Genetics of preschool wheeze and its progression to childhood asthma

Wheezing is a common and heterogeneous condition in preschool children. In some countries, the prevalence can be as high as 30% and up to 50% of all children experience wheezing before the age of 6. Asthma often starts with preschool wheeze, but not all wheezing children will develop asthma at school age. At this moment, it is not possible to accurately predict which wheezing children will develop asthma. Recently, studying the genetics of wheeze and the childhood‐onset of asthma have grown in interest. Childhood‐onset asthma has a stronger heritability in comparison with adult‐onset asthma. In early childhood asthma exacerbations, CDHR3, which encodes the receptor for Rhinovirus C, was identified, as well as IL33, and the 17q locus that includes GSDMB and ORMDL3 genes. The 17q locus is the strongest wheeze and childhood‐onset asthma locus, and was shown to interact with many environmental factors, including smoking and infections. Finally, ANXA1 was recently associated with early‐onset, persistent wheeze. ANXA1 may help resolve eosinophilic inflammation. Overall, despite its complexities, genetic approaches to unravel the early‐onset of wheeze and asthma are promising, since these shed more light on mechanisms of childhood asthma‐onset. Implicated genes point toward airway epithelium and its response to external factors, such as viral infections. However, the heterogeneity of wheeze phenotypes complicates genetic studies. It is therefore important to define accurate wheezing phenotypes and forge larger international collaborations to gain a better understanding of the pathways underlying early‐onset asthma.

and parents was observed.As a result of this, wheezing is not a precise diagnosis, but merely a symptom, and this inaccuracy is especially relevant when relying on parental reports in epidemiological studies.
As the airway diameter in the developing lung is small, wheezing is a prevalent symptom in childhood.Approximately 30% of all children experience wheezing before the age of 3 years and up to 50% of all children experience wheezing before the age of 6 years. 3,46][7] Up to a 20-fold difference in prevalence of wheeze was reported between the different study centers around the world. 5The highest prevalence of wheeze (ranging from 29.1 to 36.7%) was seen in developed English-speaking countries such as the UK, Australia, and Scotland and some countries in Latin-America (Peru and Costa Rica), while the lowest prevalence (ranging from 1.6 to 4.4%) was found in some other parts of Europe such as Greece and Romania and parts of Asia (India, Indonesia, and China). 5Moreover, there were relatively small (mean of 0.5%) changes in prevalence seen over a 5-year interval. 7These differences in population prevalence may be due to variation in genetic make-up, environmental factors, or their interactions, as well as wheeze definitions across different languages.Therefore, it is important to take the population on which a study of wheeze has been conducted into account.Not all wheezing preschoolers will be diagnosed with asthma at school age, because wheezing may be nonspecific and could reflect a transient episode of viral respiratory tract infection. 1,3,4Approximately 30% of preschool wheezing children will have asthma at school age, 3,8 but it is difficult to predict who. 8ediction models that use clinical information (wheeze prevalence, family history, presence of eczema, IgE sensitization, and/ or eosinophil numbers in blood) have modest ability to diagnose or rule out asthma, but not both. 9Only few of these models have been externally validated, with at best modest generalizability.
Clinical evidence-based guidelines to diagnose asthma in children are primarily intended for older children.For example, the 2021 ERS task force clinical practice guideline for the diagnosis of asthma 1 is only suitable for children above the age of 5 years, because diagnostic tests for asthma are rarely successfully conducted on younger children.Without knowing which wheezing children develop asthma, it is difficult to study the mechanisms of the onset of asthma or predict the responsiveness to therapeutic strategies.
Preschool wheeze can be categorized in four different ways: based on timing, triggers, severity of wheeze, or presence of allergy.Martinez et al. were the first to describe preschool wheeze using longitudinal phenotypes based on the timing of symptoms. 3 the US Tucson Children's Respiratory Study, they distinguished four categories: children who never wheeze; children who start wheezing before the age of 3, but stopped wheezing by the age of 6 (transient early wheeze); children who did not wheeze before the age of 3, but were wheezing by the age of 6 (late-onset wheeze); and children who started wheezing before the age of 3 and continued wheezing at the age of 6 (persistent wheeze).This categorization was clinically relevant, as different risk factors could be identified for these wheezing phenotypes.Smoking during pregnancy was for instance associated with transient early wheeze, while a positive family history of asthma and eczema in the first year of life was associated with persistent wheeze. 3Furthermore, these phenotypes were differentially associated with asthma at school age, ranging from no risk for asthma (transient wheeze) to high risk (persistent wheeze). 3,4This suggested different underlying mechanisms and illustrated the heterogeneity of wheeze.
Although this was a novel way to categorize wheezing children at that time, there were only four categories since no data at age  4,10 Furthermore, they modified the "persistent wheeze" phenotype to children who started wheezing before the age of 1 and continued wheezing after the age of 6.However, these were also longitudinal definitions, and an important drawback of longitudinal definitions is that these can only be established

Key Message
Wheezing in preschool children is a common and heterogeneous condition and can progress toward childhoodonset asthma.Studying the genetics of wheeze can help us to unravel the early-onset of asthma.One Genome Wide Association Study identified loci for early childhood asthma exacerbations, including CDHR3, which encodes the receptor for Rhinovirus C, as well as the 17q locus that includes the GSDMB and ORMDL3 genes.This locus is the strongest wheeze and childhood-onset asthma locus, and was shown to interact with many environmental factors, including smoking.Finally, ANXA1, was recently associated with early-onset, persistent wheeze.ANXA1 may help resolve eosinophilic inflammation.Genetic approaches to unravel the early origins of asthma are promising, but complicated by wheeze heterogeneity.We therefore emphasize the importance of defining accurate wheezing phenotypes and international collaborations to unravel the early origins of asthma.
retrospectively.Therefore, this phenotype categorization had little to no value for treatment decisions early on in life and could not be used for the prevention or prognosis of asthma.Moreover, a meta-analysis of risk factors for these wheezing phenotypes only showed few consistent risk factors, suggesting heterogeneity between different study populations. 11 2008, an ERS Task Force tried to establish consensus with the introduction of the "trigger definitions": episodic viral wheeze (EVW; i.e., "wheezing during discrete time periods, often in association with clinical evidence of viral cold, with absence of wheeze between episodes") and multiple-trigger wheeze (MTW; i.e., "wheezing that shows discrete exacerbations, but also symptoms between episodes"), although the evidence to base their recommendations on was limited. 12It was thought that MTW could be a precursor of asthma.In 2014, however, the ERS Task Force proposed some modifications on their previous recommendations after multiple studies pointed out that wheeze patterns vary over time and with treatment in young children. 13This made it difficult to distinguish between EVW and MTW.Moreover, severity and frequency of wheezing episodes were stronger predictors of longterm outcome. 13,14Thus, the underlying pathophysiology of preschool wheeze and the development of asthma remained unclear and evidence-based definitions of preschool wheezing remained difficult to make. 13her studies used classifications based on severity of the disease, response to treatment, IgE sensitization or type of inflammation. 15However, there was no consensus on what classification should be used, possibly due to the heterogeneity of the used phenotypes. 1,15 conclusion, defining wheeze in childhood suffers from three different problems: inaccuracy in defining the wheeze symptom, heterogeneity of wheeze in the first 6 years of life, and inability to diagnose asthma at preschool age.This could mean that wheeze is the result of different underlying mechanisms, complicating clinical and molecular studies.

| APPROACHE S TO S TUDY THE G ENE TI C S OF WHEE ZE AND CHILDHOOD -ONS E T A S THMA
The strongest risk factor for asthma is a family history in first-degree relatives, reflecting shared genetics and environmental factors. 13,16assical approaches to disentangle genetics from environmental contribution to a phenotype include the twin or family study; however, these studies have not been reported on different wheeze definitions.Nevertheless, a large Danish population-based twin study on self-reported asthma including twins as young as 3 years of age showed that genetic factors are more important at a younger age group (3-20 years), compared with older subjects (>20 years); an effect that was particularly relevant among males. 17Many twin studies show that if one co-twin has asthma, the other monozygotic co-twin has a higher risk of developing asthma compared with a dizygotic co-twin, which indicates a strong genetic contribution. 18In general, twin studies indicate that heritability of childhood asthma is rather high (between 60 and 80%), with limited evidence for the relevance of shared environmental factors. 17This has inspired researchers to investigate which specific genetic factors may underlie wheeze and asthma development in childhood.
Two study designs have contributed to our insight into the genetics of wheeze and childhood-onset asthma: Genome Wide Association Studies (GWAS) and candidate gene studies.Genome Wide Association Studies investigate single base pair variations across the genome (single nucleotide polymorphisms, SNPs) that are relatively prevalent in the population under study (>1%). 19Genome Wide Association Studies aim to relate one allele, for example a C or a G, to a disease, by simply comparing the prevalence of this allele in large groups of cases and controls.The size of one copy of the human genome is approximately 3 billion base pairs; but of these, over 99% is exactly the same between humans.Thus, genotyping arrays that can investigate up to 650,000 to 1,000,000 SNPs focus on prevalent genetic variations and are conveniently used to screen the genome.One advantage is that no prior hypothesis needs to be formulated on which gene may be important, as the genome is almost completely covered.Thus, novel genes and mechanisms may be discovered that were previously not known to be involved in wheeze or childhood-onset asthma.A disadvantage is, however, that many genetic variants are tested, leading to a high multiple testing burden.
Therefore, a large sample size (thousands or tens of thousands cases and controls) is used to generate power. 20This inherently leads to a second disadvantage: GWAS work with very general symptoms or disease definitions, such as self-reported wheeze or doctor's diagnosis, as it is too costly to thoroughly and repeatedly investigate study participants.Since GWAS use a broad phenotype definition, these probably include different wheeze phenotypes with possibly different underlying (genetic) pathology, leading to a reduction in power. 21e candidate gene study selects genetic variation in genes that are thought to have an important role in disease development.
Similar to GWAS, the prevalence of alleles is compared between groups of cases and controls, but now for a limited number of SNPs (tens to hundreds).Smaller sample sizes are needed to reach statistical significance, and therefore, more detailed phenotypic definitions may be used.Candidate gene studies have been criticized in the past for reporting false-positive results due to underpowered studies, genetically unbalanced case-control populations, unclarity about the number of SNPs and phenotypes tested and possibly publication bias. 19However, when executed properly, these studies may reveal important insights into the genetic contribution to wheeze and asthma, as these can also model the interaction of a SNP with another SNP in a pathway (gene-gene interaction) or with an environmental factor (gene-environment interaction), such as viral infections, or exposure to tobacco smoke.Thus, genes identified by GWAS for a general phenotype may further be investigated in cohorts of well-characterized participants, to elucidate SNPphenotype associations and provide better insight into the interaction with other genes and the environment.

| G ENOME WIDE A SSO CIATI ON S TUD IE S OF WHEE ZE AND CHILDHOOD -ONS E T A S THMA
Genome Wide Association Studies have been performed on early childhood asthma exacerbations (age 2-6 years), wheezing phenotypes, and childhood-onset asthma, either studied as age-of-onset or defined as asthma-onset <12 or <18 years of age.
In 2014, Bønnelykke et al. performed a relatively small GWA study in Denmark (1173 cases and 2522 controls) of a clinically relevant phenotype in children aged 2-6 years: multiple exacerbations of asthma for which hospitalization was necessary. 21This phenotype was associated with SNPs in CDHR3, encoding for cadherinrelated family member 3, a transmembrane protein expressed in ciliated airway epithelial cells.(Table 1) CDHR3 was subsequently shown to mediate Rhinovirus C binding, a common cold virus known to cause severe respiratory tract infections and asthma exacerbations in childhood. 22,23One strongly associated SNP resulted in an amino acid change in the CDHR3 protein that not only mediated enhanced viral binding and replication, but also regulated the amount of CDHR3 protein (Figure 1). 21Thus, children carrying this risk genotype at the CDHR3 locus are more susceptible to Rhinovirus C infection, as they express more CDHR3 surface receptors on the airway epithelium when bound to Rhinovirus C, resulting in more severe infections and asthma exacerbations. 22,23sides the novel CDHR3 gene, other genetic loci related to severe childhood asthma exacerbations were found.These were located at the 17q locus (GSDMB), in the IL33 gene (Interleukin-33) and its receptor IL1RL1 (Interleukin-1 receptor-like1). 21These important childhood-onset asthma susceptibility loci will be discussed in detail in the section on candidate loci.
In 2020, the much larger iPSYCH (Integrative Psychiatric Research) cohort, which included 1662 children with at least one hospitalization for asthma in the first 6 years of life, and 60,087 non-asthmatic controls, was conducted. 24A meta-analysis was performed on the iPSYCH cohort and the Danish COPSAC severe (Copenhagen Prospective Studies on Asthma in Childhood-severe) cohort.Nine loci surpassed the genome wide significance threshold, including many previously known asthma loci, such as GSDMB, CDHR3, HLA-DQA1, IL33, IL1RL1 and IL13. 24In addition, the FUT2 locus on chromosome 19 was identified as a novel risk locus and a strong gene-gene interaction between FUT2 and ABO genes was demonstrated in the most severe asthma cases.FUT2 encodes the enzyme fucosyltransferase 2, which determines the ability to secrete the soluble ABO blood group antigens and express them on mucosal surfaces, including the bronchial epithelium. 24(Table 1) The nonsense FUT2 mutation inactivates the FUT2 enzyme and homozygosity results in the "non-secretor" status, associated with a decreased risk of asthma. 24In a previous candidate-gene study in 1831 infants of the Southampton Women's Survey (SWS) motheroffspring cohort, the risk allele resulting in the "secretor" status had been associated with an increased susceptibility to lower respiratory illness (pneumonia or bronchiolitis) and nocturnal cough between 12 and 24 months. 25This increased susceptibility to respiratory tract infections provides a plausible mechanism for the relationship with preschool exacerbations, as these are the main trigger of asthmatic symptoms in young children.Furthermore, fut2-deficient (Fut2−/−) mice showed significantly less eosinophilic inflammation and airway hyperresponsiveness in house dust mite-induced asthma models compared with wild-type mice, indicating fucosyltransferase 2 also enhances Type 2 inflammation. 26In a further analysis, the sentinel FUT2 SNP was associated with asthma-onset <6 years in the UK Biobank dataset, but not with asthma-onset after 6 years of life, highlighting the importance of precise and homogeneous phenotype definitions.Finally, the link between early-life infections (including symptoms of cold, otitis media, pneumonia and gastroenteritis between ages 0 and 3 years) and asthma-like symptoms (cough, wheeze, and shortness of breath) was investigated in the Danish COPSAC 2010 study. 27Infection burden significantly mediated (30.6%) the association of a polygenic risk score of exacerbations based on the iPSYCH study and asthma-like symptoms.These findings support the link between genetic susceptibility to exacerbations, early-life infections and asthma-like symptoms. 27This study further supports the role of early-life infections, but also proposed that this may be an interesting target of prevention of asthma-like symptoms in the first years of life.
In 2023, Granell et al. published the first GWA study on different wheezing phenotypes, constructed by machine learning technology. 20After applying LCA on participants from five different UK birth cohorts from infancy to adolescence, the following four wheezing phenotypes were defined: (1) early-onset pre-school remitting wheeze; (2) early-onset middle-childhood remitting wheeze; (3) early-onset persistent wheeze; and (4) late-onset wheeze.These groups were compared with the control group, consisting of never or infrequent wheezers, which comprised approximately half of the population.They analyzed the genomes of 9568 individuals.Next to the known 17q21 locus, a novel locus at Chr9q21 nearby Annexin A1 (ANXA1) was associated with early-onset, persistent wheeze.Individuals classified as this LCA-derived phenotype had a 53% probability of wheeze during infancy (½ to 1 year) and a 70-80% probability of wheeze thereafter.ANXA1 is an anti-inflammatory protein expressed in immune and structural cells, which functions as a resolvin to dampen inflammation. 20(Table 1) Using a protein-protein interaction network, ANXA1 was shown to interact with other proteins such as IL-4 and IL-13, suggesting a role in Type 2 inflammation.This was confirmed in a knock-out mouse model, as Anxa1 deficiency exaggerated an eosinophilic, Type 2 high inflammatory response upon intranasal house dust mite exposure. 20Because ANXA1 was only associated with one specific wheezing phenotype, these findings strengthen the notion that a more precise phenotype definition may elucidate specific underlying disease mechanisms, as this locus was not found with GWAS with a general asthma phenotype.However, no genome wide significant findings were reported for any of the other wheezing phenotypes, underscoring that larger and collaborative efforts are needed to improve power and elucidate the genetics of wheezing phenotypes.

TA B L E 1
Main proposed wheeze or childhood-onset asthma genes discussed in this review with its proposed function.Several GWAS investigated the genetics of onset of asthma, either using the age of asthma-onset, or an age-of-onset cut-off as phenotype.One study used age-of-onset of allergy (either asthma/ hay-fever/eczema) instead of asthma only, and showed very strong overlap between allergy and childhood asthma genes. 28Although these studies did not use 'wheeze' in its definition but self-reported (doctor's diagnosis of) asthma, these findings may help to elucidate the early origins of asthma.The largest GWA study on age-of-onset of any allergic disease was performed in the UK Biobank, which investigated the earliest self-reported age-of-onset of either asthma and/or hay-fever and/or eczema in 117,130 participants. 28Using the age-of-onset, but not disease status, as the phenotype, in total 50 significant genetic variants were identified, of which 45 conferred equal risk between asthma, hay fever and eczema.Of the remaining five, one locus in 17q (GSDMB) had stronger association with asthma compared to the other allergic diseases.This GWA study was performed in adult subjects with a mean age of 55 years, therefore these results may be subject to recall bias.Furthermore, the mean age-of-onset of any allergic disease in the cohort was 26.3 (median: a heritability of 25.6%, whereas adult-onset asthma (20-60 years, n = 26,582) had a heritability of only 10.6%.When these asthma patients were compared to 300,671 non-allergic controls, in total 123 independent associations were found for childhood-onset asthma, versus 56 loci for adult-onset asthma.Of these, 37 overlapped.Thus, childhood-onset asthma has a stronger genetic contribution than adult-onset asthma, with some overlap between the two asthma types.After independent replication in a separate analysis of the self-reported age-of-onset of asthma in the US 23 and me study, a replicated set of genes that caused childhood-onset asthma but not adult-onset disease was identified. 29 addition, Pividori et al. 30 also used the UK Biobank to identify risk loci for childhood-onset asthma and adult-onset asthma.They used a different age cutoff of childhood-onset disease (onset <12 years) and included 37,846 individuals with asthma of whom 9433 were childhood-onset (onset <12 years) and compared those to 318,237 controls.In this study, they identified 61 independent asthma loci.

Gene
Of these loci, 23 were childhood-onset specific, 37 were shared with adult-onset asthma and only one was adult-onset specific.(Figure 2) Furthermore, they showed that the effect size of the childhoodonset loci was larger than the effect size of adult-onset loci, even in the shared loci.This suggested that childhood-onset asthma is more genetically driven and adult-onset asthma could be more driven by environmental stimuli.Moreover, they identified distinct mechanisms of childhood-onset asthma, by linking childhood-onset asthma SNPs to mRNA in five different tissues using a method called Transcriptome Wide Association Study. 30This method reveals if disease SNPs are also regulators of mRNA expression and enables pathway analysis for groups of implicated mRNA transcripts.Interestingly, implicated pathways for childhood-onset asthma were mostly found in the skin, whereas adult-onset asthma pathways were more found in the lung and spleen.This underlines the idea that childhood-onset asthma could be due to impaired barrier function in more epithelial surfaces than the skin alone, which could promote allergen sensitization.
In conclusion, GWAS have shown a stronger heritability of childhood-onset asthma compared with adult-onset asthma, and GWAS have shown that childhood-onset disease has a set of unique genetic causes, not shared with adult-onset asthma.Although different approaches were used, using either asthma exacerbations, wheeze definitions or self-reported childhood-onset asthma, a replicable set of genes emerged.Important mechanisms for childhoodonset asthma include overlap with allergic diseases and epithelial barrier function, pointing to novel targets of intervention.

| C AND IDATE LO CI FOR WHEE ZE AND A S THMA
The most highly replicated childhood asthma susceptibility locus is the chromosome 17q12-21 locus ("17q"). 31,32SNPs at the core region of this locus are associated with mRNA levels of several genes, including orosomucoid 1-like 3 (ORMDL3) and gasdermin B (GSDMB). 33hers implicated Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2), Ikaros family zinc finger 3 (IKZF3), zona pellucida binding protein 2 (ZPBP2), Post-GPI attachment to proteins 3 (PGAP3) and gasdermin A (GSDMA), in the flanking regions, as independent asthma loci. 34,35cent work, using mRNA expression in nasal epithelial brushes from African American children implicated GSDMB as the most likely target gene in this complex locus. 36GSDMB is expressed in the nuclei of airway epithelial cells and is known for its role in pyroptosis. 36Pyroptosis is an inflammatory form of programmed cell death, mostly in response to intracellular pathogens.Furthermore, GSDMB is known for increasing airway remodeling and airway hyperreactivity without airway inflammation. 37(Table 1).
Risk variants at the 17q locus are related to the age-of-onset of asthma, 28 showing strong associations with childhood-onset, but not adult-onset asthma. 29,30,38Several candidate gene studies aimed to assess the association between SNPs at the 17q locus and preschool wheezing phenotypes.Early studies showed an increased risk for development of wheeze in children <6 years carrying a risk allele for ORMDL3 39 and in children <4 years carrying a risk allele for GSDMB. 40Furthermore, an interaction was found between 17q variants and human rhinovirus induced wheezing in early life with respect to the development of childhood-onset asthma. 41More recently, a number of studies have correlated 17q variants to LCA derived wheeze phenotypes.Granell et al. 42  finding was recently extended in five UK birth cohorts by a novel approach, called Partition-around-Medoids clustering, which derives phenotypes based on variables such as duration, temporal sequence, persistence or recurrence.This method was shown to provide more robust phenotypes, compared to previous clustering methods.Here, SNPs in 17q were associated with persistent wheeze and intermittent wheeze, but not early transient wheeze or late-onset wheeze. 43Similarly, in 1033 children from the Project Viva birth cohort an increased odds for persistent wheeze was reported for a SNP in ORMDL3, but not for transient or late-onset wheeze. 44In the largest study so far, using LCA on harmonized data from seven US-based birth cohorts, 17q SNPs were associated with higher odds ratios for all transient, late-onset and persistent wheezing phenotypes in subjects of both African and European ancestry. 45The finding that 17q SNPs were associated with any of the LCA-derived wheezing phenotypes suggests that these have a shared genetic origin and, thus, that differences may actually be influenced by environmental factors.Early-life environmental exposures may reduce or aggravate the likelihood of wheeze in children carrying 17q risk alleles.7][48] Conversely, the increased risk of asthma conferred by 17q genetic variants is enhanced by early-life exposure to environmental tobacco smoke. 38Taken together, these data suggest that this wheeze locus appears to be important in host responses to the environment.
IL33 and its receptor IL1RL1 are important loci for both childhood-onset asthma and asthma exacerbations, but were also studied in relation to LCA-defined wheezing phenotypes in two birth cohorts: ALSPAC and PIAMA.SNPs in these genes were most strongly associated with intermediate-onset wheeze, late-onset wheeze and persistent wheeze. 49IL33 is an epithelial cytokine that is expressed in the airway epithelium and endothelium, where it acts as an alarmin upon damage or infections.(Table 1) IL33 can activate its receptor IL1RL1-b to enhance eosinophilic inflammation.This receptor is present on many immune cells, including T-helper 2 cells, Innate Lymphoid type 2 cells, eosinophils and mast cells.Thus, this pathway links epithelial damage to activation of Type 2 inflammation in childhood-onset asthma. 50It is an attractive pathway for the intervention of early childhood asthma, as monoclonal antibodies have been developed against IL33, which were shown to be effective in preventing loss of asthma control in adult asthma patients. 51nally, several other potential candidate genes were reported for the progression of wheeze to asthma, including ICAM-1 52 and ADAM33. 53Independent replication in well-powered studies is needed before definitive conclusions can be drawn.

| SUMMARY AND FUTURE D IREC TI ON S
Genetic factors play an important role in childhood-onset asthma, and specific genes that provide susceptibility to childhood, but not adult-onset asthma, have been discovered.However, genetic studies of wheeze have been proven challenging, due to difficulties in wheeze definition, the imprecise phenotype of self-reported wheeze, as well as heterogeneous mechanisms of wheeze.Thus, genetic factors that determine the progression from wheeze to asthma have been proven difficult to find.To unravel underlying pathways from wheeze to childhood-onset asthma, we emphasize the importance of better phenotype definitions to limit the effect of heterogeneity.We suggest the use of patient registries to limit the reliance on parental reports and questionnaires, and investigate severe wheezing symptoms observed in hospitals.23]27 Furthermore, it is important to perform more studies specifically in children as we cannot only rely on studies in adults.Additionally, novel collaborations are needed worldwide to investigate early childhood wheeze and asthma genes.
In these worldwide collaborations, populations of diverse ancestries need to be included to reduce inequality; and make sure that the results of these studies are relevant to all patients.Moreover, it may accelerate the search for functional SNPs due to low linkage disequilibrium in populations of African descent. 54

PE E R R E V I E W
The peer review history for this article is available at https:// www.

4 and 5
years were available in that study.In 2008, Henderson et al. proposed a new classification using annual data until 8 years of age based on a computer-based Latent Class Analysis (LCA) of self-reported wheezing symptoms in the UK ALSPAC (Avon Longitudinal Study of Parents and Children) population-based birth cohort. 4Similar patterns were subsequently observed in the Dutch birth cohort PIAMA (Prevention and Incidence of Asthma and Mite Allergy), adding at least two wheezing phenotypes: children who were wheezing until approximately 6 years, but stopped afterwards (prolonged early wheeze) and children who started wheezing between the age of 1 and 2 (intermediate-onset wheeze).
22) years, indicating this study was not performed to provide information on preschool wheeze.Two GWAS used an age-cut-off of childhood-onset asthma versus adult-onset asthma.In 2019, Ferreira et al. performed a genetic association study in children and adults with a European background in the UK Biobank. 29They identified 40,544 cases with selfreported doctor-diagnosed asthma and sufficient data on age-ofonset.Childhood-onset asthma (0-19 years, n = 13,962 subjects) had

F I G U R E 1
Schematic representation on interaction of CDHR3 receptor with viral infections.Left panel: Expression of CDHR3 is related to increased infection with HRV-C15 (human rhinovirus species C15).Right panel: This effect is even stronger in carriers of the risk CDHR3 risk alleles AA from the asthma SNP rs6967330.Reprint from Everman et al.22 (Copyright (2019), with permission from Elsevier).
described a strong association with persistent and intermediate-onset childhood wheezing phenotypes in 7045 children from the ALSPAC cohort, but a much weaker association with transient wheeze.This F I G U R E 2 Miami plot of childhood-onset asthma vs controls GWAS (panel A, blue) and adult-onset asthma vs controls GWAS (Panel B, red).Some genes are overlapping, others are childhood-or adult-specific.Panel A (childhood-onset asthma) clearly shows more genetic significant SNPs compared to Panel B (adult-onset asthma).Reprint from Pividori et al. 30 (Copyright (2019), with permission from Elsevier).
If these SNPs have been identified, their function(s) need to be understood.Genes related to these early life wheeze and asthma SNPs are interesting drug targets.Although this may take a lot of effort and time, it is worthwhile to pursue, as genetically validated drug targets improve change of successful drug interventions.These novel drugs could thus be targeted to stop the progression from wheeze to asthma.AUTH O R CO NTR I B UTI O N S Alba Alida Bruinetta Wolters: Investigation; conceptualization; writing -original draft; writing -review and editing; methodology; visualization.Elin Theodora Geertruida Kersten: Writing -review and editing; supervision; conceptualization; writing -original draft; methodology; investigation; visualization.Gerard Henk Koppelman:Writing -review and editing; supervision; conceptualization; writing -original draft; methodology; investigation; visualization.CO N FLI C T O F I NTE R E S T S TATE M E NTAABW and ETGK report no conflicts of interest.GHK reports grant support from Netherlands Lung Foundation, TEVA the Netherlands, GSK, Vertex, Ubbo Emmius Foundation, European Union (H2020) and Zon-MW outside the submitted work.GHK reports lecture and/ or advisory fees from GSK, Astra Zeneca and Pure-IMS (money to institution).