title: Hemizygous Deletion on Chromosome 3p26.1 Is Associated with Heavy Smoking among African American Subjects in the COPDGene Study.
abstract: Many well-powered genome-wide association studies have identified genetic determinants of self-reported smoking behaviors and measures of nicotine dependence, but most have not considered the role of structural variants, such as copy number variation (CNVs), influencing these phenotypes. Here, we included 2,889 African American and 6,187 non-Hispanic White subjects from the COPDGene cohort (http://www.copdgene.org) to carefully investigate the role of polymorphic CNVs across the genome on various measures of smoking behavior. We identified a CNV component (a hemizygous deletion) on chromosome 3p26.1 associated with two quantitative phenotypes related to smoking behavior among African Americans. This polymorphic hemizygous deletion is significantly associated with pack-years and cigarettes smoked per day among African American subjects in the COPDGene study. We sought evidence of replication in African Americans from the population based Atherosclerosis Risk in Communities (ARIC) study. While we observed similar CNV counts, the extent of exposure to cigarette smoking among ARIC subjects was quite different and the smaller sample size of heavy smokers in ARIC severely limited statistical power, so we were unable to replicate our findings from the COPDGene cohort. But meta-analyses of COPDGene and ARIC study subjects strengthened our association signal. However, a few linkage studies have reported suggestive linkage to the 3p26.1 region, and a few genome-wide association studies (GWAS) have reported markers in the gene (GRM7) nearest to this 3p26.1 area of polymorphic deletions are associated with measures of nicotine dependence among subjects of European ancestry.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Ferdouse
authors.identifier: http://orcid.org/0000-0001-7835-8051
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: Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, United States of America.
authors.forename: John E
authors.initials: JE
authors.lastname: Hokanson
authors.affiliation: Department of Biostatisitics and Informatics, Colorado School of Public Health, Aurora, Colorado, United States of America.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Lutz
authors.affiliation: Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Parker
authors.affiliation: Channing Division of Network Medicine and Division of Pulmonary and Critical Care 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 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 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 Medicine, National Jewish Health, Denver, Colorado, United States of America.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: Channing Division of Network Medicine and Division of Pulmonary and Critical Care 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: 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*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D055106:Genome-Wide Association Study; D057898:Hemizygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012306:Risk; D017384:Sequence Deletion; D012907:Smoking / Q000009:adverse effects*