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

Kim Valette, Zhonglin Li, Valentin Bon-Baret, Arnaud Chignon, Jean-Christophe Bérubé, Aida Eslami, Jennifer Lamothe, Nathalie Gaudreault, Philippe Joubert, Ma'en Obeidat, Maarten van den Berge, Wim Timens, Don D Sin, David C Nickle, Ke Hao, Catherine Labbé, Krystelle Godbout, Andréanne Côté, Michel Laviolette, Louis-Philippe BouletPatrick Mathieu, Sébastien Thériault, Yohan Bossé*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Kim Valette et al. perform a genomic study on asthma integrating genome-wide association study, functional mapping using lung and blood transcriptome-wide profiles, as well as Mendelian randomization. They show candidate causal genes expressed in lung and blood tissues that are putative therapeutic targets for asthma.

Original languageEnglish
Article number700
Number of pages15
JournalCommunications biology
Volume4
Issue number1
DOIs
Publication statusPublished - 8-Jun-2021

Keywords

  • GENOME-WIDE
  • ASSOCIATION
  • RISK
  • SET
  • VARIANTS
  • EQTL

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