Dataset Information

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank.

ABSTRACT: To identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (P_GWAS < 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (P_TWAS = 1.42E-54). Other TWAS genes include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). We demonstrate that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants is in the blood. We map 485 blood eQTL-regulated genes associated with asthma and 50 of them are causal by Mendelian randomization. Prioritization of druggable genes reveals known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.

SUBMITTER: Valette K

PROVIDER: S-EPMC8187656 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank.

Valette Kim K Li Zhonglin Z Bon-Baret Valentin V Chignon Arnaud A Bérubé Jean-Christophe JC Eslami Aida A Lamothe Jennifer J Gaudreault Nathalie N Joubert Philippe P Obeidat Ma'en M van den Berge Maarten M Timens Wim W Sin Don D DD Nickle David C DC Hao Ke K Labbé Catherine C Godbout Krystelle K Côté Andréanne A Laviolette Michel M Boulet Louis-Philippe LP Mathieu Patrick P Thériault Sébastien S Bossé Yohan Y

Communications biology 20210608 1

To identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (P<sub>GWAS</sub> < 5.0E-8). The most significant lun ...[more]

PMID: 34103634

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Project description:BackgroundHundreds of candidate genes have been associated with coronary artery disease (CAD) through genome-wide association studies. However, a systematic way to understand the causal mechanism(s) of these genes, and a means to prioritize them for further study, has been lacking. This represents a major roadblock for developing novel disease- and gene-specific therapies for patients with CAD. Recently, powerful integrative genomics analyses pipelines have emerged to identify and prioritize candidate causal genes by integrating tissue/cell-specific gene expression data with genome-wide association study data sets.MethodsWe aimed to develop a comprehensive integrative genomics analyses pipeline for CAD and to provide a prioritized list of causal CAD genes. To this end, we leveraged several complimentary informatics approaches to integrate summary statistics from CAD genome-wide association studies (from UK Biobank and CARDIoGRAMplusC4D) with transcriptomic and expression quantitative trait loci data from 9 cardiometabolic tissue/cell types in the STARNET study (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task).ResultsWe identified 162 unique candidate causal CAD genes, which exerted their effect from between one and up to 7 disease-relevant tissues/cell types, including the arterial wall, blood, liver, skeletal muscle, adipose, foam cells, and macrophages. When their causal effect was ranked, the top candidate causal CAD genes were CDKN2B (associated with the 9p21.3 risk locus) and PHACTR1; both exerting their causal effect in the arterial wall. A majority of candidate causal genes were represented in cross-tissue gene regulatory co-expression networks that are involved with CAD, with 22/162 being key drivers in those networks.ConclusionsWe identified and prioritized candidate causal CAD genes, also localizing their tissue(s) of causal effect. These results should serve as a resource and facilitate targeted studies to identify the functional impact of top causal CAD genes.

Dataset Information

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank.

Publications

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank.

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