Genetics of Gene Expression in the Lung to Elucidate the Susceptibility of Asthma

Bérubé Jean-Christophe1, Postma Dirkje S2, Sin Don D3, Hao Ke4, Nickle David C5, Timens Wim2, Paré Peter D3, Laviolette Michel1 and Bossé Yohan1,6

1. Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec, Canada; 2. University Medical Center Groningen, GRIAC research institute, University of Groningen, Groningen, The Netherlands; 3. The University of British Columbia Center for Heart Lung Innovation, St-Paul’s Hospital, Vancouver, Canada; 4. Icahn School of Medicine at Mount Sinai, New York, New York, United-States; 5. Merck Research Laboratories, MRL, Seattle, Washington, United States; 6. Department of Molecular Medicine, Laval University, Quebec, Canada

Introduction: Over the past decade, genome-wide association studies (GWAS) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with asthma. However, their relationships with one or more genes involved in disease development remain mostly unexplored.

Aims and Objectives: The main objective of this study is to determine the effect of asthma-associated SNPs discovered by GWAS on gene expression in human lung. Ultimately, the project will uncover new genes most likely involved in the pathogenesis of asthma.

Methodology: Complementary genomic data sets on asthma were used for this project. The main data set consists of an expression quantitative trait loci (eQTL) mapping study in lung tissues from 1038 individuals. Summary statistics of the most important GWAS on asthma were obtained from the GABRIEL consortium. Recent statistical methods that integrate GWAS and eQTL were used to identify causal genes.

Results: Integrative analyses of asthma GWAS and lung eQTL demonstrated colocalization on chromosome 17q21 with the GSDMA gene. For the 5q31 locus, despite nearby genes coding for inflammatory cytokines, the causal gene identified in the lung tissue is SLC22A5. This gene is responsible for the uptake of an anticholinergic drug used in the treatment of asthma. Finally, the IDUA gene is found as the most likely causal gene on chromosome 4p16.

Conclusion: The integration of GWAS results with lung eQTL reveals a potential causal role of GSDMA, SLC22A5 and IDUA genes in asthma. The involvement of these genes in the pathology of asthma must be confirmed experimentally.