A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing
- University of Bristol, United Kingdom
- University of Manchester, United Kingdom
- Imperial College London, United Kingdom
- University of Southampton, United Kingdom
- Queen Mary University of London, United Kingdom
- University of Groningen, Netherlands
- David Hide Asthma and Allergy Research Centre, United Kingdom
- 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.
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A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing (GWAS ANXA1)Dryad Digital Repository, doi:10.5061/dryad.3r2280gm3.
Article and author information
Author details
Negusse Tadesse Kitaba
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
- 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
- Received: October 19, 2022
- Preprint posted: March 5, 2023 (view preprint)
- Accepted: May 22, 2023
- Accepted Manuscript published: May 25, 2023 (version 1)
- 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.
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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
Further reading
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- Epidemiology and Global Health
Background:
The Zanzibar archipelago of Tanzania has become a low-transmission area for Plasmodium falciparum. Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania and continued local transmission.
Methods:
To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 282 P. falciparum isolates collected across Zanzibar and in Bagamoyo district on the coastal mainland from 2016 to 2018.
Results:
Overall, parasite populations on the coastal mainland and Zanzibar archipelago remain highly related. However, parasite isolates from Zanzibar exhibit population microstructure due to the rapid decay of parasite relatedness over very short distances. This, along with highly related pairs within shehias, suggests ongoing low-level local transmission. We also identified highly related parasites across shehias that reflect human mobility on the main island of Unguja and identified a cluster of highly related parasites, suggestive of an outbreak, in the Micheweni district on Pemba island. Parasites in asymptomatic infections demonstrated higher complexity of infection than those in symptomatic infections, but have similar core genomes.
Conclusions:
Our data support importation as a main source of genetic diversity and contribution to the parasite population in Zanzibar, but they also show local outbreak clusters where targeted interventions are essential to block local transmission. These results highlight the need for preventive measures against imported malaria and enhanced control measures in areas that remain receptive to malaria reemergence due to susceptible hosts and competent vectors.
Funding:
This research was funded by the National Institutes of Health, grants R01AI121558, R01AI137395, R01AI155730, F30AI143172, and K24AI134990. Funding was also contributed from the Swedish Research Council, Erling-Persson Family Foundation, and the Yang Fund. RV acknowledges funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 program supported by the European Union. RV also acknowledges funding by Community Jameel.
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- Computational and Systems Biology
- Epidemiology and Global Health
The chemical composition of foods is complex, variable, and dependent on many factors. This has a major impact on nutrition research as it foundationally affects our ability to adequately assess the actual intake of nutrients and other compounds. In spite of this, accurate data on nutrient intake are key for investigating the associations and causal relationships between intake, health, and disease risk at the service of developing evidence-based dietary guidance that enables improvements in population health. Here, we exemplify the importance of this challenge by investigating the impact of food content variability on nutrition research using three bioactives as model: flavan-3-ols, (–)-epicatechin, and nitrate. Our results show that common approaches aimed at addressing the high compositional variability of even the same foods impede the accurate assessment of nutrient intake generally. This suggests that the results of many nutrition studies using food composition data are potentially unreliable and carry greater limitations than commonly appreciated, consequently resulting in dietary recommendations with significant limitations and unreliable impact on public health. Thus, current challenges related to nutrient intake assessments need to be addressed and mitigated by the development of improved dietary assessment methods involving the use of nutritional biomarkers.
