Prioritization of Candidate Causal Genes for Asthma in Susceptibility Loci Derived from UK Biobank

Overview

Journal Commun Biol

Specialty Biology

Date 2021 Jun 9

PMID 34103634

Citations 68

Authors

Kim Valette

Zhonglin Li

Valentin Bon-Baret

Arnaud Chignon

Jean-Christophe Berube

Aida Eslami

Jennifer Lamothe

Nathalie Gaudreault

Philippe Joubert

Maen Obeidat

Maarten van den Berge

Wim Timens

Don D Sin

David C Nickle

Ke Hao

Catherine Labbe

Krystelle Godbout

Andreanne Cote

Michel Laviolette

Louis-Philippe Boulet

Patrick Mathieu

Sebastien Theriault

Yohan Bosse

Affiliations

Soon will be listed here.

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 < 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (P = 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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