylation effects on gene expression at asthma colocalized loci.
Asthma and allergic disease-associated GWAS SNPs were specifically enriched among molecular QTLs in AECs, but not in GWASs from non-immune diseases, and in AEC eQTLs, but not among eQTLs from other tissues. Colocalization analyses of AEC QTLs with asthma GWAS variants revealed potential molecular mechanisms of asthma, including QTLs at the TSLP locus that were common to both the RV and vehicle treatments and to both childhood onset and adult onset asthma, as well as QTLs at the 17q12-21 asthma locus that were specific to RV exposure and childhood onset asthma, consistent with clinical and epidemiological studies of these loci.
This study provides evidence of functional effects for asthma risk variants in AECs and insight into RV-mediated transcriptional and epigenetic response mechanisms that modulate genetic effects in the airway and risk for asthma.
全基因组关联研究（GWAS）已经确定了数千个与哮喘和其他复杂疾病相关的变异。然而，这些变异的大多数功能影响仍然未知。此外，GWAS 并不能提供特定于细胞类型或环境因素的信息，而这些因素会影响特定疾病的风险和结果。为了解决这些限制，我们使用上呼吸道上皮细胞（AEC）培养模型来评估呼吸道合胞病毒（RV）对哮喘促进病原体的转录和表观遗传反应，并为哮喘 GWAS 中发现的变异提供特定于细胞类型的功能注释。
从 104 名患有气道疾病（n=66）或健康参与者（n=38）的个体中收集了在 RV 和对照处理的上呼吸道 AEC 中的全基因组遗传、基因表达和 DNA 甲基化数据。我们在每个处理条件（RV 和对照）中映射了 cis 表达和甲基化数量性状基因座（cis-eQTLs 和 cis-meQTLs）。使用贝叶斯检验在 AEC 分子 QTL 与成人发病哮喘和儿童发病哮喘 GWAS SNP 之间的 colocalization，并进行了多民族哮喘 GWAS，用于将与哮喘相关的变异分配到功能上。我们使用 Mendelian 随机化来证明 DNA 甲基化对哮喘 colocalized 基因座的基因表达的影响。
哮喘和过敏疾病相关的 GWAS SNP 在上呼吸道上皮细胞的分子 QTL 中特异性富集，但在非免疫疾病的 GWAS 中没有富集，在上呼吸道上皮细胞的 eQTL 中富集，但在其他组织的 eQTL 中没有富集。AEC QTL 与哮喘 GWAS 变异的 colocalization 分析揭示了哮喘的潜在分子机制，包括 TSLP 基因座的 QTL 在 RV 和对照处理中以及儿童发病和成人发病哮喘中都是共同的，以及 17q12-21 哮喘基因座的 QTL 仅在 RV 暴露和儿童发病哮喘中特异性富集，与这些基因座的临床和流行病学研究一致。
这项研究为 AEC 中的哮喘风险变异提供了功能效应的证据，并深入了解了 RV 介导的转录和表观遗传反应机制，这些机制调节了气道中的遗传效应和哮喘的风险。
