Genomics of chronic dry cough unravels neurological pathways

Abstract

Background: Chronic dry cough is a symptom of common lung conditions, can occur as a side-effect of angiotensin-converting enzyme inhibitors (ACEis), or may be unexplained. Despite the substantial health burden presented by chronic dry cough, its biological mechanisms remain unclear. We hypothesised shared genetic architecture between chronic dry cough and ACEi-induced cough and aimed to identify causal genes underlying both phenotypes.

Methods: We performed multi-ancestry genome-wide association studies (GWAS) of chronic dry cough and ACEi-induced cough, and a multi-trait GWAS of both phenotypes, utilising data from five cohort studies. Chronic dry cough was defined by questionnaire responses, and ACEi-induced cough by treatment switches or clinical diagnosis in electronic health records. We mapped putative causal genes and performed phenome-wide association studies (PheWAS) of associated variants, and polygenic scores for ACEi-induced cough, to identify pleiotropic effects.

Results: We found seven novel genetic association signals reaching p<5×10^-8 in the multi-trait or single-trait analyses of chronic dry cough and ACEi-induced cough. The novel variants mapped to 10 novel genes, and we mapped an additional three novel genes to known risk variants, many of which implicate neurological functions (CTNNA1, KCNA10, MAPKAP1, OR4C12, OR4C13, SIL1). The polygenic-score-based PheWAS highlighted associations with an elevated risk of several clinical conditions including asthma, diabetes and multi-site chronic pain.

Conclusion: Our findings provide support for neuronal dysfunction underlying cough hypersensitivity in chronic dry cough and ACEi-induced cough, and identify diseases and traits associated with genetic predisposition to cough that could inform drug target discovery.

Overview of the study. GWAS: genome-wide association study; ACEi: angiotensin-converting enzyme inhibitor.

FIGURE 1

Study design. GWAS: genome-wide association studies; EUR: European; SAS: South Asian; ACEi: angiotensin-converting enzyme inhibitor; AFR: African; EAS: East Asian; PheWAS: phenome-wide association studies; QTL: quantitative trait loci. ^#: defined by the authors of that study [19].

FIGURE 2

Manhattan plot for the multi-trait genome-wide association study of chronic dry cough and angiotensin-converting enzyme induced cough. The dotted grey line represents the genome-wide significance threshold (p<5×10^–8). Sentinels are highlighted orange and mapped genes are labelled; grey boxes indicate novel sentinels.

FIGURE 3

Functional summary of putative causal genes. Based on integration of evidence from multiple sources, including GeneCards [30], Open Targets Platform [31], Online Mendelian Inheritance in Man [32], the Drug–Gene Interaction Database [33] and published literature. Variant-to-gene mapping evidence is provided in supplementary figure S1 and supplementary table S8. Novel genes are presented in bold.

FIGURE 4

Angiotensin-converting enzyme induced cough polygenic score-based phenotype-wide association study results stratified by a) quantitative and b) binary phenotypes. FDR: false discovery rate; DFP: data-field phenotype; cDFP: combined data-field phenotype; CP: composite phenotype.