Using Integrative Genomics To Identify and Characterize Emphysema-Associated eQTL
Using Integrative Genomics To Identify and Characterize Emphysema-Associated eQTL
批准号:
10653966
负责人:
Peter Castaldi
金额:
$72.22万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
未结题
起止时间:
2014-09-01 至 2025-05-31
关键词:
ACVR1B geneAffectAlternative SplicingAlveolar CellApoptosisBase SequenceBioinformaticsBiological AssayBiologyBloodBlood specimenCell AgingCellsChronic Obstructive Pulmonary DiseaseDataDiseaseDrug TargetingElementsEpithelial CellsFDA approvedFibroblastsGene ExpressionGenesGeneticGenetic DiseasesGenomicsGenotypeGoalsHematological DiseaseHumanHuman GeneticsInflammationInterdisciplinary StudyLeadershipLungMapsMeasuresMethodsMinorityMolecular BiologyPersonsPhasePhenotypePlayProtein IsoformsPulmonary EmphysemaQuantitative Trait LociRNARNA SplicingReporterResearchResearch PriorityResourcesRoleSamplingSpliced GenesStructure of parenchyma of lungTGFB2 geneTechnologyTestingTissue ProcurementsTissuesTrans-Omics for Precision MedicineTransforming Growth Factor Beta 2Translational ResearchVariantVascular Endothelial Cellairway epitheliumcell bankcell typecigarette smokecohortdifferential expressiondisorder riskgenetic variantgenome wide association studygenome-widegenomic locusimprovedlung injurymortalitynanoporenovelprogramspublic health relevancetranscriptome sequencing
中文摘要
项目概述:慢性阻塞性肺疾病(COPD)是一种进行性、使人衰弱的疾病,
哪些新的疾病治疗方法是迫切需要的。由于药物靶点由人类支持,
基因证据更有可能导致FDA批准的治疗,基因组的功能表征,
广泛关联研究(GWAS)基因座是翻译研究的优先事项。我们小组起了带头作用
在COPD GWAS中,迄今为止最大的COPD GWAS已经确定了82个重要位点,其中大多数具有
没有功能特征。在该项目的第一阶段,我们结合了肺气肿GWAS结果,
与表达数量性状基因座(eQTL)的研究,采用GWAS-eQTL共定位方法,
COPD GWAS靶基因。这种方法使我们能够优先考虑TGFB 2和ACVR 1B进行功能研究
在呼吸道上皮细胞和肺成纤维细胞中发现了这些基因座的功能变异。然而,>50%
的COPD GWAS位点尚未显示出与eQTL的强共定位,部分原因是固有的局限性
依赖于基因水平表达定量的eQTL,不反映替代效应。
拼接选择性剪接是GWAS基因座的一种重要功能机制,可能与
重要的eQTL。在该项目的下一阶段,我们建议鉴定新的COPD相关遗传学。
改变剪接的变体(sQTL)并表征其异构体特异性效应。在目标1中,我们将
使用两个具有大量的RNA序列的RNA-seq资源,在全基因组范围内发现剪接QTL(sQTL)。
COPD受试者-来自COPD基因研究中4,515名受试者的血液RNA-seq和来自
肺组织研究联盟(LTRC)中的1,078例受试者。使用colocalization方法,我们将
鉴定新COPD GWAS靶基因,其剪接被COPD相关遗传变异体改变。在
目的2,我们将通过评估COPD中差异表达和差异使用的亚型,
来自LTRC中1,078例COPD病例和对照的短读肺组织RNA-seq的同种型定量。
然后,我们将生成10个COPD GWAS基因的Oxford Nanopore Technologies(ONT)长读段RNA-seq
在80名患有COPD的LTRC受试者和80名对照者中使用靶向富集方法。在目标3中,我们
联合收割机精细定位和功能研究,以确定COPD GWAS变异,改变原发性
肺细胞首先,我们将使用靶向长读段RNA-seq来表征细胞类型特异性同种型
在四种主要肺细胞类型中的COPD GWAS靶基因谱。我们将在功能上验证精细-
使用剪接报告基因检测绘制COPD GWAS变异体,我们将描述这些变异体的作用。
通过来自Marsico的基因型选择的气道上皮细胞中COPD相关细胞表型的变体
肺脏研究所细胞库。我们的多学科研究团队在COPD遗传学方面具有必要的专业知识
以及基因组学、分子生物学、长读段测序、剪接和RNA生物学来完成这一重要的
该项目旨在鉴定参与选择性剪接的新型COPD GWAS靶基因。
英文摘要
Project Summary: Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disease for
which new, disease-modifying treatments are desperately needed. Since drug targets supported by human
genetic evidence are more likely to lead to FDA-approved treatments, functional characterization of genome-
wide association study (GWAS) loci is a translational research priority. Our group has played a leading role
in COPD GWAS, and the largest COPD GWAS to date has identified 82 significant loci, most of which have
not been functionally characterized. In the first phase of this project, we combined emphysema GWAS results
with expression quantitative trait locus (eQTL) studies, using GWAS-eQTL colocalization methods to identify
COPD GWAS target genes. This approach allowed us to prioritize TGFB2 and ACVR1B for functional studies
in airway epithelial cells and lung fibroblasts that identified functional variants in these loci. However, >50%
of COPD GWAS loci have not yet shown strong colocalization with eQTLs, due in part to inherent limitations
of eQTLs which depend on gene-level expression quantifications that do not reflect effects of alternative
splicing. Alternative splicing is an important functional mechanism for GWAS loci, perhaps equally as
important as eQTLs. In the next phase of this project, we propose to identify novel COPD-associated genetic
variants that alter splicing (sQTLs) and characterize their isoform-specific effects. In Aim 1, we will perform
genome-wide discovery of splicing QTLs (sQTLs) using two RNA-seq resources with large numbers of
subjects with COPD – blood RNA-seq from 4,515 subjects in the COPDGene Study and lung RNA-seq from
1,078 subjects in the Lung Tissue Research Consortium (LTRC). Using colocalization methods, we will
identify novel COPD GWAS target genes whose splicing is altered by COPD-associated genetic variants. In
Aim 2, we will identify differentially expressed and differentially used isoforms in COPD using estimated
isoform quantifications from short read lung tissue RNA-seq in 1,078 COPD cases and controls in the LTRC.
We will then generate Oxford Nanopore Technologies (ONT) long read RNA-seq for 10 COPD GWAS genes
in 80 LTRC subjects with COPD and 80 controls using a targeted enrichment approach. In Aim 3, we will
combine fine mapping and functional studies to identify COPD GWAS variants that alter splicing in primary
lung cells. First, we will use targeted long read RNA-seq to characterize the cell-type specific isoform
profiles of COPD GWAS target genes in four primary lung cell types. We will then functionally validate fine-
mapped COPD GWAS variants using splicing reporter assays, and we will characterize the effects of these
variants on COPD-related cellular phenotypes in airway epithelial cells selected by genotype from the Marsico
Lung Institute cell bank. Our multi-disciplinary research team has the requisite expertise in COPD genetics
and genomics, molecular biology, long read sequencing, splicing and RNA biology to complete this important
project to identify novel COPD GWAS target genes involved in alternative splicing.
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DOI:
10.1186/s12931-017-0558-1
发表时间:
2017-04-24
期刊:
Respiratory research
影响因子:
5.8
作者:
[Obeidat M, Nie Y, Chen V, Shannon CP, Andiappan AK, Lee B, Rotzschke O, Castaldi PJ, Hersh CP, Fishbane N, Ng RT, McManus B, Miller BE, Rennard S, Paré PD, Sin DD]
通讯作者:
Sin DD
Turning subtypes into disease axes to improve prediction of COPD progression.
将亚型转化为疾病轴以改善对慢性阻塞性肺病进展的预测。
DOI:
10.1136/thoraxjnl-2018-213005
发表时间:
2019
期刊:
Thorax
影响因子:
10
作者:
[Chen,Junxiang, Cho,Michael, Silverman,EdwinK, Hokanson,JohnE, Kinney,GregL, Crapo,JamesD, Rennard,Stephen, Dy,Jennifer, Castaldi,Peter]
通讯作者:
Castaldi,Peter
A Bayesian Nonparametric Model for Disease Subtyping: Application to Emphysema Phenotypes.
贝叶斯非参数模型用于疾病亚型:应用于肺气肿表型。
DOI:
10.1109/tmi.2016.2608782
发表时间:
2017-01
期刊:
IEEE transactions on medical imaging
影响因子:
10.6
作者:
[Ross JC, Castaldi PJ, Cho MH, Chen J, Chang Y, Dy JG, Silverman EK, Washko GR, Jose Estepar RS]
通讯作者:
Jose Estepar RS
DOI:
10.1038/s41598-023-28156-4
发表时间:
2023-01-24
期刊:
Scientific reports
影响因子:
4.6
作者:
[]
通讯作者:
Peripheral blood microbial signatures in current and former smokers.
当前和前吸烟者中的外周血微生物特征。
DOI:
10.1038/s41598-021-99238-4
发表时间:
2021-10-06
期刊:
Scientific reports
影响因子:
4.6
作者:
[Morrow JD, Castaldi PJ, Chase RP, Yun JH, Lee S, Liu YY, Hersh CP]
通讯作者:
Hersh CP
共 15 条
Prospective Health Outcomes and Inflammatory Biomarkers Associated with e-Cigarette Use
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批准号:10018099
-
项目类别:
-
资助金额:$50.93万
-
财政年份:2019
-
负责人:Peter Castaldi
-
依托单位:
Prospective Health Outcomes and Inflammatory Biomarkers Associated with e-Cigarette Use
-
批准号:10226191
-
项目类别:
-
资助金额:$51.27万
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财政年份:2019
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负责人:Peter Castaldi
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依托单位:
Using Integrative Genomics To Identify and Characterize Emphysema-Associated eQTL
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批准号:8762578
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项目类别:
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资助金额:$87.32万
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财政年份:2014
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负责人:Peter Castaldi
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依托单位:
Using Integrative Genomics To Identify and Characterize Emphysema-Associated eQTL
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批准号:10471299
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项目类别:
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资助金额:$63.4万
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财政年份:2014
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负责人:Peter Castaldi
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依托单位:
Using Integrative Genomics To Identify and Characterize Emphysema-Associated eQTL
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批准号:8913766
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项目类别:
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资助金额:$86.88万
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财政年份:2014
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负责人:Peter Castaldi
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依托单位:
Using Integrative Genomics To Identify and Characterize Emphysema-Associated eQTL
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批准号:10298583
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项目类别:
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资助金额:$67.63万
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财政年份:2014
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负责人:Peter Castaldi
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依托单位:
Predictive Modeling with Clinical and Genomic Data in COPD
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批准号:8063638
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项目类别:
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资助金额:$12.83万
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财政年份:2010
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负责人:Peter Castaldi
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依托单位:
Predictive Modeling with Clinical and Genomic Data in COPD
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批准号:8500430
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项目类别:
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资助金额:$12.83万
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财政年份:2010
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负责人:Peter Castaldi
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依托单位:
Predictive Modeling with Clinical and Genomic Data in COPD
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批准号:8668035
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项目类别:
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资助金额:$12.83万
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财政年份:2010
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负责人:Peter Castaldi
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依托单位:
Predictive Modeling with Clinical and Genomic Data in COPD
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批准号:7875053
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项目类别:
-
资助金额:$12.83万
-
财政年份:2010
-
负责人:Peter Castaldi
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依托单位:
Predictive Modeling with Clinical and Genomic Data in COPD
-
批准号:8261100
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项目类别:
-
资助金额:$12.83万
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财政年份:2010
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负责人:Peter Castaldi
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依托单位:
Systematic Review and Meta-Analysis of COPD Genetic Studies
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批准号:7545112
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项目类别:
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资助金额:$7.1万
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财政年份:2008
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负责人:Peter Castaldi
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依托单位:
海外基金