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. University of Bristol, United Kingdom
  2. University of Manchester, United Kingdom
  3. Imperial College London, United Kingdom
  4. University of Southampton, United Kingdom
  5. Queen Mary University of London, United Kingdom
  6. University of Groningen, Netherlands
  7. David Hide Asthma and Allergy Research Centre, United Kingdom
  8. University of Aberdeen, United Kingdom

Abstract

Background:

Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes.

Methods:

We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9,568 individuals from five UK birth-cohorts.

Results:

44 independent SNPs were associated with early-onset persistent, 25 with preschool remitting, 33 with mid-childhood remitting and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 (ANXA1), p<6.7×10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge.

Conclusions:

Targeting this pathway in persistent disease may represent an exciting therapeutic prospect.

Funding:

UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108,818/15/Z) provided most of the funding for this study.

Data availability

The informed consent obtained from all included participants does not allow the data to be made freely available through any third party maintained public repository.However, data used for this submission can be made available on request to the corresponding cohort Executive. Researchers will need to submit a research proposal to each cohort Executive Committee. Data access will have a cost, for more details re. ALSPAC contact alspac-data@bristol.ac.uk, for any other cohort contact philip.couch@manchester.ac.uk.The ALSPAC website provides information on how to request and access its data ( http://www.bristol.ac.uk/alspac/researchers/access/). For queries regarding access of data from MAAS, IoW, SEATON or Ashford please contact Philip Couch philip.couch@manchester.ac.uk). All code used to analyse the individual level data and all summary data and code used to plot the figures in our manuscript has been deposited in Dryad.

The following data sets were generated

Article and author information

Author details

  1. Raquel Granell

    Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom
    For correspondence
    Raquel.Granell@bristol.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4890-4012
  2. John A Curtin

    Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, United Kingdom
    Competing interests
    No competing interests declared.
  3. Sadia Haider

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  4. Negusse Tadesse Kitaba

    Faculty of Medicine, University of Southampton, Southampton, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7518-9096
  5. Sara A Mathie

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  6. Lisa G Gregory

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  7. Laura L Yates

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  8. Mauro Tutino

    Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, United Kingdom
    Competing interests
    No competing interests declared.
  9. Jenny Hankinson

    Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, United Kingdom
    Competing interests
    No competing interests declared.
  10. Mauro Perretti

    William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2068-3331
  11. Judith M Vonk

    Department of Epidemiology, University of Groningen, Groningen, Netherlands
    Competing interests
    No competing interests declared.
  12. Hasan S Arshad

    David Hide Asthma and Allergy Research Centre, Isle of Wight, United Kingdom
    Competing interests
    No competing interests declared.
  13. Paul Cullinan

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  14. Sara Fontanella

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  15. Graham C Roberts

    Faculty of Medicine, University of Southampton, Southampton, United Kingdom
    Competing interests
    Graham C Roberts, MRC grant to my institutionPresident of the British Society of Allergy and Clinical Immunology.
  16. Gerard H Koppelman

    Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, Netherlands
    Competing interests
    Gerard H Koppelman, Dutch Lung Foundation, Ubbo Emmius Foundation (Money to insititution)Dutch Lung Foundation, Vertex, TEVA the Netherlands, GSK, ZON-MW (VICI grant), European Union (Money to institution)Astra Zeneca, Pure IMS, GSK (Money to institution)Sanofi, Boehringer Ingelheim (Money to institution).
  17. Angela Simpson

    Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, United Kingdom
    Competing interests
    Angela Simpson, Medical research council Research grantJP Moulton Charitable Foundation Research grantAsthma UK Research grant.
  18. Steve W Turner

    Child Health, University of Aberdeen, Aberdeeen, United Kingdom
    Competing interests
    No competing interests declared.
  19. Clare S Murray

    Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, United Kingdom
    Competing interests
    Clare S Murray, has received grants from Asthma Uk, the National Institute for Health Research, the Moulton Charitable Foundation and the North West Lung Centre Charity (to the Institution). They received lecture fees from GSK and Novartis, and received a travel grant from Sanofi. The authors has no other competing interests to declare..
  20. Clare M Lloyd

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    Clare M Lloyd, Wellcome Trust 107059/Z/15/Z.
  21. John W Holloway

    Faculty of Medicine, University of Southampton, Southampton, United Kingdom
    Competing interests
    John W Holloway, Medial Research Council grant MR/S025340/1 (to institution)American Academy of Allergy Asthma and Immunology (AAAI) (Support for speaker travel to AAAAI annual congress ).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9998-0464
  22. Adnan Custovic

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    For correspondence
    a.custovic@imperial.ac.uk
    Competing interests
    Adnan Custovic, MRC (research grants)EPSRC (research grant)Wellcome Trust (research grant)Worg Pharmaceoticals (Personal payment <US$5000)GSK Honorarium for lecture, personal, <US$ 5000AstraZenecaHonorarium for lecture, personal, <US$ 5000Sanofi Honorarium for lecture, personal, <US$ 5000Stallergens-Greer Honorarium for lecture, personal, <US$ 5000WAO (Board of officers, unpaid).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5218-7071

Funding

UK Medical Research Council (MR/S025340/1)

  • Raquel Granell
  • Adnan Custovic

Wellcome Trust (108818/15/Z)

  • Raquel Granell
  • Adnan Custovic

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Anurag Agrawal, Ashoka University, India

Ethics

Animal experimentation: In accordance with the Animals (scientific procedures) act 1986, all animal experiments were conducted under the approved UK Home Office Project License No: PPL 70/7643, reviewed by Imperial College's Animal Welfare and Ethical Review body.

Human subjects: ALSPAC: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. All self-completion questionnaire content is approved by the ALSPAC Ethics and Law Committee. Bristol and Weston Health Authority: E1808 Children of the Nineties: Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC). (28th November 1989); Southmead Health Authority: 49/89 Children of the Nineties -"ALSPAC". (5th April 1990); Frenchay Health Authority: 90/8 Children of the Nineties. (28th June 1990).MAAS: The study was approved by the North West - Greater Manchester East Research Ethics Committee. ERP/94/032 Up to 5 yrs. Allergen avoidance, Primary Prevention, genetics, sRaw age 3 and 5; SOU/00/259 5 year; ERP/95/137 Exposure to pet allergens, atopy, genetics; ERP/97/023 IFWIN, genetics; 03/SM/400 8 year; 06/Q1403/142 10-12 years; 11/NW/0228 13-15 years; 14/NW/1309 18+ years.SEATON: The study was approved by the North of Scotland Research Ethics Committee. REC reference: 13/NS/0108; Protocol number: 2/048/13; Amendment number: AM03.Ashford: The Asthma in Ashford study was reviewed by the Imperial College Research Ethics Committee on 11/11/2014. On 08/01/2015 the Joint Research Compliance Office granted full approval of the study on the basis described in the revised documents. ICREC reference: 14|C2288.IOW: Ethics approval for the IoW cohort was originally given by the Isle of Wight local research ethics committee in 1989 and at each subsequent follow up (1,2 and 4 years) (this is pre "numbers")Age 10 follow up (including DNA and genotyping): Isle of Wight Health Authority Local Research Ethics Committee 18/98. Age 18 Follow up(including DNA and genotyping): Isle of Wight, Portsmouth & South East Hampshire Research Ethics Committee 06/Q1701/34.

Version history

  1. Received: October 19, 2022
  2. Preprint posted: March 5, 2023 (view preprint)
  3. Accepted: May 22, 2023
  4. Accepted Manuscript published: May 25, 2023 (version 1)
  5. Version of Record published: June 26, 2023 (version 2)

Copyright

© 2023, Granell et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 849
    views
  • 124
    downloads
  • 2
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.84315

Further reading

    1. Epidemiology and Global Health
    Yuchen Zhang, Yitang Sun ... Kaixiong Ye
    Research Article

    Background:

    Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality.

    Methods:

    We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors.

    Results:

    Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend <0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15–38%) higher total mortality, 14% (95% CI, 0–31%) higher cancer mortality, and 31% (95% CI, 10–55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects.

    Conclusions:

    Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality.

    Funding:

    Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institute of Health under the award number R35GM143060 (KY). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    1. Ecology
    2. Epidemiology and Global Health
    Aleksandra Kovacevic, David RM Smith ... Lulla Opatowski
    Research Article

    Non-pharmaceutical interventions implemented to block SARS-CoV-2 transmission in early 2020 led to global reductions in the incidence of invasive pneumococcal disease (IPD). By contrast, most European countries reported an increase in antibiotic resistance among invasive Streptococcus pneumoniae isolates from 2019 to 2020, while an increasing number of studies reported stable pneumococcal carriage prevalence over the same period. To disentangle the impacts of the COVID-19 pandemic on pneumococcal epidemiology in the community setting, we propose a mathematical model formalizing simultaneous transmission of SARS-CoV-2 and antibiotic-sensitive and -resistant strains of S. pneumoniae. To test hypotheses underlying these trends five mechanisms were built into the model and examined: (1) a population-wide reduction of antibiotic prescriptions in the community, (2) lockdown effect on pneumococcal transmission, (3) a reduced risk of developing an IPD due to the absence of common respiratory viruses, (4) community azithromycin use in COVID-19 infected individuals, (5) and a longer carriage duration of antibiotic-resistant pneumococcal strains. Among 31 possible pandemic scenarios involving mechanisms individually or in combination, model simulations surprisingly identified only two scenarios that reproduced the reported trends in the general population. They included factors (1), (3), and (4). These scenarios replicated a nearly 50% reduction in annual IPD, and an increase in antibiotic resistance from 20% to 22%, all while maintaining a relatively stable pneumococcal carriage. Exploring further, higher SARS-CoV-2 R0 values and synergistic within-host virus-bacteria interaction mechanisms could have additionally contributed to the observed antibiotic resistance increase. Our work demonstrates the utility of the mathematical modeling approach in unraveling the complex effects of the COVID-19 pandemic responses on AMR dynamics.