title: Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population.
abstract: Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping.
  
  
  
  We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10(-5)) in an independent set of 866 cases and 796 controls in stage 2.
  
  
  
  In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p=1.3×10(-9); OR=1.32; 95% CI=1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p=2.8×10(-9); OR=1.28; 95% CI=1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p=1.3×10(-8); OR=1.37; 95% CI=1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans.
authors.affiliation: Division of Cancer Control and Population Sciences, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: zanettik@mail.nih.gov.
authors.forename: Krista A
authors.initials: KA
authors.lastname: Zanetti
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: wangzha@mail.nih.gov.
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Epidemiology, Vanderbilt University Medical Center, 1161 21st Avenue South, D-3100 Medical Center North, Nashville, TN 37232, USA; Department of Thoracic Surgery, Vanderbilt University Medical Center, 609 Oxford House, 1313 21st Ave South, Nashville, TN 37232-4682, USA. Electronic address: melinda.aldrich@Vanderbilt.Edu.
authors.forename: Melinda
authors.initials: M
authors.lastname: Aldrich
authors.affiliation: Department of Biomedical Data Science, Geisel School of Medicine, 1 Rope Ferry Road, Dartmouth, Lebanon, NH 03755-1404, USA. Electronic address: Christopher.I.Amos@Dartmouth.edu.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Division of Epidemiology, Vanderbilt University Medical Center, 1161 21st Avenue South, D-3100 Medical Center North, Nashville, TN 37232, USA. Electronic address: blotw@iei.us.
authors.forename: William J
authors.initials: WJ
authors.lastname: Blot
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Building 37, Room 3068A, Bethesda, MD 20892, USA. Electronic address: bowmane@intra.nci.nih.gov.
authors.forename: Elise D
authors.initials: ED
authors.lastname: Bowman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: burdettl@mail.nih.gov.
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdette
authors.affiliation: Division of Epidemiology, Vanderbilt University Medical Center, 1161 21st Avenue South, D-3100 Medical Center North, Nashville, TN 37232, USA. Electronic address: qiuyin.cai@Vanderbilt.Edu.
authors.forename: Qiuyin
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: caporasn@mail.nih.gov.
authors.forename: Neil
authors.initials: N
authors.lastname: Caporaso
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: chungcc@mail.nih.gov.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chung
authors.affiliation: Division of Cancer Control and Population Sciences, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: lgilland@mail.nih.gov.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Gillanders
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California and Norris Comprehensive Cancer Center, 1975 Zonal Avenue, Los Angeles, CA 90033, USA. Electronic address: haiman@usc.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Department of Neurological Surgery, University of California, 505 Parnassus Ave., Room 779 M, San Francisco, San Francisco, CA 94143-00112, USA. Electronic address: helen.hansen@ucsf.edu.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Hansen
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California and Norris Comprehensive Cancer Center, 1975 Zonal Avenue, Los Angeles, CA 90033, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.affiliation: Epidemiology Program, Cancer Research Center, University of Hawaii, 701 Ilalo Street, Honolulu, HI 96813, USA. Electronic address: lkolonel@cc.hawaii.edu.
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.affiliation: Epidemiology Program, Cancer Research Center, University of Hawaii, 701 Ilalo Street, Honolulu, HI 96813, USA. Electronic address: Loic@cc.hawaii.edu.
authors.forename: Loic Le
authors.initials: LL
authors.lastname: Marchand
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: shengchao.li@nih.gov.
authors.forename: Shengchao
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Health Disparities Research, Division of OVP, Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 91, Houston, TX 77030, USA. Electronic address: lmcneill@mdanderson.org.
authors.forename: Lorna Haughton
authors.initials: LH
authors.lastname: McNeill
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Building 37, Room 3068A, Bethesda, MD 20892, USA. Electronic address: ryanb@mail.nih.gov.
authors.forename: Bríd M
authors.initials: BM
authors.lastname: Ryan
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, Detroit, MI 48201, USA. Electronic address: schwarta@karmanos.org.
authors.forename: Ann G
authors.initials: AG
authors.lastname: Schwartz
authors.affiliation: Department of Neurological Surgery, University of California, 505 Parnassus Ave., Room 779 M, San Francisco, San Francisco, CA 94143-00112, USA. Electronic address: jennette.sison@ucsf.edu.
authors.forename: Jennette D
authors.initials: JD
authors.lastname: Sison
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Mail Stop BCM225, Houston, TX 77030, USA. Electronic address: spitz@bcm.edu.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: tuckerp@mail.nih.gov.
authors.forename: Margaret
authors.initials: M
authors.lastname: Tucker
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, Detroit, MI 48201, USA. Electronic address: wenzlaff@karmanos.org.
authors.forename: Angela S
authors.initials: AS
authors.lastname: Wenzlaff
authors.affiliation: Department of Neurological Surgery, University of California, 505 Parnassus Ave., Room 779 M, San Francisco, San Francisco, CA 94143-00112, USA. Electronic address: john.wiencke@ucsf.edu.
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.affiliation: Epidemiology Program, Cancer Research Center, University of Hawaii, 701 Ilalo Street, Honolulu, HI 96813, USA. Electronic address: lynne@cc.hawaii.edu.
authors.forename: Lynne
authors.initials: L
authors.lastname: Wilkens
authors.affiliation: Department of Neurological Surgery, University of California, 505 Parnassus Ave., Room 779 M, San Francisco, San Francisco, CA 94143-00112, USA. Electronic address: Margaret.Wrensch@ucsf.edu.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
authors.affiliation: Department of Epidemiology, Division of OVP, Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Unit 1340, PO Box 301439, Houston, TX 77230-1439, USA. Electronic address: xwu@mdanderson.org.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Epidemiology, Vanderbilt University Medical Center, 1161 21st Avenue South, D-3100 Medical Center North, Nashville, TN 37232, USA. Electronic address: wei.zheng@vanderbilt.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: zhouw@mail.nih.gov.
authors.forename: Weiyin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Harvard School of Public Health, Massachusetts General Hospital/Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. Electronic address: dchris@hsph.harvard.edu.
authors.forename: David
authors.initials: D
authors.lastname: Christiani
authors.affiliation: Slone Epidemiology Cancer Center at Boston University, 1010 Commonwealth Avenue, 4th Floor, Boston, MA 02215, USA. Electronic address: jpalmer@bu.edu.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Palmer
authors.affiliation: Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia PA 19104, USA; Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia PA 19104, USA. Electronic address: PENNING@UPENN.EDU.
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Penning
authors.affiliation: Department of General Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Electronic address: arieber@mdanderson.org.
authors.forename: Alyssa G
authors.initials: AG
authors.lastname: Rieber
authors.affiliation: Slone Epidemiology Cancer Center at Boston University, 1010 Commonwealth Avenue, 4th Floor, Boston, MA 02215, USA. Electronic address: lrosenbe@bu.edu.
authors.forename: Lynn
authors.initials: L
authors.lastname: Rosenberg
authors.affiliation: Slone Epidemiology Cancer Center at Boston University, 1010 Commonwealth Avenue, 4th Floor, Boston, MA 02215, USA. Electronic address: eruiznar@bu.edu.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Ruiz-Narvaez
authors.affiliation: Harvard School of Public Health, Massachusetts General Hospital/Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. Electronic address: lisu@hsph.harvard.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.affiliation: Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia, PA 19104, USA. Electronic address: avachani@mail.med.upenn.edu.
authors.forename: Anil
authors.initials: A
authors.lastname: Vachani
authors.affiliation: Harvard School of Public Health, Massachusetts General Hospital/Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. Electronic address: ywei@hsph.harvard.edu.
authors.forename: Yongyue
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia PA 19104, USA; Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia PA 19104, USA. Electronic address: aswhiteh@mail.med.upenn.edu.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Whitehead
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: chanocks@mail.nih.gov.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Building 37, Room 3068A, Bethesda, MD 20892, USA. Electronic address: Curtis_Harris@nih.gov.
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
mesh_terms: D001741:Black or African American / Q000235:genetics*; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15; D002895:Chromosomes, Human, Pair 5; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D040641:Quantitative Trait Loci
keywords: African Americans; Genome-wide association study; Lung neoplasms; Receptors, Cholinergic; Smoking; Telomerase