1. Epidemiology and Global Health
  2. Genetics and Genomics

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing

  1. Raquel Granell  Is a corresponding author
  2. John A Curtin
  3. Sadia Haider
  4. Negusse Tadesse Kitaba
  5. Sara A Mathie
  6. Lisa G Gregory
  7. Laura L Yates
  8. Mauro Tutino
  9. Jenny Hankinson
  10. Mauro Perretti
  11. Judith M Vonk
  12. Hasan S Arshad
  13. Paul Cullinan
  14. Sara Fontanella
  15. Graham C Roberts
  16. Gerard H Koppelman
  17. Angela Simpson
  18. Steve W Turner
  19. Clare S Murray
  20. Clare M Lloyd
  21. John W Holloway
  22. Adnan Custovic  Is a corresponding author
  23. on behalf of UNICORN and Breathing Together investigators
  1. MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, United Kingdom
  2. Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, and Manchester University NHS Foundation Trust, United Kingdom
  3. National Heart and Lung Institute, Imperial College London, United Kingdom
  4. Human Development and Health, Faculty of Medicine, University of Southampton, United Kingdom
  5. William Harvey Research Institute, Barts and The London School of Medicine Queen Mary University of London, United Kingdom
  6. Department of Epidemiology, University of Groningen, University Medical Center Groningen\, Netherlands
  7. University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Netherlands
  8. NIHR Southampton Biomedical Research Centre, University Hospitals Southampton NHS Foundation Trust, United Kingdom
  9. David Hide Asthma and Allergy Research Centre, United Kingdom
  10. Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, United Kingdom
  11. Department of Pediatric Pulmonology and Pediatric Allergology, University of Groningen, University Medical Center Groningen, Beatrix Children’s Hospital, Netherlands
  12. Child Health, University of Aberdeen, United Kingdom
https://doi.org/10.7554/eLife.84315
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Cite this article
  1. Raquel Granell
  2. John A Curtin
  3. Sadia Haider
  4. Negusse Tadesse Kitaba
  5. Sara A Mathie
  6. Lisa G Gregory
  7. Laura L Yates
  8. Mauro Tutino
  9. Jenny Hankinson
  10. Mauro Perretti
  11. Judith M Vonk
  12. Hasan S Arshad
  13. Paul Cullinan
  14. Sara Fontanella
  15. Graham C Roberts
  16. Gerard H Koppelman
  17. Angela Simpson
  18. Steve W Turner
  19. Clare S Murray
  20. Clare M Lloyd
  21. John W Holloway
  22. Adnan Custovic
  23. on behalf of UNICORN and Breathing Together investigators
(2023)
A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing
eLife 12:e84315.
https://doi.org/10.7554/eLife.84315
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12 figures, 17 tables and 2 additional files

Figures

Figure 1 with 1 supplement
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Circular Manhattan plot showing an overview of the genome-wide association study (GWAS) results by wheeze phenotype (from outside to inside: early-onset persistent, early-onset pre-school remitting, early-onset mid-childhood remitting, and late-onset wheeze).

The red line indicates the genome-wide significance threshold (p < 5 × 10−8), while the blue line indicates the threshold for genetic variants that showed a suggestive significant association (p < 10−5).

Figure 1—figure supplement 1
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QQ plots for each wheezing phenotype.
Figure 2 with 1 supplement
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Scatter plots illustrating the heterogeneity in the genetic profile of the wheezing phenotypes.

Top plots compare phenotype-specific beta effects for persistent and early-onset mid-childhood remitting wheezing. Shared nominal beta effects only found when relaxing p<10–4 for early-onset mid-childhood remitting wheezing. Bottom plots compare phenotype-specific beta effects for persistent and early-onset pre-school remitting. No shared beta effects (same or opposite direction) were found at p<10–5 for any of the comparisons. Abbreviations used: pw = persistent, er = early-onset pre-school remitting, and pe = early-onset mid-childhood remitting.

Figure 2—figure supplement 1
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Scatter plots illustrating the heterogeneity in the genetic profile of wheezing phenotypes.

No shared beta effects (same or opposite direction) were found at p<10–5 for any of the comparisons. Abbreviations used: pw = persistent, er = early-onset pre-school remitting, pe = early-onset mid-childhood remitting, and lo = late-onset wheezing. Scatter plot for pw vs. lo (top left), er vs. pe (top right), er vs. lo (bottom left), pe vs lo (bottom right).

Figure 3
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Chromatin interactions between rs75260654 and the ANXA1 promoter in CD4+ cells in Manchester Asthma and Allergy Study (MAAS) rs75260654 physically interacts with ANXA1 promoter in CD4+ T cells and overlaps a region of active (POLR2AphosphoS2 ChIP-seq) open (ATAC-seq) chromatin in A549 cell line (lung epithelial carcinoma).

The region is also predicted to be an active enhancer (ChromHMM 18-state model) in the A549 cell type. Only ChromHMM enhancer chromatin are displayed. Yellow shaded area indicates the Promoter Capture Hi-C (PCHi-C) fragment overlapping rs75260654 (red bar) and interacting with the ANXA1 promoter.

Figure 4
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eQTL ANXA1 and rs75260654 across different tissue types.

Point size is proportional to -log10 p-value.

Figure 5
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Annexin A1 is induced following house dust mite (HDM) challenge and mice deficient in ANXA1 have exacerbated airway hyper-reactivity.

(A) Schematic of HDM allergen dosing protocol, N=4–6 per group, data representative of two animal experiments. (B, C) Immunofluorescent staining of paraffin-embedded lung tissue sections incubated with anti-annexin A1, counterstained with DAPI (N=4 per group). (D) mRNA expression of annexin A1 in lung tissue following HDM exposure, expression normalised to housekeeping gene hprt. Mice receiving HDM were analysed for changes in airway hyper-reactivity following methacholine (MCh) challenge in tracheotomised restrained mice. (E) Airway resistance at top MCh dose 100 mg/ml. (F) Eosinophils quantified in BAL, (F) T1/ST2+ lymphocytes quantified in the BAL. (H) IL-4, (I) IL-5, and (J) IL-13 quantified in lung tissue by ELISA. *p<0.05 and **p<0.01 relative to PBS control group by Mann-Whitney test. +p < 0.05 and ++p < 0.01 comparing HDM annexin A1 knock-out (KO) mice relative to HDM wildtype (WT) group by Mann-Whitney test.

Appendix 1—figure 1
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Flowchart of individuals included in the final meta-analysis.
Appendix 2—figure 1
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Zoom locus plots for short-listed independent top hits for persistent wheezing.
Appendix 2—figure 2
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Zoom locus plots for short-listed independent top hits for early-onset pre-school remitting wheezing.
Appendix 2—figure 3
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Zoom locus plots for short-listed independent top hits for early-onset mid-childhood remitting wheezing.
Appendix 2—figure 4
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Zoom locus plots for short-listed independent top hits for late-onset wheezing.
Appendix 5—figure 1
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Linkage disequilibrium between single nucleotide polymorphisms (SNPs) downstream of ANXA1 that were associated with persistent wheeze.
Appendix 5—figure 2
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ANXA1 interactors.

Protein-protein interaction of ANXA1 including IL-4, IL-13, and NR3C1.

Tables

Table 1
Genome-wide association study (GWAS) meta-analysis: short-listed 85 top independent single nucleotide polymorphisms (SNPs) across the four wheezing phenotypes.
Early-onset persistent wheezing
LocusIndependent SNPsNearby genes (SNPnexus)Effect allele(freq)/ other alleleBetaSEp-ValueEffect direction (3 GWAS)min_pval_other*Previous relevant associations†
1q43rs4620530CHRM3g(0.56)/t0.250.052.45E-06+++0.79FEV1, FEV1/FVC, asthma- high priority drug target
2p25.1rs13398488RNF144Ag(0.29)/a0.250.052.18E-06+--0.13Asthma, allergy, childhood onset asthma, allergic rhinitis
2q12.2rs6543291FHL2c(0.4)/t0.230.056.97E-06+++0.10Bronchial hyper-responsiveness, airway inflammation; novel gene associated with asthma severity in human
3q21.3rs77655717EFCC1, RAB43, RAB7Ac(0.05)/t0.470.106.40E-06+++0.39RAB43: response to bronchodilator, FEV/FEC ratio; RAB7A: eosinophil count
4p16.3rs7680608eQTLRNF212, IDUA, DGKQ, SLC26A1g(0.93)/c–0.420.091.31E-06---0.154p16: asthma
rs77822621eQTLc(0.96)/t–0.500.117.16E-06---0.01
4q31.21rs115228498INPP4Bc(0.02)/t0.790.172.70E-06+++0.02Atopic asthma
5p15.31rs116494115ADCY2g(0.01)/a0.750.176.49E-06+++0.09Asthma×air pollution, childhood asthma
7q22.3rs76871421CDHR3c(0.12)/t0.370.075.71E-07+++0.22Childhood asthma
9q21.13rs75260654ANXA1, TMC1, LOC101927258, ALDH1A1c(0.98)/t–0.900.166.66E-09---0.05ANXA1: FEV1/FVC, response to bronchodilators in smokers, with anti-inflammatory properties, strongly expressed in bronchial mast cells and potentially involved in epithelial airway repair
rs116849664c(0.98)/t–0.890.161.99E-08---0.06
10q24.2rs7088157LOXL4, R3HCC1Lg(0.5)/a–0.230.057.34E-06---0.26R3HCC1L: eosinophil count, atopic eczema, psoriasis, BMI
11p15.4rs112474574TRIM5, TRIM6, TRIM22c(0.96)/t–0.550.122.29E-06---0.14Severe asthma and insulin resistance
11q23.3rs116861530eQTLSIK3g(0.94)/a–0.420.099.07E-06---0.01Triglycerides, glucose metabolism, eosinophil count
14q22.1rs1105683KTN1c(0.07)/t0.410.099.15E-06+++0.24Severe asthma
5q13.3rs2202714eQTLFAM227Bg(0.36)/a0.230.058.71E-06+++0.01rs35251997 and FEV1; FEV1/FVC
15q25.2rs117540214eQTLADAMTSL3g(0.06)/a0.420.109.82E-06+++3.91E-03FEV1/FVC
17q12rs17676191IKZF3g(0.10)/a0.360.082.18E-06+++3.06E-03Early-onset asthma, persistent wheezing (chr17q12-q21)
rs79026872c(0.03)/t0.640.132.08E-06+++2.56E-03
17q21rs4795400GSDMBc(0.53)/t0.300.055.42E-09+++1.96E-04
rs1031460g(0.50)/t0.270.058.71E-08+++1.87E-04
rs56199421c(0.45)/t–0.230.054.50E-06---9.61E-04
rs4795406LRRC3Cg(0.55)/c–0.240.059.91E-07---1.51E-03
rs72832972GSDMAc(0.92)/t–0.380.088.91E-06---0.01
rs4794821c(0.47)/t0.270.059.43E-08+++1.07E-03
rs59843584c(0.78)/a–0.310.066.38E-08---6.63E-03
19p13.2rs4804311MARCH2, HNRNPM, MYO1Fg(0.08)/a0.420.099.65E-07+-+0.05Triglycerides, HDL cholesterol, metabolic syndrome; MYO1F: FEV1 and FVC
rs2013694c(0.89)/t–0.380.088.29E-07--+0.39
rs73501545g(0.16)/a0.310.078.39E-06+++0.29
rs111644945g(0.9)/a–0.410.084.01E-07---0.02
22q11.1rs5994170CECR5g(0.4)/a0.230.054.95E-06+++0.58Triglycerides, eosinophil count, and body height
rs34902370c(0.75)/t–0.250.066.80E-06---0.41
Early-onset pre-school remitting wheezing
LocusSNPNearby genes (SNPnexus)Coded(freq)/other alleleBetaSEp-ValueDirectionmin_pval_otherPrevious relevant associations
1q32.3rs12730098eQTLPPP2R5Ac(0.79)/t–0.220.058.44E-06---0.53Waist circumference and obesity
2p24.2rs2880066FAM49A or CYRIAt(0.09)/a0.320.074.34E-06+++0.20Airway repair in non-atopic asthma
rs10180268c(0.06)/t0.430.096.56E-07+++0.19
3q26.31rs3861377NLGN1g(0.89)/a–0.280.067.75E-06---0.28Smoking
rs10513743NAALADL2c(0.84)/t–0.250.064.97E-06-+-0.06Exacerbations requiring hospitalisation in asthma-suggestive p-value
5q13.3rs10075253SV2Cc(0.85)/t–0.270.061.20E-06---0.17BMI
6q27rs2453395PDE10Ag(0.33)/a0.190.049.51E-06+++0.01Birth weight; asthma and BMI
7q21.11rs4730561MAGI2g(0.36)/a–0.200.046.78E-06---0.13Allergic diseases and atopy, smoking, BMI, airway wall thickness
rs73144976g(0.97)/a–0.470.119.41E-06---0.26
rs67259321c(0.06)/t0.430.081.65E-07+-+0.76
9p13.3rs10758259eQTLC9orf24g(0.17)/a–0.270.064.64E-06---0.01Airway repair
11q22.3rs72994149GUCY1A2c(0.84)/t–0.240.058.33E-06-+-0.06Systolic blood pressure
13q21.1rs2872948PRR20A/B/C/D/Et(0.96)/a–0.540.105.93E-08---0.27Systolic blood pressure
rs73527654g(0.08)/a0.340.072.85E-06+++0.41
15q21.1rs116966886SEMA6Dg(0.99)/a–0.820.187.55E-06-+-0.57Smoking
rs117565527g(0.99)/a–0.870.172.38E-07-+-0.43
Early-onset mid-childhood remitting wheezing
LocusSNPNearby genes (SNPnexus)Coded(freq)/ other alleleBetaSEp-ValueDirectionmin_pval_otherPrevious relevant associations
1q23.2rs35725789CADM3, FCER1A, MPTX1, OR10J1c(0.95)/a–0.560.125.42E-06-+-0.01Neutrophil count, CRP
rs146141555c(0.98)/t–0.890.172.04E-07-+-0.08
rs146575092g(0.98)/a–0.850.178.73E-07-+-0.07
2p22.3rs7595553MRPL50P1g(0.16)/c–0.460.103.26E-06---0.12PM 2.5 exposure level and global DNA methylation level
3p25.3rs34315999eQTLRAD18c(0.03)/t0.690.141.11E-06+++0.14Atopy/SPT
3q29rs146961758MRPL50P1, LSG1, TMEM44-AS1, TMEM44, ATP13A3t(0.05)/a0.570.126.01E-06+-+0.113q29: BMI
TMEM44-AS1, TMEM44, ATP13A3: diastolic blood pressure; LSG1: BMI, eosinophil count
4q24rs138794367SLC9B1c(0.99)/t–1.020.225.47E-06---0.13Eosinophil count, allergic rhinitis
5q14.1rs115719402AP3B1g(0.96)/a–0.600.137.20E-06---0.06Vital capacity, BMI
13q31.1rs9602218RNU6-67P, SLITRK1c(0.06)/a0.580.121.74E-06+-+0.05RNU6-67P/ rs976078: food allergy
rs61960366g(0.97)/a–0.790.157.09E-08-+-0.12
rs74589927g(0.02)/a0.730.163.78E-06+-+0.02
rs2210726VENTXP2, UBE2D3P4, MTND4P1c(0.91)/t–0.470.101.33E-06---0.02
rs4390476c(0.08)/a0.460.108.81E-06+++0.12
14q24.2rs117443464ZFYVE1g(0.95)/a–0.570.124.68E-06--+0.19LDL cholesterol and systolic blood pressure
20p12.3-p12.2rs6077514PLCB4c(0.88)/t–0.390.094.03E-06---0.43Neutrophil count
Late-onset wheezing
LocusSNPNearby genes (SNPnexus)Coded(freq)/ other alleleBetaSEp-ValueDirectionmin_pval_otherPrevious relevant associations
1p36.13rs9439669KLHDC7At(0.82)/a–0.340.075.15E-06---0.311p36.13: metabolic syndrome
1p32.2rs2051039PPAP2B, PRKAA2c(0.08)/t0.470.106.06E-06+-+0.08PRKAA2: lymphocyte count and asthma susceptibility
1p31.1rs72673642HMGB1P18g(0.77)/a–0.310.076.25E-06---0.01Smoking, BMI
2q13rs140983998ACOXL, BUB1c(0.98)/t–0.880.194.71E-06---0.40ACOXL: later onset asthma and obesity
2q14.3rs148008098AMMECR1Lc(0.96)/t–0.690.153.41E-06---0.01Body height, blood protein; growth, bone, and heart alterations
3p24.2rs4072729RARBc(0.03)/t0.610.134.20E-06+-+0.23FEV1/FVC, adult lung function
3q13.2rs145629570KIAA2018, NAA50, SIDT1, CD200c(0.02)/t0.920.186.83E-07+++0.10SIDT1: FEV1/FVC; CD200: adult-onset non-allergic asthma
3q23rs113643470TFDP2, XRN1c(0.98)/t–0.910.191.68E-06---0.03XRN1: eosinophil count; 3q23: allergic disease and atopic sensitisation
4p11rs17472015SLAIN2, SLC10A4, FRYLc(0.01)/t1.000.239.49E-06+++0.46FRYL: body height, age at menopause
7q36.1rs117660982KRBA1, ZNF467g(0.97)/a–0.740.167.63E-06-+-0.18Systolic blood pressure
rs118027705GIMAP family, AOC1c(0.97)/t–0.770.176.48E-06-+-0.01AOC1: CV disease, smoking; GIMAP family: autoimmune diabetes, asthma, and allergy
rs139489493LOC105375566c(0.98)/t–0.950.202.28E-06---0.03
7q36.3rs144271668PTPRN2c(0.01)/a0.880.192.91E-06+++0.28Eczema
8q21.3rs990182LOC105375631t(0.42)/a0.280.062.57E-06+++0.468q21.3: type 1 diabetes
9p22.3rs79110962NFIB, ZDHHC21c(0.08)/t0.510.103.98E-07+++0.059p22.3: asthma (mean age <16 years)
10q23.31rs7896106SLC16A12, IFIT family, PANK1g(0.35)/t0.300.061.35E-06+++0.05SLC16A12: Body height; PANK1: insulin
11q23.3rs141958628CBL, CCDC84, MCAMc(0.98)/t–0.980.201.33E-06-+-0.27CCDC84: asthma, allergy
15q15.3-q21.1rs139134265SPG11, CTDSPL2g(0.02)/c0.870.209.11E-06+-+0.13CTDSPL2: alcohol drinking
15q25.2rs143862030ADAMTSL3, GOLGA6L4, UBE2Q2P8c(0.04)/t0.640.131.65E-06+++0.08ADAMTSL3: FEV1/FVC; lean mass
16p13.3rs113390367SSTR5-AS1, CACNA1Hg(0.86)/a–0.400.081.04E-06---0.16CACNA1H: eosinophil count
16p12.1rs4788025GSG1Lg(0.46)/a–0.300.067.99E-07---0.1916p12.1: current asthma and rhino-conjunctivitis at 10–15 years
22q13.32rs133498FAM19A5 or TAFA5g(0.94)/a–0.480.115.35E-06---0.84Obesity and metabolic dysfunction

  1. eQTL: identified in expression analyses of whole blood and/or lung tissues using Genotype-Tissue Expression database (https://gtexportal.org) using the European reference panel.

  2. Bold p-values are genome-wide significant (p < 5 × 10−8).

  3. *

    Minimum p-value across associations with the other three wheezing phenotypes, using the never/infrequent wheeze as the baseline phenotype.

  4. †

    List of references or sources (GeneCards, GWAS Catalog, PhenoScanner) available in Appendix 5—tables 1–4.

Appendix 1—table 1
Definition of variables in each of the five Study Team for Early Life Asthma Research (STELAR) birth cohorts.
VariableDefinition
Cohort: ALSPAC
Mother – asthmaHave you ever had asthma? (recruitment)
Mother smokingMother smoked when expecting (recruitment)
Doctor-diagnosed asthma everHas a doctor ever said that your child has asthma? (years 8 and 14)
Current wheezingTwo questions combined: Occurrence of wheezing and/or wheezing with whistling on the chest in the last 12 months (year ½, 2½, 4¾, 8½, and 14)
Current asthma medicationAsthma medication in the last 12 months (years 8½ and 14)
Current rhinitisChild had problem with sneezing/runny nose without cold/flu in last 12 months (years 7 and 16½)
Current hay feverChild had hay fever in last 12 months (years 10½ and 14)
Cohort: MAAS
Mother – asthmaHas a doctor ever told you that you had asthma? (recruitment)
Mother smokingDo you smoke − mother (recruitment)
Doctor-diagnosed asthma everHas your doctor ever told you that your child has or had asthma? (years 8 and 16)
Asthma everHas your child ever suffered from asthma (years 8 and 16)
Current wheezingHas your child had wheezing or whistling in the chest in the last 6/12 months (years 1, 3, 5, 8, and 16)
Current asthma medicationAsthma medication in the last 12 months (years 8 and 16)
Current rhinitisHas your child ever had a problem with sneezing, or a runny nose, or a blocked nose when he /she did not have a cold or the flu? (years 8 and 16)
Current hay feverDoes your child have hay fever now? (years 8 and 16)
Cohort: SEATON
Mother – asthmaDo you suffer from asthma? (recruitment)
Mother smokingWhich of the following best describes your smoking status? (recruitment)
Doctor-diagnosed asthma everHas your child ever suffered from asthma? If yes, has this been confirmed by a doctor? (years 10 and 15)
Asthma everHas your child ever suffered from asthma? (year 10); Have you ever suffered from asthma? (year 15)
Current wheezingHas your child had wheezing in the chest in the last 12 months (years 1, 2, 5, 10, and 15)
Current asthma medicationHas your child been prescribed medicines/inhalers for asthma in the last 12 months? (year 10); Have you been prescribed medicines/inhalers for asthma in the last 12 months? (year 15)
Current hay feverHas your child suffered from hay fever last 12 months? (years 10 and 15)
Cohort: Ashford
Mother – asthmaDo you have or have you ever been told you have asthma? (recruitment)
Mother smokingDo you smoke cigarettes? (recruitment)
Doctor-diagnosed asthma everHas your doctor ever told you that your child has or had asthma? (years 8 and 14)
Asthma everIn the past 12 months has your daughter suffered from asthma? (year 8); Has she/he ever suffered from asthma? (year 14)
Current wheezingWhich one best describes your child’s wheeze in past 12 months? ‘Yes’ (B:1–6, C:7+), ‘No’ (A:0) (years 1, 2, 5, 8, and 14)
Current asthma medicationOver the last 12 months has your daughter taken any of the following treatments (preventer, reliever, nebuliser, steroids) for asthma? (years 8 and 14)
Current rhinitisIn the last 12 months has your child had a problem with sneezing or a runny or blocked nose? (years 8 and 14)
Current hay feverIn your opinion does your child have hay fever now? (year 8)
Has your child ever had hay fever? (year 14)
Cohort: IOW
Mother − asthmaDo you or have you suffered from asthma or wheezing (recruitment)
Mother smokingDo you smoke in the house? (recruitment)
Doctor-diagnosed asthma everAsthma cared for by hospital specialist/ GP or nurse (years 10, 18, and 26)
Asthma everChild ever had asthma (years 10 and 18)
Current wheezingPresence of wheeze since previous review (years 1, 2, 4, 10, and 18)
Asthma medication everChild ever had asthma treatment (year 18) combined with asthma treatment questions being asked at years 1, 2, 4, 10, and 18
Current rhinitisIn the past 12 months have you had a problem with sneezing, or a runny or blocked nose when you did not have a cold or the flu? (years 10, 18, and 26)
Appendix 1—table 2
The cohort-specific time points and sample size used to ascertain wheeze phenotypes.
Birth cohort:IOWMAASSEATONAshfordALSPAC
Year of birth19891995199719921991
QuestionnaireInterviewer-administeredInterviewer-administeredPostalInterviewer-administeredPostal
Data collection age (years)1, 2, 4, 10, 181, 3, 5, 8, 161, 2, 5, 10, 151, 2, 5, 8, 14½, 2½, 4¾, 8½, 14
No. of children with ≥2 observations on wheezing at five selected time points14601150153562011,176
Appendix 1—table 3
Characteristics of the participants in Study Team for Early Life Asthma Research (STELAR) cohorts included in this analysis (restricted to individuals with genetic data).

Numbers are N (%) except for age, where we report mean (SD).

ALSPACMAASSEATONAshfordIOW
N=6,833(71.4%)N=887(9.3%)N=548(5.7%)N=348(3.6%)N=952(9.9%)
Males3492 (51.1)475 (53.6)260 (47.5)179 (51.4)466 (49.0)
Maternal history of asthma748 (11.5)120 (13.5)77 (14.1)49 (14.1)106 (11.2)
Maternal smoking1423 (22.1)122 (13.8)107 (19.5)52 (14.9)217 (23.1)
Wheeze phenotypes
Never/infrequent4331 (63.4)506 (57.1)332 (60.6)145 (41.7)573 (60.2)
Early-onset persistent656 (9.6)133 (15.0)36 (6.6)41 (11.8)77 (8.1)
Early-onset pre-school remitting1076 (15.8)145 (16.4)117 (21.4)145 (41.7)0
Early-onset mid-childhood remitting474 (6.9)48 (5.4)13 (2.4)13 (3.7)55 (5.8)
Late-onset296 (4.3)55 (6.2)50 (9.1)4 (1.2)247 (26.0)
7–8 years14–15 years8 years16 years10 years15 years8 years14 years10 years18 years
Age mean (SD) in years8.7 (0.3)15.4 (0.3)7.98 (0.16)16.09 (0.62)10.15 (0.18)15.09 (0.28)7.97 (NA)13.95 (NA)9.98 (0.27)17.87 (0.59)
Doctor-diagnosed asthma ever*1060 (19.7)796 (23.2)198 (23.9)198 (30.0)86 (16.0)80 (19.5)75 (21.6)83 (23.9)350 (40.9)255 (28.6)
Asthma everNANA193 (22.8)192 (29.5)87 (16.2)66 (21.9)54 (15.6)65 (18.7)194 (20.9)264 (29.3)
Current wheeze683 (12.5)306 (9.0)150 (17.6)112 (16.9)67 (12.4)63 (15.5)54 (15.6)54 (15.5)190 (20.4)227 (25.1)
Current asthma medication695 (12.9)361 (10.6)141 (16.5)114 (17.1)68 (12.6)58 (14.0)50 (14.41)49 (14.1)41 (11.81)38 (10.9)
  1. *

    DDA ever not available in IOW, we used asthma cared for by hospital specialist/ GP or nurse as proxy.

Appendix 1—table 4
Comparison of included vs. excluded participants in the five cohorts at different ages.
ALSPACNIncludedNExcludedp-Value
Males (%)68333492 (51.1)43432269 (52.2)0.24
Maternal history asthma (%)6497748 (11.5)4038453 (11.2)0.64
Maternal smoking-pregnancy (%)64381423 (22.1)40191167 (29.0)<0.001
At 7.5–8.5 yearsAt 14–15 years
ALSPACNIncludedNExcludedp-ValueNIncludedNExcludedp-Value
Age mean (SD) years51398.7 (0.3)18728.7 (0.3)<0.001388515.4 (0.3)123715.5 (0.4)<0.001
Current wheeze (%)5453683 (12.5)2579344 (13.3)0.3083419306 (9.0)1078105 (9.7)0.432
Asthma ever (%)53771060 (19.7)2605562 (21.6)0.0533425796 (23.2)1079279 (25.9)0.079
Current asthma medication (%)5379695 (12.9)2529368 (14.6)0.0473400361 (10.6)1077134 (12.4)0.096
MAASNIncludedNExcludedp-Value
Males (%)887475 (53.6)263149 (56.7)0.38
Maternal history asthma (%)886120 (13.5)25945 (17.4)0.12
Maternal smoking* (%)884122 (13.8)26047 (18.1)0.09
At 8 yearsAt 16 years
MAASNIncludedNExcludedp-ValueNIncludedNExcludedp-Value
Age mean (SD) years8277.98 (0.16)1498.00 (0.21)0.3160516.09 (0.62)5915.98 (0.60)0.20
Current wheeze (%)853150 (17.6)17235 (20.4)0.39664112 (16.9)8215 (18.3)0.11
Asthma ever (%)845193 (22.8)17352 (30.1)0.043651192 (29.5)7928 (35.4)0.28
Current asthma medication (%)855141 (16.5)17343 (24.9)0.009666114 (17.1)8314 (16.9)0.96
SEATONNIncludedNExcludedp-Value
Males (%)548260 (47.5)987525 (53.2)0.031
Maternal history asthma (%)54877 (14.1)985161 (16.4)0.24
Maternal smoking* (%)548107 (19.5)987276 (28.0)<0.001
At 10 yearsAt 15 years
SEATONNIncludedNExcludedp-ValueNIncludedNExcludedp-Value
Age mean (SD) years54810.15 (0.18)98710.23 (0.16)<0.00154515.09 (0.28)91615.11 (0.26)0.20
Current wheeze (%)54167 (12.4)37642 (11.2)0.5840763 (15.5)31048 (15.5)0.99
Asthma ever (%)53787 (16.2)37453 (14.2)0.4040966 (21.9)30285 (20.8)0.73
Current asthma medication (%)54268 (12.6)37839 (10.3)0.3041458 (14.0)30934 (11.0)0.23
AshfordNIncludedNExcludedp-Value
Males (%)348179 (51.4)272153 (56.3)0.23
Maternal history asthma (%)34849 (14.1)27238 (14.0)0.97
Maternal smoking* (%)34852 (14.9)27061 (22.6)0.015
At 8 yearsAt 14 years
AshfordNIncludedNExcludedp-ValueNIncludedNExcludedp-Value
Age mean (SD) years348NA272NANA348NA272NANA
Current wheeze (%)34754 (15.6)24625 (10.2)0.0634854 (15.5)15018 (12.00)0.31
Asthma ever (%)34754 (15.6)24638 (15.5)0.9734865 (18.7)15025 (16.7)0.59
Current asthma medication (%)34750 (14.41)24622 (8.9)0.0534849 (14.1)15016 (10.7)0.30
IOWNIncludedNExcludedp-Value
Males (%)952466 (49.0)508275 (54.1)0.06
Maternal history asthma (%)946106 (11.2)50552 (10.3)0.60
Maternal smoking* (%)941217 (23.1)502147 (29.3)0.01
At 10 yearsAt 18 years
IOWNIncludedNExcludedp-ValueNIncludedNExcludedp-Value
Age mean (SD) years9329.98 (0.27)42610.04 (0.31)<0.00191417.87 (0.59)38918.14 (0.67)<0.001
Current wheeze (%)932190 (20.4)42669 (16.2)0.07903227 (25.1)37758 (15.4)<0.002
Asthma ever (%)930194 (20.9)42580 (18.8)0.39900264 (29.3)385108 (28.1)0.64
Current asthma medication (%)34741 (11.81)24615 (6.10)0.0234838 (10.9)15013 (8.7)0.45
Appendix 2—table 1
List of 134 independent single nucleotide polymorphisms (SNPs) identified after clumping and associated with at least one wheezing phenotype (p<10–5).
CHRSNPBPShort-listed after inspection of locus zoom plot
Persistent wheezing
1rs4620530240063821Yes
2rs133984887142199Yes
2rs7706232353049017No
2rs6543291106011626Yes
3rs77655717128737320Yes
4rs778226211008212Yes
4rs76806081050437Yes
4rs115228498142969757Yes
4rs145937716143192224No
5rs1164941157736317Yes
5rs7870148395680422No
6rs1380999417654240No
6rs934640471606613No
6rs143979498151040328No
7rs76871421105676144Yes
8rs59670576128555771No
9rs11693312027458652No
9rs7526065475788108Yes
9rs11684966475820902Yes
9rs143481506139515723No
10rs7088157100038964Yes
11rs1124745745885773Yes
11rs116861530116962661Yes
13rs798235073106322No
13rs17461573106711373No
14rs110568356213787Yes
15rs220271449811991Yes
15rs11754021484338642Yes
17rs1767619137949924Yes
17rs7902687237965932Yes
17rs479540038067020Yes
17rs103146038072247Yes
17rs5619942138090808Yes
17rs479540638100134Yes
17rs7283297238110575Yes
17rs479482138124203Yes
17rs5984358438124892Yes
18rs11181299330353181No
19rs48043118615589Yes
19rs20136948616392Yes
19rs735015458620823Yes
19rs1116449458625081Yes
22rs599417017615213Yes
22rs3490237017632194Yes
Early-onset remitting wheezing
1rs12730098212427488Yes
1rs75639566233019116No
2rs288006617107219Yes
2rs1018026817126699Yes
3rs11503179686691640No
3rs3861377173317378Yes
3rs10513743176022304Yes
5rs1007525375548246Yes
5rs1252088484406634No
6rs11747729792565052No
6rs2453395166286532Yes
7rs5602786950072919No
7rs473056178531705Yes
7rs7314497678586112Yes
7rs6725932178686582Yes
7rs146771277154438861No
9rs1075825934392908Yes
11rs712899471242209No
11rs72994149106837223Yes
12rs11736725693508478No
13rs287294857442480Yes
13rs7352765457447994Yes
13rs215150482291577No
15rs11696688647043587Yes
15rs11756552747342882Yes
Mid-childhood onset remitting wheezing
1rs35725789159207367Yes
1rs146141555159227423Yes
1rs146575092159374228Yes
1rs140877050220848829No
1rs72745905223451086No
2rs759555336127878Yes
2rs14500750350688324No
2rs654606864583398No
2rs17387431206651315No
2rs144791928236963432No
3rs343159998969653Yes
3rs11524577099209128No
3rs146961758194285978Yes
4rs138794367103859545Yes
5rs11571940277538102Yes
6rs7602639947531792No
7rs73172838154842348No
8rs112631708134500083No
9rs7275235698094970No
13rs11319538446333770No
13rs960221884139813Yes
13rs6196036684144202Yes
13rs7458992784208697Yes
13rs221072684492936Yes
13rs439047684598570Yes
14rs11744346473460284Yes
16rs7282081481916262No
17rs19052669712274299No
18rs7528653426206826No
18rs13888808663591085No
18rs7655153571879807No
19rs7749644419192132No
20rs60775149302948Yes
Late-onset wheezing
1rs943966918859049Yes
1rs205103957067560Yes
1rs7267364280727443Yes
2rs14755711719778063No
2rs140983998111402871Yes
2rs117617447123387601No
2rs13025116127505482No
2rs148008098128633620Yes
3rs407272924780393Yes
3rs14396066631227943No
3rs467710272193991No
3rs145629570113422516Yes
3rs113643470141728174Yes
4rs1747201548467594Yes
7rs117660982149438923Yes
7rs118027705150456728Yes
7rs139489493150481499Yes
7rs144271668157934780Yes
8rs99018289976447Yes
9rs7911096214432953Yes
10rs932546082492323No
10rs789610691196402Yes
10rs115465993109372900No
11rs1693564341395746No
11rs141958628119083284Yes
14rs11336366069410278No
15rs13913426544923960Yes
15rs14386203084922146Yes
16rs1133903671118849Yes
16rs478802528003221Yes
18rs7291826451009510No
22rs13349848913809Yes
Appendix 4—table 1
References to previous relevant associated traits for each region/gene identified in early-onset persistent wheezing.
Early-onset persistent wheezing
Gene(s)LocusPrevious associated traitReference or source
CHRM31q43FEV1, FEV1/FVC, asthma – high priority drug targetPatel, K.R. et al. Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma. FASEB J 31, 4335–4346 (2017).
RNF144A2p25.1Asthma, allergy, childhood onset asthma, allergic rhinitisSchoettler, N. et al. Advances in asthma and allergic disease genetics: Is bigger always better? J Allergy Clin Immunol 144, 1495–1506 (2019).
FHL22q12.2Bronchial hyper-responsiveness, airway inflammation, novel gene associated with asthma severity in humanKurakula, K. et al. Deficiency of FHL2 attenuates airway inflammation in mice and genetic variation associates with human bronchial hyper-responsiveness. Allergy 70, 1531–44 (2015).
RAB7A3q21.3Eosinophil countGeneCards
RAB433q21.3Response to bronchodilator, FEV1/FEC ratioGWAS Catalog
RNF212, IDUA, DGKQ, SLC26A14p16.3AsthmaGautam, Y. et al. Comprehensive functional annotation of susceptibility variants associated with asthma. Hum Genet 139, 1037–1053 (2020).
INPP4B4q31.21Atopic asthmaSharma, M. et al. A genetic variation in inositol polyphosphate 4 phosphatase a enhances susceptibility to asthma. Am J Respir Crit Care Med 177, 712–9 (2008).
ADCY25p15.31Asthma×air pollution, childhood asthmaGref, A. et al. Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up. Am J Respir Crit Care Med 195, 1373–1383 (2017).
CDHR37q22.3Childhood asthmaEverman, J.L. et al. Functional genomics of CDHR3 confirms its role in HRV-C infection and childhood asthma exacerbations. J Allergy Clin Immunol 144, 962–971 (2019).
ANXA19q21.13FEV1/FVC, response to bronchodilators in smokersLutz, S.M. et al. A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry. BMC Genet 16, 138 (2015).
ANXA19q21.13Anti-inflammatory properties, strongly expressed in bronchial mast cellsVieira Braga FA et al. A cellular census of human lungs identifies novel cell states in health and in asthma. (2019).
ANXA19q21.13Potentially involved in epithelial airway repairLeoni, G. et al. Annexin A1-containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair. J Clin Invest 125, 1215–27 (2015).
R3HCC1L10q24.2Atopic eczema, psoriasisGWAS Catalog
R3HCC1L10q24.2Eosinophil count, BMIGeneCards
TRIM5, TRIM6, TRIM2211p15.4Severe asthma and insulin resistanceKimura, T. et al. Precision autophagy directed by receptor regulators - emerging examples within the TRIM family. J Cell Sci 129, 881–91 (2016).
SIK311q23.3Triglycerides, glucose metabolism, eosinophil countSun, Z. et al. The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis. Sig Transduct Target Ther 5 (2020).
KTN114q22.1Severe asthmaBigler, J. et al. A Severe Asthma Disease Signature from Gene Expression Profiling of Peripheral Blood from U-BIOPRED Cohorts. Am J Respir Crit Care Med 195, 1311–1320 (2017).
FAM227B5q13.3rs35251997 and FEV1, FEV1/FVCShrine, N. et al. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries. Nat Genet 51, 481–493 (2019).
ADAMTSL315q25.2FEV1/FVCSakornsakolpat, P. et al. Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations. Nat Genet 51, 494–505 (2019).
IKZF3, GSDMB, LRRC3C, GSDMA17q12Early-onset asthma, persistent wheezing (chr17q12-q21)Granell R et al. Examination of the relationship between variation at 17q21 and childhood wheeze phenotypes. J Allergy Clin Immunol. 2013 Mar;131(3):685–94.
MARCH2, HNRNPM, MYO1F19p13.2Triglycerides, HDL cholesterol, metabolic syndromeSajuthi, S.P. et al. Genetic regulation of adipose tissue transcript expression is involved in modulating serum triglyceride and HDL-cholesterol. Gene 632, 50–58 (2017).
MYO1F19p13.2FEV1 and FVCGeneCards
CECR522q11.1Triglycerides, eosinophil count, and body heightLiu, D.J. et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet 49, 1758–1766 (2017).
Appendix 4—table 2
References to previous relevant associated traits for each region/gene identified in early-onset pre-school remitting wheezing.
Early-onset pre-school remitting wheezing
Gene(s)LocusPrevious associated traitReference or source
PPP2R5A1q32.3Waist circumference and obesityKim, H.J. et al. Combined linkage and association analyses identify a novel locus for obesity near PROX1 in Asians. Obesity (Silver Spring) 21, 2405–12 (2013).
FAM49A or CYRIA2p24.2Airway repair in non-atopic asthmaHoang, T.T. et al. Epigenome-wide association study of DNA methylation and adult asthma in the Agricultural Lung Health Study. Eur Respir J 56 (2020).
NLGN13q26.31SmokingDrgon, T. et al. Genome-wide association for nicotine dependence and smoking cessation success in NIH research volunteers. Mol Med 15, 21–7 (2009).
NAALADL23q26.31Suggestive association with severe asthma exacerbationsHerrera-Luis E et al. Genome-wide association study reveals a novel locus for asthma with severe exacerbations in diverse populations. Pediatr Allergy Immunol. 2021;32(1):106–115.
SV2C5q13.3BMI, diastolic blood pressureGeneCards
PDE10A6q27Birth weight, asthma, and BMIMelen, E. et al. Analyses of shared genetic factors between asthma and obesity in children. J Allergy Clin Immunol 126, 631–7 e1-8 (2010).
MAGI27q21.11Allergic diseases and atopyFreidin, M.B. et al. [Genome-wide association study of allergic diseases in Russians of Western Siberia]. Mol Biol (Mosk) 45, 464–72 (2011).
MAGI27q21.11SmokingQuach, B.C. et al. Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits. Nat Commun 11, 5562 (2020).
MAGI27q21.11BMIGeneCards
MAGI27q21.11Airway wall thicknessGWAS Catalog
C9orf249p13.3Airway repairYoshisue, H. et al. Characterisation of ciliated bronchial epithelium 1, a ciliated cell-associated gene induced during mucociliary differentiation. Am J Respir Cell Mol Biol 31, 491–500 (2004).
GUCY1A211q22.3Systolic/diastolic blood pressureGeneCards
PRR20A/B/C/D/E13q21.1Systolic blood pressureGeneCards
SEMA6D15q21.1SmokingMinica, C.C. et al. Pathways to smoking behaviours: biological insights from the Tobacco and Genetics Consortium meta-analysis. Mol Psychiatry 22, 82–88 (2017).
Appendix 4—table 3
References to previous relevant associated traits for each region/gene identified in early-onset mid-childhood remitting wheezing.
Early-onset mid-childhood remitting wheezing
Gene(s)LocusPrevious associated traitReference
CADM3, FCER1A, MPTX1, OR10J11q23.2Neutrophil count, CRPBarreto, M. et al. Duffy phenotyping and FY*B-67T/C genotyping as screening test for benign constitutional neutropenia. Hematol Transfus Cell Ther (2020).
MRPL50P12p22.3PM 2.5 exposure level and global DNA methylation levelLiu, J. et al. Genetic variants, PM2.5 exposure level and global DNA methylation level: A multi-center population-based study in Chinese. Toxicol Lett 269, 77–82 (2017).
RAD183p25.3Atopy/SPTBouzigon, E. et al. Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy. Eur J Hum Genet 18, 700–6 (2010).
MRPL50P13q29BMIKettunen, J. et al. Multicenter dizygotic twin cohort study confirms two linkage susceptibility loci for body mass index at 3q29 and 7q36 and identifies three further potential novel loci. Int J Obes (Lond) 33, 1235–42 (2009).
LSG13q29BMI, eosinophil, and neutrophil countGeneCards
TMEM44-AS1, TMEM44, ATP13A33q29Diastolic blood pressureGeneCards
SLC9B14q24Eosinophil countAschard, H. et al. Sex-specific effect of IL9 polymorphisms on lung function and polysensitization. Genes Immun 10, 559–65 (2009).
SLC9B14q24Allergic rhinitisHaagerup, A. et al. Allergic rhinitis--a total genome-scan for susceptibility genes suggests a locus on chromosome 4q24-q27. Eur J Hum Genet 9, 945–52 (2001).
AP3B15q14.1Vital capacity, BMIGeneCards, GWAS Catalog
RNU6-67P, SLITRK1, VENTXP2, UBE2D3P4, MTND4P113q31.1RNU6-67P/ rs976078: food allergyLiu, X. et al. Genome-wide association study of maternal genetic effects and parent-of-origin effects on food allergy. Medicine (Baltimore) 97, e0043 (2018).
ZFYVE114q24.2LDL cholesterol and systolic blood pressureGWAS Catalog
PLCB420p12.3-p12.2Neutrophil countOkada, Y. et al. Common variations in PSMD3-CSF3 and PLCB4 are associated with neutrophil count. Hum Mol Genet 19, 2079–85 (2010).
Appendix 4—table 4
References to previous relevant associated traits for each region/gene identified in late-onset wheezing.
Late-onset wheezing
Gene(s)LocusPrevious associated traitReference
KLHDC7A1p36.131p36.13: metabolic syndromeHoffmann, K. et al. A German genome-wide linkage scan for type 2 diabetes supports the existence of a metabolic syndrome locus on chromosome 1p36.13 and a type 2 diabetes locus on chromosome 16p12.2. Diabetologia 50, 1418–22 (2007).
PPAP2B, PRKAA21p32.2PRKAA2: lymphocyte count and asthma susceptibilityCusanovich, D.A. et al. The combination of a genome-wide association study of lymphocyte count and analysis of gene expression data reveals novel asthma candidate genes. Hum Mol Genet 21, 2111–23 (2012).
HMGB1P181p31.1Smoking, BMIGeneCards
ACOXL, BUB12q13ACOXL: later onset asthma and obesityZhu, Z. et al. Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank. J Allergy Clin Immunol 145, 537–549 (2020).
AMMECR1L2q14.3Body height, blood protein, growth, bone, and heart alterationsMoyses-Oliveira, M. et al. Inactivation of AMMECR1 is associated with growth, bone, and heart alterations. Hum Mutat 39, 281–291 (2018).
RARB3p24.2FEV1/FVC, adult lung functionCollins, S.A. et al. HHIP, HDAC4, NCR3 and RARB polymorphisms affect fetal, childhood and adult lung function. Eur Respir J 41, 756–7 (2013).
KIAA2018, NAA50, SIDT1, CD2003q13.2SIDT1: FEV1/FVC, CD200: adult-onset non-allergic asthmaSiroux, V. et al. Genetic heterogeneity of asthma phenotypes identified by a clustering approach. Eur Respir J 43, 439–52 (2014).
TFDP2, XRN13q23XRN1: eosinophil count, 3q23: allergic disease and atopic sensitisationFreidin, M.B. et al. [Genome-wide association study of allergic diseases in Russians of Western Siberia]. Mol Biol (Mosk) 45, 464–72 (2011).
SLAIN2, SLC10A4, FRYL4p11FRYL: body height, age at menopauseGeneCards
KRBA1, ZNF4677q36.1Systolic blood pressureGWAS Catalog
GIMAP family, AOC1, LOC1053755667q36.1AOC1: CV disease, smoking, GIMAP family: autoimmune diabetes, asthma and allergyHeinonen, M.T. et al. GIMAP GTPase family genes: potential modifiers in autoimmune diabetes, asthma, and allergy. J Immunol 194, 5885–94 (2015).
PTPRN27q36.3EczemaBogari, N.M. et al. Whole exome sequencing detects novel variants in Saudi children diagnosed with eczema. J Infect Public Health 13, 27–33 (2020).
LOC1053756318q21.38q21.3: type 1 diabetesMukhopadhyay, N., Noble, J.A., Govil, M., Marazita, M.L. & Greenberg, D.A. Identifying genetic risk loci for diabetic complications and showing evidence for heterogeneity of type 1 diabetes based on complications risk. PLoS One 13, e0192696 (2018).
NFIB, ZDHHC219p22.39p22.3: asthma (mean age <16 years)Denham, S. et al. Meta-analysis of genome-wide linkage studies of asthma and related traits. Respir Res 9, 38 (2008).
SLC16A12, IFIT family, PANK110q23.31SLC16A12: body height, PANK1: insulin resistanceYang, L. et al. P53/PANK1/miR-107 signalling pathway spans the gap between metabolic reprogramming and insulin resistance induced by high-fat diet. J Cell Mol Med 24, 3611–3624 (2020).
CBL, CCDC84, MCAM11q23.3CBL: sex hormone-binding globulin levels; MCAM: blood protein levelsGWAS Catalog
SPG11, CTDSPL215q15.3-q21.1CTDSPL2: alcohol drinkingGWAS Catalog
ADAMTSL3, GOLGA6L4, UBE2Q2P815q25.2ADAMTSL3: FEV1/FVC, lean massKarasik, D. et al. Disentangling the genetics of lean mass. Am J Clin Nutr 109, 276–287 (2019).
SSTR5-AS1, CACNA1H16p13.3CACNA1H: eosinophil countGWAS Catalog
GSG1L16p12.116p12.1: current asthma and rhino-conjunctivitis at 10–15 yearsSottile, G. et al. An association analysis to identify genetic variants linked to asthma and rhino-conjunctivitis in a cohort of Sicilian children. Ital J Pediatr 45, 16 (2019).
FAM19A5 or TAFA522q13.32Obesity and metabolic dysfunctionRecinella L. et al. Adipokines: New Potential Therapeutic Target for Obesity and Metabolic, Rheumatic, and Cardiovascular Diseases. Front Physiol. 2020 Oct 30;11:578966
Appendix 5—table 1
Single nucleotide polymorphisms (SNPs) near ANXA1 associated with persistent wheeze.
ChrRsidPositionA1A2freqA2BetaSEp-ValueDirection(3 GWAS)
9rs7526065475788108tc0.020.900.166.66e-09---
9rs11684966475820902tc0.020.890.161.99e-08---
9rs7832098475844302tg0.020.810.156.41e-08---

  1. A1 is the effect allele, A2 is the reference allele.

Appendix 5—table 2
Allele frequencies of rs75260654 across different wheeze phenotypes.
PhenotypeCCCTTT
Never/infrequent5641 (97.2)161 (2.8)0 (0)
Early-onset pre-school remitting1409 (97.1)42 (2.9)0 (0)
Early-onset mid-childhood remitting572 (96.1)23 (3.9)0 (0)
Late-onset613 (95.2)31 (4.8)0 (0)
Early-onset persistent867 (94.2)51 (5.5)2 (0.2)
Appendix 5—table 3
Selected immune eQTLs of rs75260654.
Rsidp-ValueBetaSEanSymbolStudy
rs752606540.014–0.650.26382ANXA1Quach_2016_monocyte_R848
rs752606540.015–1.020.41396ANXA1Quach_2016_monocyte_IAV
Appendix 5—table 4
Lung eQTLs of rs75260654.
Rsidp-ValueBetaSEanSymbolStudy
rs1168496640.04890.220.11620ANXA1GTEx_exon_lung
rs783209840.04890.220.11620ANXA1GTEx_exon_lung
Appendix 5—table 5
Functional enrichment for ANXA1: top 10 GO terms.
Term nameDescriptionFDR value
GO.0007186G protein-coupled receptor signalling pathway3.57×10–18
GO.0006954Inflammatory response1.13×10–16
GO.0006874Cellular calcium ion homeostasis5.55×10–15
GO.0007204Positive regulation of cytosolic calcium ion concentration1.65×10–14
GO.0060326Cell chemotaxis1.95×10–14
GO.0006955Immune response4.23×10–14
GO.0006935Chemotaxis4.93×10–14
GO.0006952Defense response1.68×10–13
GO.0050801Ion homeostasis2.23×10–13
GO.0002376Immune system process2.87×10–13
Appendix 5—table 6
Replication of associations between single nucleotide polymorphisms (SNPs) downstream of ANXA1 and early-onset persistent wheezing in Prevention and Incidence of Asthma and Mite Allergy (PIAMA).
CW (40) vs NI (1557)
Rsidchr:positionR2A2/freqA2BetaSEp-Value
rs752606549:757881080.60c/0.02–0.2870.910.75
rs1168496649:758209020.61c/0.020.1191.080.91
rs783209849:758443020.59g/0.020.1251.040.90

  1. A2 is the reference allele. CW = continuous wheezing, IR = intermediate wheezing derived from LCA 1–12 years in PIAMA.

Appendix 6—table 1
Antibodies used in the flow cytometry analysis.
MoleculeManufacturerIsotypeConjugated dyeClone
T1/ST2Morwell Diagnostics GMBH, SwitzerlandRat IgG1FITCDJ8
CD45e-Bioscience Ltd, Hatfield, UKRat IgG2bPerCP-CY5.530-F11
CD11bBD Biosciences, Oxford, UKRat IgG2be450M1/70
CD11ce-Bioscience Ltd, Hatfield, UKHamster IgG1PerCP-CY5.5N418
Siglec FBD Biosciences, Oxford, UKRat IgG2aPEE50-2440

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STROBE flowchart.

https://cdn.elifesciences.org/articles/84315/elife-84315-repstand1-v2.docx

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  1. Raquel Granell
  2. John A Curtin
  3. Sadia Haider
  4. Negusse Tadesse Kitaba
  5. Sara A Mathie
  6. Lisa G Gregory
  7. Laura L Yates
  8. Mauro Tutino
  9. Jenny Hankinson
  10. Mauro Perretti
  11. Judith M Vonk
  12. Hasan S Arshad
  13. Paul Cullinan
  14. Sara Fontanella
  15. Graham C Roberts
  16. Gerard H Koppelman
  17. Angela Simpson
  18. Steve W Turner
  19. Clare S Murray
  20. Clare M Lloyd
  21. John W Holloway
  22. Adnan Custovic
  23. on behalf of UNICORN and Breathing Together investigators
(2023)
A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing
eLife 12:e84315.
https://doi.org/10.7554/eLife.84315