title: Identifying a Deletion Affecting Total Lung Capacity Among Subjects in the COPDGene Study Cohort.
abstract: Chronic obstructive pulmonary disease (COPD) is a progressive disease with both environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified multiple genomic regions influencing risk of COPD. To thoroughly investigate the genetic etiology of COPD, however, it is also important to explore the role of copy number variants (CNVs) because the presence of structural variants can alter gene expression and can be causal for some diseases. Here, we investigated effects of polymorphic CNVs on quantitative measures of pulmonary function and chest computed tomography (CT) phenotypes among subjects enrolled in COPDGene, a multisite study. COPDGene subjects consist of roughly one-third African American (AA) and two-thirds non-Hispanic white adult smokers (with or without COPD). We estimated CNVs using PennCNV on 9,076 COPDGene subjects using Illumina's Omni-Express genome-wide marker array. We tested for association between polymorphic CNV components (defined as disjoint intervals of copy number regions) for several quantitative phenotypes associated with COPD within each racial group. Among the AAs, we identified a polymorphic CNV on chromosome 5q35.2 located between two genes (FAM153B and SIMK1, but also harboring several pseudo-genes) giving genome-wide significance in tests of association with total lung capacity (TLCCT ) as measured by chest CT scans. This is the first study of genome-wide association tests of polymorphic CNVs and TLCCT . Although the ARIC cohort did not have the phenotype of TLCCT , we found similar counts of CNV deletions and amplifications among AA and European subjects in this second cohort.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Ferdouse
authors.initials: F
authors.lastname: Begum
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.affiliation: Cancer Genomics Research Laboratory (CGR), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Shengchao
authors.initials: S
authors.lastname: Li
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Lynch
authors.affiliation: Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, Colorado, United States of America.
authors.forename: Douglas
authors.initials: D
authors.lastname: Curran-Everett
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Crapo
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Scharpf
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Parker
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Jacqueline B
authors.initials: JB
authors.lastname: Hetmanski
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
mesh_terms: D001741:Black or African American / Q000235:genetics; D000368:Aged; D015415:Biomarkers; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D012907:Smoking; D014109:Total Lung Capacity; D044465:White People / Q000235:genetics
chemical_list: D015415:Biomarkers
keywords: COPD; copy number variant (CNV); genome-wide association study (GWAS); lung hyperinflation; pulmonary function; total lung capacity (TLCCT)