Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank
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 (PGWAS < 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (PTWAS = 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.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2021 |
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Erschienen: |
2021 |
Enthalten in: |
Zur Gesamtaufnahme - volume:4 |
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Enthalten in: |
Communications biology - 4(2021), 1 vom: 08. Juni, Seite 700 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Valette, Kim [VerfasserIn] |
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Anmerkungen: |
Date Completed 11.08.2021 Date Revised 23.02.2022 published: Electronic Citation Status MEDLINE |
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doi: |
10.1038/s42003-021-02227-6 |
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funding: |
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PPN (Katalog-ID): |
NLM326517316 |
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520 | |a 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 (PGWAS < 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (PTWAS = 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 | ||
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700 | 1 | |a Chignon, Arnaud |e verfasserin |4 aut | |
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700 | 1 | |a Eslami, Aida |e verfasserin |4 aut | |
700 | 1 | |a Lamothe, Jennifer |e verfasserin |4 aut | |
700 | 1 | |a Gaudreault, Nathalie |e verfasserin |4 aut | |
700 | 1 | |a Joubert, Philippe |e verfasserin |4 aut | |
700 | 1 | |a Obeidat, Ma'en |e verfasserin |4 aut | |
700 | 1 | |a van den Berge, Maarten |e verfasserin |4 aut | |
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700 | 1 | |a Hao, Ke |e verfasserin |4 aut | |
700 | 1 | |a Labbé, Catherine |e verfasserin |4 aut | |
700 | 1 | |a Godbout, Krystelle |e verfasserin |4 aut | |
700 | 1 | |a Côté, Andréanne |e verfasserin |4 aut | |
700 | 1 | |a Laviolette, Michel |e verfasserin |4 aut | |
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700 | 1 | |a Thériault, Sébastien |e verfasserin |4 aut | |
700 | 1 | |a Bossé, Yohan |e verfasserin |4 aut | |
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