慢性干咳的基因组学揭示了神经通路。

IF 16.6 1区 医学 Q1 RESPIRATORY SYSTEM
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
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引用次数: 0

摘要

背景:慢性干咳是常见肺部疾病的症状,作为ACE抑制剂(ACEis)的副作用发生,或者可能无法解释。尽管慢性干咳是一种严重的健康负担,但其生物学机制尚不清楚。我们假设慢性干咳和acei引起的咳嗽之间存在共同的遗传结构,并旨在确定这两种表型的致病基因。方法:我们利用5项队列研究的数据,对慢性干咳和acei诱导的咳嗽进行了多祖先全基因组关联研究(GWAS),以及两种表型的多性状GWAS。慢性干咳是通过问卷调查来定义的,而acei诱发的咳嗽是通过电子病历中的治疗开关或临床诊断来定义的。我们绘制了假定的致病基因,并对相关变异进行了全表型关联研究(PheWAS),并对acei诱发的咳嗽进行了多基因评分,以确定多效性效应。结果:在慢性干咳和acei致咳的多性状或单性状分析中,我们发现了7个新的p值达到-8的遗传关联信号。这些新变异映射到10个新基因,我们将另外3个新基因映射到已知的风险变异,其中许多与神经功能有关(CTNNA1, KCNA10, MAPKAP1, OR4C12, OR4C13, SIL1)。基于多基因评分的PheWAS强调了与哮喘、糖尿病和多部位慢性疼痛等几种临床疾病风险升高的关联。结论:我们的研究结果为慢性干咳和acei诱导的咳嗽过敏的神经功能障碍提供了支持,并确定了与咳嗽遗传易感性相关的疾病和特征,为药物靶点的发现提供了信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
European Respiratory Journal
European Respiratory Journal 医学-呼吸系统
CiteScore
27.50
自引率
3.30%
发文量
345
审稿时长
2-4 weeks
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.
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