Genomics of chronic cough unravels neurological pathways

Abstract

AbstractBackgroundChronic 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.MethodsWe 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.FindingsWe found seven novel genetic association signals reachingp-value <5×10−8in 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.InterpretationOur 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.FundingMedical Research Council, Wellcome Trust, National Institute for Health and Care Research, Orion Pharma.Research in contextEvidence before this studyWe searched the National Human Genome Research Institute-European Bioinformatic Institute Catalog of human genome-wide association studies (GWAS) from inception through to 21stMay 2024, using the search term “cough” to identify publications which tested association between genetic variants and cough. Additionally, we searched PubMed for English language articles published before 21stMay 2024 using the terms “cough” or “ACE inhibitor” combined with “genome-wide association” to find relevant publications. We manually filtered the results from both searches to ensure the cough-related publications related to a dry, unproductive cough. To date, there have been no GWAS of unexplained dry cough, while several for ACE inhibitor (ACEi)-induced cough have identified 11 associated genetic loci at genome-wide significance (p-value <5×10−8). These loci have implicated genes involved in neuronal excitability and the bradykinin pathway.Added value of this studyWe present the first multi-ancestry GWAS of chronic dry cough, defined using questionnaire responses, and the largest multi-ancestry GWAS of ACEi-induced cough, characterised by either a medication switch from an ACEi to an angiotensin-II receptor blocker or a clinical diagnosis. By leveraging the clinical and genetic overlap between these two traits, we conducted a multi-trait GWAS to identify novel associated loci. Across the multi-trait and single-trait analyses, we identified seven novel associated loci at genome-wide significance (p-value <5×10−8), mapped to 10 genes which have not previously been linked to cough phenotypes.Implications of all the available evidenceWe identified novel genes involved in neurological processes (CTNNA1, KCNA10, OR4C12, OR4C13) or implicated in neurological or neurodegenerative conditions (SIL1andMAPKAP1). The genes we implicate from all genetic associations with cough to date support the role of neurobiological processes underlying dry cough biology, and highlight potential therapeutic targets.