Polygenic risk scores identify heterogeneity in asthma and chronic obstructive pulmonary disease

Matthew Moll; Joanne E Sordillo; Auyon J Ghosh; Lystra P Hayden; Gregory McDermott; Michael J McGeachie; Amber Dahlin; Anshul Tiwari; Monica G Manmadkar; Eric D Abston; Chandan Pavuluri; Aabida Saferali; Sofina Begum; John P Ziniti; Amund Gulsvik; Per S Bakke; Hugues Aschard; Carlos Iribarren; Craig P Hersh; Jeffrey A Sparks; Brian D Hobbs; Jessica A Lasky-Su; Edwin K Silverman; Scott T Weiss; Ann Chen Wu; Michael H Cho

doi:10.1016/j.jaci.2023.08.002

Polygenic risk scores identify heterogeneity in asthma and chronic obstructive pulmonary disease

J Allergy Clin Immunol. 2023 Dec;152(6):1423-1432. doi: 10.1016/j.jaci.2023.08.002. Epub 2023 Aug 16.

Authors

Matthew Moll¹, Joanne E Sordillo², Auyon J Ghosh³, Lystra P Hayden⁴, Gregory McDermott⁵, Michael J McGeachie⁶, Amber Dahlin⁶, Anshul Tiwari⁶, Monica G Manmadkar⁶, Eric D Abston⁷, Chandan Pavuluri¹, Aabida Saferali⁶, Sofina Begum⁶, John P Ziniti⁶, Amund Gulsvik⁸, Per S Bakke⁸, Hugues Aschard⁹, Carlos Iribarren¹⁰, Craig P Hersh¹, Jeffrey A Sparks⁵, Brian D Hobbs¹, Jessica A Lasky-Su⁶, Edwin K Silverman⁶, Scott T Weiss⁶, Ann Chen Wu², Michael H Cho¹¹

Affiliations

¹ Department of Medicine, Channing Division of Network Medicine, Division of Pulmonary and Critical Care Medicine, Harvard Medical School, Boston, Mass; Harvard Medical School, Brigham and Women's Hospital, Boston, Mass.
² Department of Population Medicine, PRecisiOn Medicine Translational Research (PROMoTeR) Center, Harvard Medical School and Harvard Pilgrim Health Care, Boston, Mass.
³ Division of Pulmonary and Critical Care Medicine, Department of Medicine, SUNY Upstate Medical Center, Syracuse, NY.
⁴ Department of Pediatrics, Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Massachusetts General Hospital, Boston, Mass; Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, Massachusetts General Hospital, Boston, Mass.
⁵ Harvard Medical School, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Mass.
⁶ Harvard Medical School, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, Massachusetts General Hospital, Boston, Mass.
⁷ Department of Thoracic Surgery, Massachusetts General Hospital, Boston, Mass.
⁸ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁹ Department of Computational Biology, Institut Pasteur, Universit de Paris, Paris, France.
¹⁰ Division of Research, Kaiser Permanente Northern California, Oakland, Calif.
¹¹ Department of Medicine, Channing Division of Network Medicine, Division of Pulmonary and Critical Care Medicine, Harvard Medical School, Boston, Mass; Harvard Medical School, Brigham and Women's Hospital, Boston, Mass. Electronic address: remol@channing.harvard.edu.

PMID: 37595761
PMCID: PMC10841234 (available on 2024-12-01)
DOI: 10.1016/j.jaci.2023.08.002

Abstract

Background: Asthma and chronic obstructive pulmonary disease (COPD) have distinct and overlapping genetic and clinical features.

Objective: We sought to test the hypothesis that polygenic risk scores (PRSs) for asthma (PRS_Asthma) and spirometry (FEV₁ and FEV₁/forced vital capacity; PRS_spiro) would demonstrate differential associations with asthma, COPD, and asthma-COPD overlap (ACO).

Methods: We developed and tested 2 asthma PRSs and applied the higher performing PRS_Asthma and a previously published PRS_spiro to research (Genetic Epidemiology of COPD study and Childhood Asthma Management Program, with spirometry) and electronic health record-based (Mass General Brigham Biobank and Genetic Epidemiology Research on Adult Health and Aging [GERA]) studies. We assessed the association of PRSs with COPD and asthma using modified random-effects and binary-effects meta-analyses, and ACO and asthma exacerbations in specific cohorts. Models were adjusted for confounders and genetic ancestry.

Results: In meta-analyses of 102,477 participants, the PRS_Asthma (odds ratio [OR] per SD, 1.16 [95% CI, 1.14-1.19]) and PRS_spiro (OR per SD, 1.19 [95% CI, 1.17-1.22]) both predicted asthma, whereas the PRS_spiro predicted COPD (OR per SD, 1.25 [95% CI, 1.21-1.30]). However, results differed by cohort. The PRS_spiro was not associated with COPD in GERA and Mass General Brigham Biobank. In the Genetic Epidemiology of COPD study, the PRS_Asthma (OR per SD: Whites, 1.3; African Americans, 1.2) and PRS_spiro (OR per SD: Whites, 2.2; African Americans, 1.6) were both associated with ACO. In GERA, the PRS_Asthma was associated with asthma exacerbations (OR, 1.18) in Whites; the PRS_spiro was associated with asthma exacerbations in White, LatinX, and East Asian participants.

Conclusions: PRSs for asthma and spirometry are both associated with ACO and asthma exacerbations. Genetic prediction performance differs in research versus electronic health record-based cohorts.

Keywords: Asthma; asthma-COPD overlap; chronic obstructive pulmonary disease; heterogeneity; polygenic risk scores.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adult
Asthma* / epidemiology
Asthma* / genetics
Child
Forced Expiratory Volume
Humans
Pulmonary Disease, Chronic Obstructive* / epidemiology
Pulmonary Disease, Chronic Obstructive* / genetics
Respiratory Function Tests
Vital Capacity

Abstract

Publication types

MeSH terms

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