Genomics of chronic cough unravels neurological pathways

Abstract

Background Chronic cough is a symptom of common lung conditions, occurs as a side effect of ACE inhibitors (ACEis), or may be unexplained. Despite chronic cough representing a substantial health burden, 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 genetic risk scores (GRS) for these phenotypes to identify pleotropic effects. Findings We found seven novel genetic association signals reaching p-value <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 implicating neurological functions (CTNNA1, KCNA10, MAPKAP1, OR4C12, OR4C13, SIL1). The GRS-PheWAS highlighted associations with increased risk of several conditions reported as comorbidities of chronic cough, including fibromyalgia pain, and with spirometry measurements. Interpretation Our findings advance the understanding of neuronal dysfunction underlying cough hypersensitivity in chronic dry cough and ACEi-induced cough at the population-level, and the identification of comorbidities associated with genetic predisposition to cough could inform drug target discovery. Funding Medical Research Council, Wellcome Trust, National Institute for Health and Care Research, Orion Pharma.