Genetic characterization of preschool wheeze phenotypes

Kasper Fischer-Rasmussen¹, Raquel Granell², Anders Ulrik Eliasen¹, Eskil Kreiner¹, Casper-Emil Tingskov Pedersen¹, Yang Luo¹, Bo Chawes³, Jakob Stokholm¹, Ann-Marie Malby Schoos⁴, Ashish Kumar⁵, Anne-Marie Nybo Andersen⁶, Bjarke Feenstra⁷, Frank Geller⁷, Valérie Siroux⁸, Florence Demenais⁸, Emmanuelle Bouzigon⁸, Vincent Jaddoe⁹, Ralf J P van der Valk⁹, Liesbeth Duijts¹⁰, Jordi Sunyer¹¹, Mónica Guxens¹², Marcella Marinelli¹³, Mariona Bustamante¹⁴, Joachim Heinrich¹⁵, Marie Standl¹⁶, John Curtin¹⁷, Angela Simpson¹⁸, Clare Murray¹⁸, Bo Jacobsson¹⁹, Ronny Myhre²⁰, Craig E Pennell²¹, Denise Daley²², Carole Ober²³, James E Gern²⁴, Daniel Jackson²⁵, Dorret I Boomsma²⁶, Jouke-Jan Hottenga²⁶, Abdel Abdellaoui²⁶, John W Holloway²⁷, Sam Collins²⁸, Stephen Turner²⁹, S Hasan Arshad³⁰, Anhar Ullah³¹, Erik Melén³², John Henderson², Hans Bisgaard¹, Anders Gorm Pedersen³³, Adnan Custovic³⁴, Judith M Vonk³⁵, Gerard H Koppelman³⁶, Michael Kabesch³⁷, Klaus Bønnelykke³⁸; Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community (GABRIEL) consortium; EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium

Affiliations

¹ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
² MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
³ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark; Department of Pediatrics, Copenhagen University Hospital - Næstved, Slagelse and Ringsted, Slagelse, Denmark.
⁵ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
⁸ Université Paris Cité, INSERM, UMR 1124, Group of Genomic Epidemiology of Multifactorial Diseases, Paris, France.
⁹ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁰ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹¹ ISGlobal, Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
¹² ISGlobal, Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública, Madrid, Spain; ICREA, Barcelona, Spain.
¹³ Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
¹⁴ Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
¹⁵ Division of Metabolic and Nutritional Medicine, Ludwig-Maximilians-Universitat (LMU) Munich, Dr von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany; Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Munich, Germany.
¹⁶ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Lung Research (DZL); German Center for Child and Adolescent Health (DZKJ), Munich, Germany.
¹⁷ Division of Immunology, Immunity to Infection and Respiratory Medicine, Manchester Academic Health Science Centre, School of Biological Sciences, University of Manchester, Manchester, United Kingdom; National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, Manchester University Hospital NHS Foundation Trust, Manchester, United Kingdom.
¹⁸ National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, Manchester University Hospital NHS Foundation Trust, Manchester, United Kingdom.
¹⁹ Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway; Department of Obstetrics and Gynecology, Sahlgrenska Academy, Gothenburg, Sweden.
²⁰ Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway.
²¹ Hunter Medical Research Institute, New Lambton Heights, Australia; Mothers and Babies Research Centre and John Hunter Hospital, New Lambton Heights, Australia; School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, Australia.
²² Center for Heart and Lung Innovation, University of British Columbia, Vancouver, Canada; University of British Columbia, Faculty of Medicine, Vancouver, Canada.
²³ Department of Human Genetics, University of Chicago, Chicago, Ill.
²⁴ Department of Medicine, University of British Columbia, Vancouver, Canada; Pediatrics, School of Medicine and Public Health, University of Wisconsin, Madison, Wis.
²⁵ Department of Medicine, University of British Columbia, Vancouver, Canada.
²⁶ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
²⁷ NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, The Netherlands; Human Development and Health, University of Southampton Faculty of Medicine, Southampton, The Netherlands.
²⁸ NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, The Netherlands; Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, The Netherlands.
²⁹ Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, The Netherlands; Child Health, University of Aberdeen, Aberdeen, United Kingdom.
³⁰ NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, The Netherlands; Human Development and Health, University of Southampton Faculty of Medicine, Southampton, The Netherlands; Women and Children Division, NHS Grampian, Aberdeen, United Kingdom.
³¹ National Heart and Lung Institute, Imperial College London, London, United Kingdom.
³² Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Sach's Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden.
³³ Department of Health Technology, Section for Bioinformatics, Technical University of Denmark, Kongens Lyngby, Denmark.
³⁴ Pediatric Allergy, Imperial College London, London, United Kingdom.
³⁵ Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, Groningen, The Netherlands.
³⁶ Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, Groningen, The Netherlands; Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³⁷ Department of Pediatric Pneumology and Allergy, St Hedwig's Hospital of the Order of St John, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
³⁸ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: kb@copsac.com.

PMID: 40769318
DOI: 10.1016/j.jaci.2025.07.015

Free article

Genetic characterization of preschool wheeze phenotypes

Kasper Fischer-Rasmussen et al. J Allergy Clin Immunol. 2025.

Free article

. 2025 Aug 5:S0091-6749(25)00803-6.

doi: 10.1016/j.jaci.2025.07.015. Online ahead of print.

Authors

Affiliations

¹ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
² MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
³ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark; Department of Pediatrics, Copenhagen University Hospital - Næstved, Slagelse and Ringsted, Slagelse, Denmark.
⁵ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
⁸ Université Paris Cité, INSERM, UMR 1124, Group of Genomic Epidemiology of Multifactorial Diseases, Paris, France.
⁹ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁰ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹¹ ISGlobal, Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
¹² ISGlobal, Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública, Madrid, Spain; ICREA, Barcelona, Spain.
¹³ Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
¹⁴ Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
¹⁵ Division of Metabolic and Nutritional Medicine, Ludwig-Maximilians-Universitat (LMU) Munich, Dr von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany; Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Munich, Germany.
¹⁶ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Lung Research (DZL); German Center for Child and Adolescent Health (DZKJ), Munich, Germany.
¹⁷ Division of Immunology, Immunity to Infection and Respiratory Medicine, Manchester Academic Health Science Centre, School of Biological Sciences, University of Manchester, Manchester, United Kingdom; National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, Manchester University Hospital NHS Foundation Trust, Manchester, United Kingdom.
¹⁸ National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, Manchester University Hospital NHS Foundation Trust, Manchester, United Kingdom.
¹⁹ Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway; Department of Obstetrics and Gynecology, Sahlgrenska Academy, Gothenburg, Sweden.
²⁰ Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway.
²¹ Hunter Medical Research Institute, New Lambton Heights, Australia; Mothers and Babies Research Centre and John Hunter Hospital, New Lambton Heights, Australia; School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, Australia.
²² Center for Heart and Lung Innovation, University of British Columbia, Vancouver, Canada; University of British Columbia, Faculty of Medicine, Vancouver, Canada.
²³ Department of Human Genetics, University of Chicago, Chicago, Ill.
²⁴ Department of Medicine, University of British Columbia, Vancouver, Canada; Pediatrics, School of Medicine and Public Health, University of Wisconsin, Madison, Wis.
²⁵ Department of Medicine, University of British Columbia, Vancouver, Canada.
²⁶ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
²⁷ NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, The Netherlands; Human Development and Health, University of Southampton Faculty of Medicine, Southampton, The Netherlands.
²⁸ NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, The Netherlands; Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, The Netherlands.
²⁹ Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, The Netherlands; Child Health, University of Aberdeen, Aberdeen, United Kingdom.
³⁰ NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, The Netherlands; Human Development and Health, University of Southampton Faculty of Medicine, Southampton, The Netherlands; Women and Children Division, NHS Grampian, Aberdeen, United Kingdom.
³¹ National Heart and Lung Institute, Imperial College London, London, United Kingdom.
³² Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Sach's Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden.
³³ Department of Health Technology, Section for Bioinformatics, Technical University of Denmark, Kongens Lyngby, Denmark.
³⁴ Pediatric Allergy, Imperial College London, London, United Kingdom.
³⁵ Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, Groningen, The Netherlands.
³⁶ Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, Groningen, The Netherlands; Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³⁷ Department of Pediatric Pneumology and Allergy, St Hedwig's Hospital of the Order of St John, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
³⁸ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: kb@copsac.com.

PMID: 40769318
DOI: 10.1016/j.jaci.2025.07.015

Abstract

Background: Preschool wheeze is a heterogenous and poorly understood clinical syndrome. As a result, current treatments are insufficient, and prevention is not possible.

Objective: We sought to increase understanding of the genetic susceptibility and underlying disease mechanisms of wheeze phenotypes in early childhood through large-scale genome-wide association study analyses.

Methods: We performed meta-analyses of genome-wide association study on early-onset wheeze, defined as recurrent wheeze or asthma in the first 3 years of life, and its subtypes, including early transient and persistent wheeze, defined by asthma/wheeze at age 3 and subsequent remission or persistence at age 6, respectively. The discovery analyses included data on more than 13,000 children from 15 cohorts; replication was sought through meta-analyses of data from 7 additional cohorts including up to 5000 children. Genetic variants associated with asthma-related traits in adulthood (adult asthma, atopy, eosinophils, and lung function) were used to quantify the degree to which genetic risk influencing asthma-related adult traits also influences genetic risk of preschool wheeze.

Results: Variants near the GSDMB gene in the 17q region showed genome-wide significant association with early-onset wheeze (rs2305480; odds ratio [95% confidence interval] = 1.26 [1.17-1.33], P = 2.30E-16) and persistent wheeze (rs11078926; 1.43 [1.30-1.578], P = 2.14E-11), but not with early transient wheeze (rs1054609; 1.08 [0.98-1.18], P = .094). Other known asthma loci were associated with early-onset wheeze, particularly CDHR3. Additionally, increased genetic risk to early-onset wheeze was associated with genetic risk for asthma at older ages, atopy, eosinophil count, and lower adult lung function. This was driven by persistent wheeze, whereas transient early wheeze was only associated with low lung function.

Conclusions: Preschool wheeze phenotypes displayed distinct patterns of single nucleotide polymorphism associations and genetic enrichment with asthma-related traits. These results indicate distinct etiologies of wheeze phenotypes, which could inform studies in optimization of prevention and treatment strategies.

Keywords: 17q21-12; Preschool wheeze; asthma comorbidities; genetic overlap; genome-wide association study.

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Conflict of interest statement

Disclosure statement Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) is funded by private and public research funds, which are all listed on www.copsac.com. The Lundbeck Foundation, Danish State Budget, Danish Council for Strategic Research, Danish Council for Independent Research, and Capital Region Research Foundation have provided core support for COPSAC. The study is further supported by the following National Institutes of Health grants: R01 HL129735 and R01 HL141826. C.E.W. was supported by the Swedish Heart–Lung Foundation (Hjärt-Lungfonden 20170734, 20180290). This project has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement 946228). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. Data-sharing statement: The COPSAC biobank is publicly available at the Danish National Biobank (www.biobankdenmark.dk), and data will become available in the Danish Data Archive (www.sa.dk) upon request to the corresponding author.

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Genetic characterization of preschool wheeze phenotypes

Affiliations

Genetic characterization of preschool wheeze phenotypes

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources

Research Materials