Kayesha Coley, Catherine John, Jonas Ghouse, David J Shepherd, Nick Shrine, Abril G Izquierdo, Stavroula Kanoni, Emma F Magavern, Richard Packer, Lorcan McGarvey, Jaclyn A Smith, Henning Bundgaard, Sisse R Ostrowski, Christian Erikstrup, Ole B V Pedersen, David A van Heel, William Hennah, Mikko Marttila, Robert C Free, Edward J Hollox, Louise V Wain, Martin D Tobin, Chiara Batini
{"title":"慢性干咳的基因组学揭示了神经通路。","authors":"Kayesha Coley, Catherine John, Jonas Ghouse, David J Shepherd, Nick Shrine, Abril G Izquierdo, Stavroula Kanoni, Emma F Magavern, Richard Packer, Lorcan McGarvey, Jaclyn A Smith, Henning Bundgaard, Sisse R Ostrowski, Christian Erikstrup, Ole B V Pedersen, David A van Heel, William Hennah, Mikko Marttila, Robert C Free, Edward J Hollox, Louise V Wain, Martin D Tobin, Chiara Batini","doi":"10.1183/13993003.02341-2024","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Chronic dry cough is a symptom of common lung conditions, occurs as a side effect of ACE inhibitors (ACEis), or may be unexplained. Despite chronic dry 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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>We found seven novel genetic association signals reaching p-value <5×10<sup>-8</sup> 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 (<i>CTNNA1</i>, <i>KCNA10</i>, <i>MAPKAP1</i>, <i>OR4C12</i>, <i>OR4C13</i>, <i>SIL1</i>). The polygenic score-based PheWAS highlighted associations with an elevated risk of several clinical conditions including asthma, diabetes and multi-site chronic pain.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":" ","pages":""},"PeriodicalIF":16.6000,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genomics of chronic dry cough unravels neurological pathways.\",\"authors\":\"Kayesha Coley, Catherine John, Jonas Ghouse, David J Shepherd, Nick Shrine, Abril G Izquierdo, Stavroula Kanoni, Emma F Magavern, Richard Packer, Lorcan McGarvey, Jaclyn A Smith, Henning Bundgaard, Sisse R Ostrowski, Christian Erikstrup, Ole B V Pedersen, David A van Heel, William Hennah, Mikko Marttila, Robert C Free, Edward J Hollox, Louise V Wain, Martin D Tobin, Chiara Batini\",\"doi\":\"10.1183/13993003.02341-2024\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Chronic dry cough is a symptom of common lung conditions, occurs as a side effect of ACE inhibitors (ACEis), or may be unexplained. Despite chronic dry 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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>We found seven novel genetic association signals reaching p-value <5×10<sup>-8</sup> 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 (<i>CTNNA1</i>, <i>KCNA10</i>, <i>MAPKAP1</i>, <i>OR4C12</i>, <i>OR4C13</i>, <i>SIL1</i>). The polygenic score-based PheWAS highlighted associations with an elevated risk of several clinical conditions including asthma, diabetes and multi-site chronic pain.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":12265,\"journal\":{\"name\":\"European Respiratory Journal\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":16.6000,\"publicationDate\":\"2025-07-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Respiratory Journal\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1183/13993003.02341-2024\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RESPIRATORY SYSTEM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Respiratory Journal","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1183/13993003.02341-2024","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
Genomics of chronic dry cough unravels neurological pathways.
Background: Chronic dry cough is a symptom of common lung conditions, occurs as a side effect of ACE inhibitors (ACEis), or may be unexplained. Despite chronic dry 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 polygenic scores for ACEi-induced cough, to identify pleiotropic effects.
Results: 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 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.
期刊介绍:
The European Respiratory Journal (ERJ) is the flagship journal of the European Respiratory Society. It has a current impact factor of 24.9. The journal covers various aspects of adult and paediatric respiratory medicine, including cell biology, epidemiology, immunology, oncology, pathophysiology, imaging, occupational medicine, intensive care, sleep medicine, and thoracic surgery. In addition to original research material, the ERJ publishes editorial commentaries, reviews, short research letters, and correspondence to the editor. The articles are published continuously and collected into 12 monthly issues in two volumes per year.