Cumulative Genetic Risk for Asthma Contributes to Disease Severity in Children with Asthma living in Urban Environments

Matthew Dapas, Division of Rheumatology, Department of Medicine; Center for Human Immunobiology; Center for Genetic Medicine; Northwestern University Feinberg School of Medicine, Chicago, IL.
William Wentworth-Sheilds, Department of Human Genetics, University of Chicago, Chicago, IL.
Emma E. Thompson, Department of Human Genetics, University of Chicago, Chicago, IL.
Rajesh Kumar, Ann and Robert H. Lurie Children's Hospital; Division of Allergy and Immunology, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL.
Elizabeth Lippner, Ann and Robert H. Lurie Children's Hospital; Division of Allergy and Immunology, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL.
Robert A. Wood, Department of Pediatrics, Johns Hopkins University Medical Center, Baltimore, MD.
George T. O'Connor, Pulmonary Center, Boston University School of Medicine, Boston, MA.
Gurjit K. Khurana Hershey, Division of Asthma Research, Cincinnati Children's Hospital, Cincinnati, OH.
Rebecca S. Gruchalla, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
Andrew H. Liu, Children's Hospital Colorado; Department of Allergy and Immunology, University of Colorado School of Medicine, Aurora, CO.
Edward M. Zoratti, Departments of Medicine and Public Health Sciences, Henry Ford Health and Michigan State University College of Human Medicine, Detroit, MI.
Leonard B. Bacharier, Monroe Carell Jr. Children's Hospital at Vanderbilt University Medical Center, Nashville, TN.
Stephanie Lovinsky-Desir, Department of Pediatrics and Environmental Health Sciences, Columbia University, New York, NY.
Michele A. Gill, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
William J. Sheehan, Children's National Hospital; Division of Allergy and Immunology, George Washington University School of Medicine and Health Sciences, Washington, DC.
Shilpa J. Patel, Division of Emergency Medicine, Children's National Hospital, Washington, DC.
Matthew C. Altman, Department of Allergy and Infectious Diseases, University of Washington, Seattle, WA.
James E. Gern, Departments of Pediatrics and Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Cynthia M. Visness, Rho Inc., Durham, NC.
Peter J. Gergen, National Institute of Allergy and Infectious Diseases, Bethesda, MD.
Patrice M. Becker, National Institute of Allergy and Infectious Diseases, Bethesda, MD.
Daniel J. Jackson, Departments of Pediatrics and Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Carole Ober, Department of Human Genetics, University of Chicago, Chicago, IL.

Document Type

Journal Article

Publication Date

9-9-2025

Journal

medRxiv : the preprint server for health sciences

DOI

10.1101/2025.09.08.25335346

Abstract

BACKGROUND: Childhood-onset asthma is highly heritable, with nearly 200 risk loci identified in genome-wide association studies. Aggregated polygenic risk scores can be used to quantify genetic predisposition to asthma, but their power to predict asthma severity in multi-ancestral groups has not been determined. OBJECTIVE: Our aim was to examine the predictive power of biobank-derived asthma polygenic risk scores in children with asthma living in urban environments. METHODS: We generated polygenic risk scores for asthma, derived from a large-scale genome-wide association meta-analysis, in four multi-ancestry asthma study cohorts of children living in urban environments. We assessed genetic predictions across different subphenotypes of asthma and tested for associations between genetic asthma risk and measures of asthma severity. RESULTS: Genetic asthma prediction was significantly stronger for more symptomatic asthma phenotypes (P<0.001). Polygenic risk scores were significantly higher in difficult-to-control vs. easy-to-control asthma (P=0.02). Genetic risk was also significantly associated with more frequent exacerbations (P=0.03), higher blood eosinophil levels (P=0.01), and lower lung function (P<0.001). CONCLUSION: Cumulative genetic risk for asthma is associated with disease severity and exacerbation risk in children with asthma living in urban environments.

Department

Pediatrics

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