基于基因的调节性变异分析确定了四个可能新的与核苷酸合成和信号转导相关的哮喘风险基因
2016/10/09
摘要
背景：数百种基因变异被认为通过调节基因表达导致哮喘风险的变化。因此很有必要找到增加全基因组关联研究（GWAS）确定风险相关的基因变异能力的方法。
目的：建立一种可通过一个基因的表达数量性状位点（eQTLs）来收集与疾病风险相关的证据的方法，并用这种方法来识别哮喘风险的基因。
方法:我们开发了一个基于基因的测试软件包叫EUGENE，（1）适用于GWAS汇总统计；（2）考虑顺式和反式eQTLs；（3）可在不同组织进行eQTLs识别；和（4）使用模拟来解释多个测试。我们将这种方法应用到两个已经发表的哮喘全基因组关联研究（GWAS）（合并的N = 46044），并用小鼠研究对有新颖遗传关系的两个基因提供初始功能研究分析。
结果：我们测试了哮喘和17190个基因之间的关系，这些基因具有在已经发表的16个eQTL研究中的顺式和/或反式eQTLs。在经验主义错误发现率为5%的情况下，48个基因与哮喘的风险相关。其中，37个基因的相关是在的过敏疾病风险位点中通过eQTLs发现的，包括六个以前没有认为是疾病病因相关的基因（如LIMS1, TINF2 和SAFB）。剩下的11个重要的基因代表了潜在的新的与哮喘相关的遗传基因。与这些基因中的4个的关联在独立的GWAS中重复：B4GALT3，USMG5，P2RY13 和P2RY14，这些基因涉及到核苷酸的合成或核苷酸依赖的细胞活化。在对鼠的研究中，p2ry13和p2ry14 -嘌呤受体分别由ADP和UDP-糖激活，变应原激发后分别上调，特别是在气道上皮细胞、嗜酸性粒细胞和中性粒细胞。受体激动剂滴鼻诱导IL-33释放，随后嗜酸性粒细胞浸润到肺。
结论：我们确定了哮喘和eQTLs新的相关性，发现了四个与核苷酸合成/信号通路相关的基因，阐明了基于基因分析的全基因组关联研究（GWAS）的作用。
（苏欣 审校）
J Allergy Clin Immunol. 2016 Aug 20. pii: S0091-6749(16)30804-1. doi: 10.1016/j.jaci.2016.07.017. [Epub ahead of print]
Gene-based analysis of regulatory variants identifies four putative novel asthma risk genes related to nucleotide synthesis and signaling.
Ferreira MA1, Jansen R2, Willemsen G3, Penninx B2, Bain LM4, Vicente CT4, Revez JA4, Matheson MC5, Hui J6, Tung JY7, Baltic S8, Le Souëf P9; AAGC collaborators, Montgomery GW4, Martin NG4, Robertson CF10, James A11, Thompson PJ12, Boomsma DI3, Hopper JL5, Hinds DA7, Werder RB13,Phipps S13.
Author information
Abstract
BACKGROUND:Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome wide association studies (GWAS) to identify risk-associated variants are needed.
OBJECTIVE:To develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes.
METHODS:We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both cis- and trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to two published asthma GWAS (combined N=46,044) and used mouse studies to provide initial functional insights into two genes with novel genetic associations.
RESULTS:We tested the association between asthma and 17,190 genes which were found to have cis-and/or trans-eQTLs across 16 published eQTL studies. At an empirical false discovery rate of 5%, 48 genes were associated with asthma risk. Of these, for 37 the association was driven by eQTLs located in established risk loci for allergic disease, including six genes not previously implicated in disease aetiology (eg. LIMS1, TINF2 and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with four of these replicated in an independent GWAS: B4GALT3, USMG5, P2RY13 and P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14 - purinergic receptors activated by ADP and UDP-sugars, respectively - were up-regulated after allergen challenge, notably in airway epithelial cells, eosinophils and neutrophils. Intranasal exposure with the receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs.
CONCLUSION:We identified novel associations between asthma and eQTLs for four genes related to nucleotide synthesis/signaling, and demonstrate the power of gene-based analyses of GWAS.
Copyright © 2016. Published by Elsevier Inc.
KEYWORDS:AOAH; CLK3; EUGENE; Inflammation; PrediXcan; TWAS; UDP-glucose; VEGAS; ZNF707; eQTL; obesity; predisposition; transcriptome
J Allergy Clin Immunol. 2016 Aug 20. pii: S0091-6749(16)30804-1. doi: 10.1016/j.jaci.2016.07.017. [Epub ahead of print]
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