The Genetic Architecture of Chronic Cough: From Sensory Hypersensitivity to Treatable Trait

Abstract

Chronic cough is a prevalent global clinical disorder with substantial quality-of-life impairment, and refractory cases remain a major unmet medical need. Cough hypersensitivity syndrome is the core pathological mechanism of chronic cough, and growing genetic evidence has confirmed that inherited susceptibility shapes cough hypersensitivity, clinical heterogeneity and therapeutic responsiveness, redefining chronic cough as a biologically mediated sensory–neural disorder rather than a non-specific secondary symptom of airway diseases. This review summarises genetic evidence for chronic cough from family-based studies, pharmacogenomics and genome-wide association studies (GWAS), revealing distinct genetic architectures of chronic dry cough and sputum production, with enrichment of sensory–neural pathway variants and key genetic loci such as replication factor C subunit 1 (RFC1) functional genomic analyses link genetic variation to vagal afferent excitability, and rare genetic neurological disorders further illuminate the neurogenic basis of cough hypersensitivity. Moreover, genetic insights identify tractable treatable traits and rationalise antitussive drug development, supporting genotype-guided patient stratification. We conclude that integrating genetic architecture into clinical phenotyping and translational research provides a critical framework for precision management of chronic cough, and future progress relies on harmonised deep phenotyping and multi-ancestry genetic studies.

Key Summary Points

Inherited susceptibility contributes to cough reflex sensitivity and clinical heterogeneity in chronic cough, but acts in concert with inflammatory, environmental and pharmacological modifiers rather than independently.

Genetic evidence from family studies, pharmacogenomics and genome-wide association studies supports a heritable contribution to chronic cough, particularly chronic dry cough, while also indicating that dry cough and sputum production have partly distinct biological architectures.

Rare sensory neuropathies, including cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) and replication factor C subunit 1 (RFC1)-associated disease, provide mechanistic support for a neurogenic framework of cough hypersensitivity, although they account for only a minority of cases.

Genetic insights identify tractable treatable traits (e.g. P2X3 purinergic signaling) and rationalise antitussive drug development, supporting genotype- guided patient stratification for precision management.

Future progress in cough genetics will depend on deep phenotyping, multi-ancestry studies and functional validation, together with better integration of genetic findings with established clinical and inflammatory treatable traits.

Introduction

Chronic cough, conventionally defined in adults as cough lasting longer than 8 weeks, is now recognised as a distinct clinical entity in international respiratory guidance rather than merely a non-specific manifestation of other airway diseases [1, 2]. It is common in the general population, frequently encountered in respiratory practice and associated with substantial impairment in quality of life and increased healthcare utilization, making it an important global clinical problem [3]. Despite structured diagnostic algorithms and guideline-directed management, a substantial proportion of patients develop refractory chronic cough (RCC) that remains resistant to therapy or has no identifiable underlying aetiology [4, 5].

The concept of cough hypersensitivity syndrome has reshaped current understanding of chronic cough by framing it as a disorder of heightened cough reflex sensitivity rather than simply the downstream consequence of airway disease [6–9]. This model helps explain differences in symptom burden, trigger sensitivity and treatment response among patients with similar comorbid diagnoses [10, 11]. Increasingly, chronic cough is viewed as a sensory–neural disorder in which inherited susceptibility interacts with inflammatory, environmental and pharmacological exposures to shape clinical expression and therapeutic responsiveness [12, 13]. In this framework, genetic factors contribute to vulnerability and heterogeneity, but do not act in isolation from external and clinical modifiers.

This perspective links chronic cough more directly to sensory–neural biology and provides a conceptual basis for moving beyond descriptive clinical labels towards mechanism-informed phenotyping [12, 13]. Thus, this review examines the genetic architecture of chronic cough through the lenses of heritability, genomic discovery, functional interpretation and translational relevance. It further explores how rare neurological disorders may inform understanding of disease susceptibility, pathophysiology and future therapeutic strategies for chronic cough [13–15].

Aim Of The Review

This review aims to summarise current evidence on the genetic basis of chronic cough and to evaluate its relevance to cough hypersensitivity, clinical heterogeneity and therapeutic development. It further examines how genomic discovery, functional interpretation and insights from rare sensory neuropathies may contribute to a more integrated and biologically informed framework for chronic cough.

Clinical Phenotype and Burden: Setting the Translational Stage

Chronic cough exhibits pronounced clinical heterogeneity, with substantial variability in symptom frequency, trigger sensitivity and response to treatment [16]. A common feature is coughing triggered by innocuous physical, chemical or thermal stimuli that would not elicit a cough reflex in healthy individuals, consistent with heightened cough reflex sensitivity [17]. These features often persist even after appropriate treatment of associated conditions, highlighting the limited explanatory value of classifying chronic cough solely based on comorbid disease diagnoses [5, 18].

The burden of chronic cough extends far beyond respiratory symptoms. Population-based studies and patient registries consistently demonstrate significant impairment in health-related quality of life, including sleep disturbance, fatigue and social dysfunction [19, 20]. Healthcare utilisation among this patient population is markedly elevated, characterised by repeated consultations, diagnostic testing and empirical therapeutic trials [21–23], due to a failure to appreciate chronic cough itself as the aetiology. These adverse impacts are observed across different countries and healthcare systems, confirming that chronic cough is a global clinical problem with substantial unmet medical needs [3, 24].

Despite its high prevalence and significant clinical impact, conventional clinical phenotyping offers little insight into why chronic cough develops in some individuals but not others exposed to similar environmental or clinical factors [22, 24]. Family history has emerged as an independent risk factor for chronic cough, supporting a role of inherited genetic susceptibility in disease pathogenesis [14]. Combined with the observed variation in prevalence across populations, these findings suggest that genetic factors may modulate individual vulnerability and shape its clinical presentation. This further strengthens the rationale for integrating genetic perspectives into both clinical assessment and translational research of chronic cough [25, 26].

An important insight from recent work is that inherited susceptibility may contribute to the marked heterogeneity of chronic cough, including differences in symptom burden, trigger profiles and treatment response [16, 27, 28]. However, this heterogeneity is unlikely to be explained by genetic factors alone. Rather, chronic cough is better understood as emerging from interaction between sensory–neural vulnerability and non-genetic influences, including airway inflammation, environmental irritants, infections and reflux-related mechanism with phenotypic subtype of cough medications [29]. This integrative framework helps explain why patients with similar diagnostic labels may follow different clinical trajectories [13].

Accumulating evidence supports a reframing of chronic cough as a biologically mediated sensory disorder in which neural susceptibility, inflammatory processes and environmental exposures interact [30]. While individual genetic associations and mechanistic pathways have been described in detail, their broader significance lies in the recognition that inherited variation modulates baseline cough reflex sensitivity and interacts with environmental and clinical exposures to shape disease expression [31, 32]. This perspective aligns with the concept of cough hypersensitivity as primary trait and positions genetics as a means of interrogating causality rather than correlation [12, 13]. Accordingly, the purpose of integrating genetics into chronic cough research is not to imply determinism, but to clarify why similar environmental or inflammatory exposures lead to persistent cough in some individuals and not in others.

Evidence For Genetic Susceptibility to Chronic Cough

Evidence supporting a genetic contribution to chronic cough has emerged from multiple complementary lines of investigation [13, 14]. These include family history studies, population-based analyses, pharmacogenomic models and genome-wide association studies (GWAS), each providing insight into inherited susceptibility from a different perspective [12]. These observations do not diminish the importance of environmental and inflammatory drivers of cough. Rather, they suggest that such exposures may act on a background of inherited susceptibility, thereby contributing to interindividual differences in symptom persistence and severity.

Family-based studies offer the most direct evidence that chronic cough is not solely determined by environmental factors. Emilsson et al. conducted a large population-based two-generation analysis of 7155 parents and 8176 adult offspring from the RHINE/RHINESSA cohorts to investigate the heritability of chronic cough. The study demonstrated that offspring of parents with persistent chronic cough (reported at two time points) had significantly higher odds of chronic cough (adjusted OR 1.75, 95%CI 1.35–2.26); 11% of offspring of parents with non-productive cough reported non-productive cough versus 7% among those without parental dry cough (adjusted OR 1.59, 95%CI 1.20–2.10); 14% of offspring of parents with productive cough reported productive cough versus 11% among those without parental productive cough (adjusted OR 1.34, 95%CI 1.07–1.67) [14]. Similar findings have been observed in epidemiological analyses of diverse populations, confirming the robustness and reproducibility of this finding [33]. Collectively, these data suggest that cough is a distinct heritable trait and that cough subtype may have clinical relevance independent of shared lifestyle or environmental influences [14].

Additional support for genetic susceptibility comes from conditions with overlapping clinical features. Chronic cough frequently coexists with asthma, a disorder with a well-established genetic basis [34]. Large-scale GWAS have demonstrated substantial shared genetic architecture across allergic and airway diseases, providing a plausible biological basis for overlapping cough phenotypes [35, 36]. However, the incomplete concordance between asthma and chronic cough indicates that cough susceptibility cannot be fully explained by asthma genetics alone and may involve distinct neural and sensory mechanisms [34].

Pharmacogenomic studies offer a particularly informative clinical model of inherited cough liability [37]. Angiotensin-converting enzyme inhibitor (ACEI)-associated cough is strongly influenced by genetic variation, as demonstrated by multiple GWAS and candidate gene studies [38, 39]. More recent analyses using polygenic risk scores indicate that individuals with a higher genetic liability to ACEI-associated cough are also more likely to develop chronic dry cough, supporting a shared genetic substrate [40]. These findings suggest that drug-induced cough unmasks an underlying predisposition to cough hypersensitivity rather than representing a purely drug-specific adverse reaction [41].

Direct evidence for genetic susceptibility to chronic cough comes from GWAS. A recent GWAS of chronic dry cough identified multiple loci enriched in genes related to neural development, synaptic function and sensory processing [13]. Importantly, these associations were largely independent of classical inflammatory or airway structural pathways, further reinforcing the concept that chronic cough is fundamentally a sensory–neural disorder [12, 13]. While GWAS identify loci rather than mechanisms, functional annotation has begun to clarify the biological relevance of these signals. Integration with expression quantitative trait loci (eQTL) data has linked chronic cough–associated variants to gene regulation in neural and sensory tissues relevant to cough generation [42, 43]. Chronic dry cough and chronic sputum production exhibit distinct genetic architectures. GWAS of chronic dry cough highlights enrichment of neurological pathways and supports neuronal dysfunction underlying cough hypersensitivity, with risk loci mapped to genes involved in neuronal excitability and neuromodulation (Table 1) [13]. In contrast, GWAS of chronic sputum production implicates pathways governing mucus biology, glycosylation and host–pathogen interactions, with strongest signals at the FUT2 locus and the chromosome 11 mucin locus (MUC2/MUC5AC/MUC5B), alongside immune signals such as HLA-DRB1 (Table 2) [44]. These findings establish a plausible mechanistic link between inherited genetic variation and altered cough reflex sensitivity in affected individuals [45].

Table 1.

Novel genome-wide significant signals of association with chronic dry cough and ACEI-induced cough [13]

Gene symbol	Genetic variant	Core mechanism	Effect (OR, 95%CI)
CTNNA1/SIL1	5:138404361:A:AAAG	Regulates neuronal cell adhesion and synaptic plasticity; modulates cough reflex signal transduction	1.08 [1.03, 1.13]
OR4C12/OR4C13	rs112658458	Encodes GPCR olfactory receptors; mediates irritant perception and cough signal initiation	1.19 [1.14, 1.32]
L3MBTL4	rs343240, rs78598167	Induces the proliferation and remodelling of vascular smooth muscle cells via the MAPK pathway, resulting in hypertension	0.91 [0.83, 0.89] 1.33 [1.31, 1.56]
CPEB2	rs141733360	Influences the expression and function of neurotransmitter receptors and ion channels	0.51 [0.41, 0.64]
KCNA10	rs7518061	Mediates potassium ion transmembrane transport across plasma membranes	0.88 [0.84, 0.92]
SRBD1	rs1544730	Likely to be a ribosomal component involved in translation	1.11 [1.10, 1.16]
PREP	rs7761208	Involves in the maturation and degradation of peptide hormones and neuropeptides	0.89 [0.84, 0.89]
NTSR1/SLCO4A1	rs6062847	Regulation of neuropeptide signalling pathways, neurotransmitter secretion and synaptic transmission	1.18 [1.15, 1.24]
KCNIP4	4:21393932:T:TAAG	Regulation of potassium ion transmembrane transport and excitability in neurons	1.13 [1.14, 1.20]
MAPKAP1	rs7848821	Regulation of plasticity and excitability in neurons	1.08 [1.05, 1.11]

Table 2.

Novel genome-wide significant signals of association with chronic sputum production [44]

Gene symbol	Genetic variant	Core mechanism	Effect (OR, 95%CI)
FUT2	rs492602	Regulates terminal fucosylation of mucin glycans and secretor status; alters mucus glycosylation and host–microbe interactions driving persistent sputum production.	1.11 (1.08–1.15)
MUC5AC/MUC5B/MUC2	rs779167905	Modulates mucus rheology and clearance; locus variation may shift mucin balance influencing sputum viscosity	1.12 (1.08–1.16)
HLA-DRB1	rs374248993	Controls antigen presentation via class II MHC; amino-acid substitution may promote chronic airway immune activation and mucus production.	1.12 (1.08–1.16)
OCIAD1	rs79998532	Intronic rare-variant signal; biological mechanism not resolved in current study	2.36 (1.76–3.16)
NKX3-1/SLC25A37	rs79401075	Association locus with expression colocalisation signals; mechanism likely mediated by neighbouring regulatory targets rather than NKX3-1 itself	1.18 (1.12–1.24)
NELL1	rs529240826	Intronic rare-variant signal; functional relevance to sputum production remains unclear	1.91 (1.52–2.4)

A key limitation of current cough genetics research is phenotypic imprecision. Duration-based definitions remain useful for clinical description, but they may group biologically distinct mechanisms under a single label, including sensory hypersensitivity, mucus-predominant phenotypes, inflammatory drivers and cough associated with broader neural dysfunction [24, 29, 46]. Such imprecision contributes to inconsistent findings across studies and limits translational impact [13, 47]. Phenotypic misclassification at this level may also mask biologically relevant subgroups, further restricting the clinical utility of genetic discovery [48, 49]. This can dilute genetic signals and limit translational interpretation. To move the field forward, future progress will require phenotyping strategies that are more closely aligned with underlying biology, including objective cough monitoring, assessment of reflex sensitivity and structured evaluation of sensory symptoms and triggers, and integration with inflammatory and comorbidity profiles [32, 50–52].

Across family history studies, pharmacogenomic models and GWAS, the evidence converges on a consistent conclusion: susceptibility to chronic cough is influenced by inherited genetic factors that preferentially implicate sensory and neural pathways. Rather than identifying a single causal mechanism, this body of work defines a paradigm in which genetic variation shapes baseline cough reflex sensitivity and drives interindividual differences in cough hypersensitivity. This perspective provides a foundation for exploring the biological mechanisms linking genetic risk to clinical phenotype and for identifying targets with potential translational relevance.

Genetic Architecture and Biological Pathways

The majority of genetic variants associated with chronic cough are predicted to reside in non-coding regions and to modulate disease risk through gene regulation rather than alterations in protein sequence. This makes post-GWAS functional interpretation a critical step in translating genetic association data into mechanistic insights [43]. Colocalisation analyses offer a principled approach to assess whether a cough-associated signal and a molecular quantitative trait locus (QTL) share a common causal variant [3]. QTLs are genomic regions containing variants that regulate quantitative molecular traits, such as gene expression. In this way, co-localisation analysis helps bridge statistical association and candidate effector genes[3]. Summary-data Mendelian randomisation and transcriptome-wide association approaches extend this framework by prioritising candidate effector genes based on genetically predicted gene expression and shared genetic effects across loci [45, 53, 54].

These analyses rely on high-quality regulatory reference resources that capture tissue- and cell-type-specific effects, including large-scale multi-tissue eQTL atlases and harmonised splicing QTL catalogues [43, 55]. Regulatory effects are frequently context dependent, varying across cellular contexts, particularly among immune cell types and activation states. This context specificity underscores the importance of aligning functional annotation with cough-relevant biology, rather than relying on generic annotations when interpreting genetic signals [56, 57].

Genetic signals implicating sensory and neural biology are biologically plausible for chronic cough, as cough generation and modulation depend on specialised vagal afferent neural circuits and their central integration in the brainstem [58]. Single-cell atlases of vagal sensory neurons provide a molecular taxonomy of no dose and jugular neuron populations, enabling candidate genes to be interpreted within defined sensory neuron subtypes [59]. Transcriptional profiling of airway-projecting vagal afferents further refines this model by linking gene expression programmes to neurons positioned to encode tussive stimuli [60]. Experimental dissection of vagal afferent control programmes supports the concept that airway protective behaviours are coordinated by genetically specified sensory circuits rather than by isolated peripheral triggers [61]. Central sensitisation may provide an additional mechanistic framework for understanding persistent cough hypersensitivity, particularly when symptom severity or trigger sensitivity appears disproportionate to ongoing peripheral pathology. In this model, repeated peripheral input or altered sensory regulation may enhance central responsiveness to tussive signals, thereby lowering the threshold for cough and amplifying responses to otherwise innocuous stimuli. Although the molecular and imaging correlates of central sensitisation in chronic cough remain incompletely defined, this concept is relevant to the persistence of symptoms, the breadth of trigger sensitivity and the partial dissociation between cough burden and overt airway disease.

Human data provide complementary support for this model. Studies of patients with chronic cough demonstrate evidence of peripheral neural remodelling, including increased airway sensory nerve density, offering a plausible substrate through which inherited susceptibility may translate into heightened cough reflex sensitivity [62]. Mechanistically, defined ion-channel systems such as Piezo2-mediated mechanotransduction illustrate how specific sensory pathways encode airway biomechanics and shape protective reflexes, providing a conceptual framework for interpreting ion-channel and synaptic genes identified in association studies [63]. A schematic interpretation of how representative chronic dry cough–associated loci may map onto sensory–neural mechanisms relevant to cough hypersensitivity is shown in Fig. 1. [13, 38, 64–69]

Fig. 1.

Proposed sensory—neural mechanisms linking representative chronic dry cough—associated loci to cough hypersensitivity pathways. This schematic figure illustrates how selected loci associated with chronic dry cough, including PREP, KCNIP4 and MAPKAP1, may be interpreted within a sensory—neural framework of cough hypersensitivity. The left panel highlights representative genes and variants identified or prioritised in genomic studies. The middle panel summarises plausible downstream functional consequences, including altered neuropeptide processing, increased vagal afferent excitability and enhanced sensory responsiveness. The right panel places these effects in the context of cough-relevant receptor and channel systems, including TRP, P2X3 and NK-1 signalling pathways, as well as ion channel regulation. The arrows indicate biologically plausible links derived from integration of genomic findings with mechanistic and pharmacological evidence. Dashed arrows denote indirect or currently unconfirmed links for which direct experimental evidence remains limited. This figure is intended as a conceptual model to support biological interpretation rather than a definitive one-to-one causal pathway. All cited studies are included in the main reference list rather than presented as a separate figure-specific reference system. Abbreviations: ATP adenosine triphosphate, KCNIP4 potassium voltage-gated channel interacting protein 4, MAPKAP1 mitogen-activated protein kinase associated protein 1, NK-1 neurokinin-1 receptor, P2X3 purinergic P2X3 receptor, PREP prolyl endopeptidase, SP substance P, TRP transient receptor potential, TRPA1 transient receptor potential ankyrin 1, TRPV1 transient receptor potential vanilloid 1

Across these layers of evidence, convergent biology highlights purinergic and transient receptor potential (TRP) pathways as tractable links between genetic susceptibility and cough hypersensitivity [70]. TRP channels are also biologically relevant in this context because they integrate thermal, chemical and inflammatory signals at the level of airway sensory nerve endings. This makes them plausible mediators of cough hypersensitivity, particularly in patients with heightened responses to environmental irritants, temperature change or inhaled stimuli. However, compared with P2X3 signalling, the translational evidence for TRP-directed therapies has so far been less consistent. This discrepancy may reflect biological redundancy within sensory pathways, incomplete target engagement, or the likelihood that TRP-related mechanisms are more important in selected phenotypic subgroups than across chronic cough as a whole.

Thoracic epithelial cells can initiate protective reflexes through ATP release, activating purinoreceptive sensory neurons and providing a mechanistic bridge between epithelial signalling and neural excitation [71]. Human challenge studies using ATP and related ligands support ATP signalling as a relevant provocation axis in cough hypersensitivity phenotypes [72]. Consistent with these observations, pharmacological modulation of P2X3 signaling reduces cough reflex sensitivity and cough frequency in clinical studies, supporting a causal role for this pathway in maintaining chronic cough [49, 73]. Receptor pharmacology has helped explain why selective targeting of P2X3 versus mixed P2X2/3 signalling does not influence efficacy and adverse event profiles, which is directly relevant when translating genetic or molecular pathway signals into drug development strategies [74].

Taken together, functional genomics and neurobiology define a coherent interpretive framework in which inherited regulatory variation biases sensory–neural excitability, lowers the threshold for cough hypersensitivity, and gives rise to clinically actionable pathways for mechanism-based phenotyping and intervention [45, 58].

Genetics Informing Treatable Traits and Drug Development

Building on the biological framework outlined above, genetic studies provide one rationale for reframing chronic cough in terms of mechanism-informed treatable traits rather than disease labels alone. Inherited susceptibility may contribute to interindividual variability in cough severity, trigger sensitivity and treatment response [75, 76], but these clinical differences are also shaped by inflammatory, environmental and pharmacological influences [12, 13, 77–79].

ACEI–associated cough represents a particularly informative human model of genetically mediated cough susceptibility. GWAS and candidate-gene studies demonstrate that the risk of developing cough during ACEI exposure is strongly modulated by inherited variation, implicating neural and neuropeptide-related pathways rather than drug metabolism per se [38, 39, 80]. Importantly, polygenic risk score analyses indicate that genetic liability to ACEI–associated cough overlaps with susceptibility to chronic dry cough in the absence of drug exposure [40]. These findings suggest that ACEI–associated cough is best understood as the pharmacological unmasking of an underlying predisposition to cough hypersensitivity, providing a natural experiment that links genotype to clinically observable phenotype [41, 81].

Genetically informed models of cough susceptibility also help to rationalise the successes and failures in antitussive drug development. Representative receptor- and pathway-level genetic or mechanistic evidence relevant to chronic cough, including TRP, P2X3, tachykinin and NGF-related signalling, is summarised in Table 3 [82–88], but failed to translate into sustained clinical benefit, highlighting the limitations of relying solely on pathway biological plausibility [86, 89, 90]. In contrast, selective targeting of the purinergic P2X3 pathway has resulted in consistent and clinically meaningful reductions in cough frequency across multiple trials in refractory and unexplained chronic cough [67, 91]. The durability of these effects supports the concept that P2X3 signalling represents a core node in cough hypersensitivity rather than a redundant peripheral modulator [92]. From a translational perspective, genetics reframes therapeutic development by shifting emphasis from pathway plausibility to biological leverage [93]. Clinical experience with interventions targeting sensory pathways supports the concept that cough hypersensitivity is modifiable rather than a fixed consequence of comorbid disease [94]. In contrast, the failure or limited efficacy of several mechanistically plausible targets underscores the limitations of pathway plausibility alone when biological redundancy and patient heterogeneity are not considered. Genetic support offers a means of identifying nodes most likely to exert meaningful control over disease expression and can inform patient stratification, endpoint selection and trial design [95]. Applied prospectively, such approaches have the potential to reduce attrition in antitussive drug development by aligning therapeutic mechanisms with underlying biology rather than surface phenotype [96, 97].

Table 3.

Genetic variant of receptor and pathway association with chronic cough

Receptor /Pathway	Gene symbol	Genetic variant	Core mechanism	Evidence/Phenotype
TRPV1 [82–84]	TRPV1	rs224546/rs4790522/rs2277675/rs222741/rs224498	Capsaicin receptor on airway sensory nerves; contributes to cough hypersensitivity	large European adult cohorts and used in cough-relevant SNP panels; multiple TRPV1 SNPs show associations with chronic cough.
TRPA1 [82]	TRPA1	N/A	Irritant/oxidant sensor on airway afferents; implicated in airway inflammatory cough pathways.	Associations between SNPs in TRPA1 and cough symptoms were not significant
P2X3 [85]	P2RX3	rs10896611/rs2276038/rs3781899	Mediates ATP-driven sensory signaling, promoting cough hypersensitivity	Case-control paediatric study: minor alleles of these P2X3 SNPs increased risk of asthmatic cough
NK-1 receptor [86]	TACR1	N/A	Mediates substance P–driven neurogenic inflammation and central/peripheral cough facilitation	Many NK-1R data are pharmacology/physiology rather than genetics
TAC1	TAC1	N/A	Controls tachykinin neuropeptide, shaping afferent/brainstem cough circuit gain and neurogenic inflammation	N/A
NGF → TrkA axis [87]	NGF/NTRK1 (TrkA)	NGF rs6330; NTRK1 rs6334	Regulates sensory nerve sensitization and upregulates irritant channels, priming cough reflex amplification	NTRK1/NGF SNPs influenced serum NGF levels; NGF/TrkA signaling is mechanistically linked to cough hypersensitivity
NK-2 receptor [86, 88]	TACR2	rs77038916(Gly231Glu; Arg375His)	Modulates neurokinin-A signaling and neurogenic inflammation, altering sensory nerve excitability and cough threshold	NK-2R SNP show associations with ACEI-cough.

Clinically, these insights argue for a shift away from prolonged, sequential exclusion of putative comorbidities toward biologically informed stratification that prioritises actionable traits when symptoms persist [30, 98, 99]. Family history emerges as a pragmatic marker of inherited liability not captured by conventional diagnostic categories and has been associated with chronic cough risk and persistence in both population-based and longitudinal studies [14, 100, 101]. Accordingly, risk stratification should increasingly integrate clinical phenotype, including triggers, sensory symptoms and objective burden where available, within structured assessment pathways rather than relying on single-disease algorithms [4, 34]. Such an approach acknowledges biological heterogeneity while avoiding genetic determinism, embedding inherited susceptibility within careful phenotyping, longitudinal follow-up and transparent uncertainty in clinical decision-making [16, 102, 103].

These observations underscore the value of integrating genetic evidence with clinical pharmacology when prioritising therapeutic targets [104, 105]. Genetic association does not simply nominate pathways; it can indicate which components of a sensory system are most likely to exert a non-redundant influence on disease expression [12, 13]. In this context, genetically supported targets may offer a higher probability of translational success, while also informing patient stratification and expectation of treatment response [67, 104, 105].

In summary, genetic susceptibility provides a practical framework for defining treatable traits in chronic cough. Beyond serving as an explanatory tool, genetics can guide the selection of drug targets and support a move towards precision approaches in the management of chronic cough [12, 106–108]. Importantly, a genetics-informed framework is not intended to displace established treatable traits such as eosinophilic or steroid-responsive cough. Rather, it is most relevant where cough persists despite appropriate evaluation and management of recognised inflammatory or comorbidity-based drivers, or where symptom burden appears disproportionate to conventional disease labels. At present, the main value of genetic findings lies in biological stratification, target prioritisation and translational research rather than routine clinical genetic testing.

Rare Genetic Disorders, Geography and Population Differences

Rare genetic disorders affecting sensory pathways offer a powerful lens for understand chronic cough as a genetically mediated condition. Among these, cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) has emerged as a particularly informative model [109–112]. Chronic cough is a frequent and sometimes prominent feature in affected individuals and may precede overt neurological manifestations [15, 113]. This clinical pattern supports the concept that inherited vulnerability of sensory afferent pathways can manifest initially as isolated cough hypersensitivity [114].

Additional familial neuropathic phenotypes, including hereditary sensory neuropathy linked to chronic cough and reflux, further support the view that cough can segregate within broader sensory pathway disorders [115].

The identification of biallelic RFC1 repeat expansions as a major cause of CANVAS has strengthened this framework [15, 116–118]. Subsequent studies have demonstrated that pathogenic RFC1 repeat expansions are also enriched in patients with refractory chronic cough, including individuals without classical neurological features [119, 120]. A cohort-based analysis of patients with pathogenic RFC1 repeat expansions demonstrated that sensory neuropathy associated with RFC1 is highly heterogeneous and frequently accompanied by chronic cough [121]. Together, these findings suggest that RFC1-associated sensory neuropathy can include chronic cough as an early or incomplete phenotypic manifestation, although such disorders account for only a minority of chronic cough cases [122].

RFC1 repeat expansions also show ancestry- and geography-related variation, being reported more frequently in populations of European ancestry [123, 124]. Although environmental and healthcare-related factors remain important, such variation highlights the need for ancestry-aware interpretation when considering international differences in chronic cough prevalence and phenotype [3, 24]. The association between chronic cough and genetically defined sensory neuropathy reinforces the view that cough hypersensitivity can arise from primary neural dysfunction rather than secondary airway pathology [29, 114].

A key paradox in RFC1-associated sensory neuropathy is that chronic cough may persist despite loss of sensory fibres. In CANVAS, cough is usually dry, may precede neurological manifestations by many years, and cannot be fully accounted for by accompanying reflux or oesophageal dysfunction [125]. Recent pathological studies further indicate that increased cough reflex sensitivity may occur even in the presence of marked bronchial nerve depletion [126]. Mechanistically, these disorders also suggest that cough hypersensitivity may arise not simply from increased innervation, but from disordered sensory processing within vulnerable peripheral and central neural networks [125, 126].

At the population level, a genetically informed framework also reshapes interpretation of epidemiological variation [127]. Substantial differences in chronic cough prevalence and phenotype are observed between countries and continents [24]. Although demographic, environmental exposures, healthcare access and diagnostic practices undoubtedly contribute, genetic architecture provides a plausible additional layer influencing observed patterns [71, 128]. Variation in ancestry-specific risk alleles and enrichment of genetically defined cough-associated conditions may shape both prevalence and clinical presentation across populations [13, 129, 130]. Recognising this possibility does not imply genetic determinism; rather, it cautions against assuming that international differences are purely environmental and highlights the need for ancestry-aware interpretation in epidemiological research and clinical inference [100, 131, 132].

Together, studies of rare genetic disorders and population-specific variation highlight the importance of considering genetic background when interpreting chronic cough epidemiology and clinical presentation. They support the hypothesis that inherited factors contribute to differences in susceptibility and disease expression at both individual and population levels, with direct implications for diagnosis, risk stratification and future precision approaches to management [13, 14]. Within this framework, rare genetic disorders illuminate biological mechanisms that may operate more subtly in the general population, strengthening the plausibility of a neurogenic cough paradigm and providing a conceptual bridge between rare monogenic disorders and common clinical phenotypes [122, 133].

Conclusions

In this review, we synthesised current evidence on the genetic architecture of chronic cough and examined how genetic findings may contribute to biological interpretation, mechanism-based phenotyping and translational development. The available evidence indicates that inherited susceptibility contributes to cough hypersensitivity and clinical heterogeneity, but acts in concert with inflammatory, environmental and pharmacological modifiers rather than in isolation. Current genetic findings are most informative for refining disease biology, supporting target prioritisation and guiding research stratification, rather than for routine clinical genetic testing. Future progress will depend on deep phenotyping, multi-ancestry studies and functional validation in cough-relevant sensory pathways. Together, these advances may help support a more biologically informed and clinically useful framework for chronic cough.

Author Contributions

Ran Dong, Mengru Zhang and Alyn H. Morice conceived the review topic and designed the manuscript structure. Ran Dong drafted the initial manuscript. Mengru Zhang contributed to literature interpretation, critical revision of the content and manuscript editing. Alyn H. Morice supervised the work, critically revised the manuscript for important intellectual content and approved the final version. All authors read and approved the final manuscript and meet the authorship criteria of the ICMJE.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Declarations

Conflict of Interest

Ran Dong has nothing to disclose. Mengru Zhang has nothing to disclose. Alyn H. Morice is an Editorial Board member of Pulmonary Therapy. Alyn H. Morice was not involved in the selection of peer reviewers for the manuscript nor in any of the subsequent editorial decisions regarding this article.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.