title: Sex-Based Genetic Association Study Identifies CELSR1 as a Possible Chronic Obstructive Pulmonary Disease Risk Locus among Women.
abstract: Chronic obstructive pulmonary disease (COPD) is a complex disease with strong environmental and genetic influences and sexually dimorphic features. Although genetic risk factors for COPD have been identified, much of the heritability remains unexplained. Sex-based genetic association studies may uncover additional COPD genetic risk factors. We studied current and former smokers from COPD case-control cohorts (COPDGene non-Hispanic whites and African Americans, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, and Genetics of Chronic Obstructive Lung Disease). COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity less than 0.70 and forced expiratory volume in 1 second percent predicted less than 80. Testing was performed across all cohorts and combined in a meta-analysis adjusted for age, pack-years, and genetic ancestry. We first performed genome-wide single-nucleotide polymorphism (SNP)-by-sex interaction testing on the outcome of COPD affection status. We performed sex-stratified association testing for SNPs with interaction P less than 10-6. We examined over 8 million SNPs in four populations, including 6,260 subjects with COPD (40.6% female) and 5,269 smoking control subjects (47.3% female). The SNP rs9615358 in the cadherin gene CELSR1 approached genome-wide significance for an interaction with sex (P = 1.24 × 10-7). In the sex-stratified meta-analysis, this SNP was associated with COPD among females (odds ratio, 1.37 [95% confidence interval, 1.25-1.49]; P = 3.32 × 10-7) but not males (odds ratio, 0.90 [95% confidence interval, 0.79-1.01]; P = 0.06). CELSR1 is involved in fetal lung development. In a human fetal lung tissue dataset, we observed greater CELSR1 expression in female compared with male samples. This SNP-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for COPD. Identifying sex-specific genetic risk factors may reveal new insights into sexually dimorphic features of COPD.
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Megan
authors.initials: M
authors.lastname: Hardin
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: 3 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.affiliation: 1 Channing Division of Network Medicine and.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Glass
authors.affiliation: 1 Channing Division of Network Medicine and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.affiliation: 1 Channing Division of Network Medicine and.
authors.forename: Merry-Lynn
authors.initials: ML
authors.lastname: McDonald
authors.affiliation: 4 Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Hugues
authors.initials: H
authors.lastname: Aschard
authors.affiliation: 1 Channing Division of Network Medicine and.
authors.forename: Jody
authors.initials: J
authors.lastname: Senter-Sylvia
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kelan
authors.initials: K
authors.lastname: Tantisira
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jarrett D
authors.initials: JD
authors.lastname: Morrow
authors.affiliation: 5 Department of Medicine, University College London, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Lomas
authors.affiliation: 6 Thoracic Institute, Hospital Clinic, Barcelona, Spain.
authors.forename: Alvar
authors.initials: A
authors.lastname: Agusti
authors.affiliation: 7 Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.affiliation: 8 Department of Geriatric Medicine Ullevaal, Institute of Clinical Medicine, Oslo University Hospital University of Oslo, Oslo, Norway.
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.affiliation: 9 Boston University School of Medicine, Boston, Massachusetts.
authors.forename: George T
authors.initials: GT
authors.lastname: O'Connor
authors.affiliation: 10 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.|11 National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts.
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: 12 Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Denver, Colorado.
authors.forename: John
authors.initials: J
authors.lastname: Hokanson
authors.affiliation: 13 Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, Denver, Colorado; and.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: 14 Johns Hopkins School of Public Health, Baltimore, Maryland.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: 4 Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Nan
authors.initials: N
authors.lastname: Laird
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
mesh_terms: D000368:Aged; D000483:Alleles; D015820:Cadherins / Q000235:genetics*; D003710:Demography; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008168:Lung / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D012307:Risk Factors
chemical_list: C454220:CELSR1 cadherin, human; D015820:Cadherins
keywords: chronic obstructive pulmonary disease; genetics; genome-wide association study; growth and development; sex