X chromosome associations with chronic obstructive pulmonary disease and related phenotypes: an X chromosome-wide association study

Lystra P Hayden; Brian D Hobbs; Robert Busch; Michael H Cho; Ming Liu; Camila M Lopes-Ramos; David A Lomas; Per Bakke; Amund Gulsvik; Edwin K Silverman; James D Crapo; Terri H Beaty; Nan M Laird; Christoph Lange; Dawn L DeMeo

doi:10.1186/s12931-023-02337-1

X chromosome associations with chronic obstructive pulmonary disease and related phenotypes: an X chromosome-wide association study

Respir Res. 2023 Feb 1;24(1):38. doi: 10.1186/s12931-023-02337-1.

Authors

Lystra P Hayden^{1

2}, Brian D Hobbs^{2

3}, Robert Busch⁴, Michael H Cho^{2

3}, Ming Liu⁵, Camila M Lopes-Ramos^{2

6}, David A Lomas⁷, Per Bakke⁸, Amund Gulsvik⁸, Edwin K Silverman^{2

3}, James D Crapo⁹, Terri H Beaty¹⁰, Nan M Laird⁶, Christoph Lange⁶, Dawn L DeMeo^{11

12}

Affiliations

¹ Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
² Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Ave, Boston, MA, 02115, USA.
³ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Division of Pulmonology, Allergy, and Critical Care, U.S. Food and Drug Administration, Silver Spring, MD, USA.
⁵ Bioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA, USA.
⁶ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁷ UCL Respiratory, University College London, London, UK.
⁸ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁹ Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, Denver, CO, USA.
¹⁰ Johns Hopkins School of Public Health, Baltimore, MD, USA.
¹¹ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Ave, Boston, MA, 02115, USA. dawn.demeo@channing.harvard.edu.
¹² Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. dawn.demeo@channing.harvard.edu.

Abstract

Background: The association between genetic variants on the X chromosome to risk of COPD has not been fully explored. We hypothesize that the X chromosome harbors variants important in determining risk of COPD related phenotypes and may drive sex differences in COPD manifestations.

Methods: Using X chromosome data from three COPD-enriched cohorts of adult smokers, we performed X chromosome specific quality control, imputation, and testing for association with COPD case-control status, lung function, and quantitative emphysema. Analyses were performed among all subjects, then stratified by sex, and subsequently combined in meta-analyses.

Results: Among 10,193 subjects of non-Hispanic white or European ancestry, a variant near TMSB4X, rs5979771, reached genome-wide significance for association with lung function measured by FEV₁/FVC ([Formula: see text] 0.020, SE 0.004, p 4.97 × 10^-08), with suggestive evidence of association with FEV₁ ([Formula: see text] 0.092, SE 0.018, p 3.40 × 10^-07). Sex-stratified analyses revealed X chromosome variants that were differentially trending in one sex, with significantly different effect sizes or directions.

Conclusions: This investigation identified loci influencing lung function, COPD, and emphysema in a comprehensive genetic association meta-analysis of X chromosome genetic markers from multiple COPD-related datasets. Sex differences play an important role in the pathobiology of complex lung disease, including X chromosome variants that demonstrate differential effects by sex and variants that may be relevant through escape from X chromosome inactivation. Comprehensive interrogation of the X chromosome to better understand genetic control of COPD and lung function is important to further understanding of disease pathology. Trial registration Genetic Epidemiology of COPD Study (COPDGene) is registered at ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008). Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Study (ECLIPSE), GlaxoSmithKline study code SCO104960, is registered at ClinicalTrials.gov, NCT00292552 (Active since February 16, 2006). Genetics of COPD in Norway Study (GenKOLS) holds GlaxoSmithKline study code RES11080, Genetics of Chronic Obstructive Lung Disease.

Keywords: COPD; Emphysema; Lung function; Sex differences; X chromosome inactivation; X chromosome-wide association study.

Publication types

Meta-Analysis

MeSH terms

Emphysema*
Female
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study
Humans
Male
Phenotype
Pulmonary Disease, Chronic Obstructive* / diagnosis
Pulmonary Disease, Chronic Obstructive* / epidemiology
Pulmonary Disease, Chronic Obstructive* / genetics
Pulmonary Emphysema*
X Chromosome

Associated data

ClinicalTrials.gov/NCT00608764
ClinicalTrials.gov/NCT00292552

Abstract

Publication types

MeSH terms

Associated data

Grants and funding