Multi-omics colocalization with genome-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus.
Multi-omics colocalization with genome-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus.
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多组学共定位与全基因组关联研究揭示了儿童哮喘发病风险位点的特定背景遗传机制。
DOI：
10.1186/s13073-021-00967-y
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发表时间：
2021-10-10
期刊：
影响因子：
12.3
通讯作者：
Ober C
中科院分区：
文献类型：
--
作者：
Soliai MM;Kato A;Helling BA;Stanhope CT;Norton JE;Naughton KA;Klinger AI;Thompson EE;Clay SM;Kim S;Celedón JC;Gern JE;Jackson DJ;Altman MC;Kern RC;Tan BK;Schleimer RP;Nicolae DL;Pinto JM;Ober C
全基因组关联研究（GWAS）已经确定了数千种与哮喘和其他复杂疾病相关的变异。然而，大多数这些变体的功能效果是未知的。此外，GWAS不提供关于影响特定疾病风险和结果的细胞类型或环境因素的特定信息。为了解决这些局限性，我们使用上呼吸道上皮细胞（AEC）培养模型来评估对鼻病毒（RV）（一种哮喘促进病原体）的转录和表观遗传反应，并为哮喘GWAS中发现的变体提供上下文特异性功能注释。从104名诊断为气道疾病（n=66）或健康参与者（n=38）的个体中收集了溶媒和RV治疗的上AEC的全基因组遗传、基因表达和DNA甲基化数据。我们映射顺式表达和甲基化数量性状基因座（cis-eQTL和cis-meQTL，分别）在每个处理条件下（RV和车辆），从这些人的AEC。AEC分子QTL与成人发作哮喘和儿童发作哮喘GWAS SNP之间共定位的贝叶斯检验，以及哮喘的多种族GWAS，用于将功能分配给与哮喘相关的变体。我们使用孟德尔随机化来证明DNA甲基化对哮喘共定位位点基因表达的影响。哮喘和过敏性疾病相关的GWAS SNPs在AEC的分子QTL中特异性富集，但在非免疫性疾病的GWAS中不富集，在AEC eQTL中特异性富集，但在其他组织的eQTL中不富集。AEC QTL与哮喘GWAS变异体的共定位分析揭示了哮喘的潜在分子机制，包括RV和溶剂治疗以及儿童发作和成人发作哮喘共同的TSLP位点的QTL，以及RV暴露和儿童发作哮喘特异性的17 q12 -21哮喘位点的QTL，与这些位点的临床和流行病学研究一致。这项研究提供了哮喘风险变异体在AEC中的功能效应的证据，并深入了解RV介导的转录和表观遗传反应机制，这些机制调节气道中的遗传效应和哮喘风险。在线版本包含补充材料，可通过10.1186/s13073-021-00967-y获得。
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. The online version contains supplementary material available at 10.1186/s13073-021-00967-y.
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
30.8
作者：
Demenais F;Margaritte-Jeannin P;Barnes KC;Cookson WOC;Altmüller J;Ang W;Barr RG;Beaty TH;Becker AB;Beilby J;Bisgaard H;Bjornsdottir US;Bleecker E;Bønnelykke K;Boomsma DI;Bouzigon E;Brightling CE;Brossard M;Brusselle GG;Burchard E;Burkart KM;Bush A;Chan-Yeung M;Chung KF;Couto Alves A;Curtin JA;Custovic A;Daley D;de Jongste JC;Del-Rio-Navarro BE;Donohue KM;Duijts L;Eng C;Eriksson JG;Farrall M;Fedorova Y;Feenstra B;Ferreira MA;Australian Asthma Genetics Consortium (AAGC) collaborators;Freidin MB;Gajdos Z;Gauderman J;Gehring U;Geller F;Genuneit J;Gharib SA;Gilliland F;Granell R;Graves PE;Gudbjartsson DF;Haahtela T;Heckbert SR;Heederik D;Heinrich J;Heliövaara M;Henderson J;Himes BE;Hirose H;Hirschhorn JN;Hofman A;Holt P;Hottenga J;Hudson TJ;Hui J;Imboden M;Ivanov V;Jaddoe VWV;James A;Janson C;Jarvelin MR;Jarvis D;Jones G;Jonsdottir I;Jousilahti P;Kabesch M;Kähönen M;Kantor DB;Karunas AS;Khusnutdinova E;Koppelman GH;Kozyrskyj AL;Kreiner E;Kubo M;Kumar R;Kumar A;Kuokkanen M;Lahousse L;Laitinen T;Laprise C;Lathrop M;Lau S;Lee YA;Lehtimäki T;Letort S;Levin AM;Li G;Liang L;Loehr LR;London SJ;Loth DW;Manichaikul A;Marenholz I;Martinez FJ;Matheson MC;Mathias RA;Matsumoto K;Mbarek H;McArdle WL;Melbye M;Melén E;Meyers D;Michel S;Mohamdi H;Musk AW;Myers RA;Nieuwenhuis MAE;Noguchi E;O'Connor GT;Ogorodova LM;Palmer CD;Palotie A;Park JE;Pennell CE;Pershagen G;Polonikov A;Postma DS;Probst-Hensch N;Puzyrev VP;Raby BA;Raitakari OT;Ramasamy A;Rich SS;Robertson CF;Romieu I;Salam MT;Salomaa V;Schlünssen V;Scott R;Selivanova PA;Sigsgaard T;Simpson A;Siroux V;Smith LJ;Solodilova M;Standl M;Stefansson K;Strachan DP;Stricker BH;Takahashi A;Thompson PJ;Thorleifsson G;Thorsteinsdottir U;Tiesler CMT;Torgerson DG;Tsunoda T;Uitterlinden AG;van der Valk RJP;Vaysse A;Vedantam S;von Berg A;von Mutius E;Vonk JM;Waage J;Wareham NJ;Weiss ST;White WB;Wickman M;Widén E;Willemsen G;Williams LK;Wouters IM;Yang JJ;Zhao JH;Moffatt MF;Ober C;Nicolae DL
通讯作者：
Nicolae DL
影响因子：
30.8
作者：
Calderon, Diego;Nguyen, Michelle L. T.;Pritchard, Jonathan K.
通讯作者：
Pritchard, Jonathan K.
DOI：
10.1073/pnas.1115761109
发表时间：
2012-01-24
影响因子：
11.1
作者：
Barreiro, Luis B.;Tailleux, Ludovic;Gilad, Yoav
通讯作者：
Gilad, Yoav