Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma.
Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma.
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DOI：
10.1111/all.12990
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发表时间：
2016-12
期刊：
影响因子：
12.4
通讯作者：
Koppelman GH
中科院分区：
文献类型：
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作者：
Nieuwenhuis MA;Siedlinski M;van den Berge M;Granell R;Li X;Niens M;van der Vlies P;Altmüller J;Nürnberg P;Kerkhof M;van Schayck OC;Riemersma RA;van der Molen T;de Monchy JG;Bossé Y;Sandford A;Bruijnzeel-Koomen CA;Gerth van Wijk R;Ten Hacken NH;Timens W;Boezen HM;Henderson J;Kabesch M;Vonk JM;Postma DS;Koppelman GH
哮喘的全基因组关联研究（GWAS）已经确定了可适度增加哮喘风险的单核苷酸多态性（SNP）。这可能是由于哮喘的表型异质性。支气管高反应性（BHR）是哮喘的表型标志。我们的目的是确定哮喘合并BHR的易感基因，并分析复制的SNPs中是否存在顺式eQTL。其次，我们将先前与（医生诊断的）哮喘相关的SNP的遗传关联与我们的哮喘与BHR的GWAS进行比较。在920例BHR哮喘患者和980例对照者中进行了GWAS。在四个复制队列中分析了我们的GWAS的顶部SNP，并对复制的SNP进行了肺顺式eQTL分析。我们在我们的数据中调查了先前与哮喘相关的SNP的关联。对368个SNP进行了复制追踪。编码ABI 3BP、NAF 1、云母和17 q21位点的基因中的6个SNP在一个或多个队列中复制，其中一个位点（17 q21）在荟萃分析后达到全基因组显著性。6个重复的SNPs中有5个在全肺中调控35个基因转录本。来自先前GWAS的20个哮喘相关SNPs中有8个与哮喘和BHR显著相关。与已发表的文献相比，IL-33和GSDMB中的三个SNP在我们的数据中显示出更大的效应量。将GWAS与随后的肺eQTL分析相结合，揭示了与疾病相关的SNP调节潜在的新哮喘基因的肺mRNA表达水平。将BHR添加到哮喘定义中不会导致比分析（医生诊断）哮喘更大的遗传效应大小。
Genome wide association studies (GWAS) of asthma have identified single nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor diagnosed) asthma to our GWAS of asthma with BHR. A GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts and lung cis-eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data. 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genome wide significance after meta-analysis. Five out of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to published literature. Combining GWAS with subsequent lung eQTL analysis revealed disease associated SNPs regulating lung mRNA expression levels of potential new asthma genes. Adding BHR to the asthma definition does not lead to an overall larger genetic effect size than analysing (doctor’s diagnosed) asthma.
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影响因子：
5.2
作者：
Ferreira, Manuel A. R.;McRae, Allan F.;Martin, Nicholas G.
通讯作者：
Martin, Nicholas G.
影响因子：
16.6
作者：
Ha, Sung Gil;Ge, Xiao Na;Bahaie, Nooshin S.;Kang, Bit Na;Rao, Amrita;Rao, Savita P.;Sriramarao, P.
通讯作者：
Sriramarao, P.
影响因子：
168.9
作者：
Ferreira, Manuel A. R.;Matheson, Melanie C.;Duffy, David L.;Marks, Guy B.;Hui, Jennie;Le Souef, Peter;Danoy, Patrick;Baltic, Svetlana;Nyholt, Dale R.;Jenkins, Mark;Hayden, Catherine;Willemsen, Gonneke;Ang, Wei;Kuokkanen, Mikko;Beilby, John;Cheah, Faang;de Geus, Eco J. C.;Ramasamy, Adaikalavan;Vedantam, Sailaja;Salomaa, Veikko;Madden, Pamela A.;Heath, Andrew C.;Hopper, John L.;Visscher, Peter M.;Musk, Bill;Leeder, Stephen R.;Jarvelin, Marjo-Riitta;Pennell, Craig;Boomsma, Dorret I.;Hirschhorn, Joel N.;Walters, Haydn;Martin, Nicholas G.;James, Alan;Jones, Graham;Abramson, Michael J.;Robertson, Colin F.;Dharmage, Shyamali C.;Brown, Matthew A.;Montgomery, Grant W.;Thompson, Philip J.
通讯作者：
Thompson, Philip J.
影响因子：
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作者：
Anantharaman R;Andiappan AK;Nilkanth PP;Suri BK;Wang de Y;Chew FT
通讯作者：
Chew FT
影响因子：
30.8
作者：
通讯作者：
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