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Author:
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Zuber, Verena; Marconett, Crystal N.; Shi, Jianxin; Hua, Xing; Wheeler, William; Yang, Chenchen; Song, Lei; Dale, Anders M.; Laplana Lafaja, Marina; Risch, Angela; Witoelar, Aree; Thompson, Wesley K.; Schork, Andrew J.; Bettella, Francesco; Wang, Yunpeng; Djurovic, Srdjan; Zhou, Beiyun; Borok, Zea; van der Heijden, Henricus F. M.; Graaf, Jacqueline de; Swinkels, Dorine; Aben, Katja K.; McKay, James D.; Hung, Rayjean J.; Bikeböller, Heike; Stevens, Victoria L.; Albanes, Demetrius; Caporaso, Neil E.; Han, Younghun; Wei, Yongyue; Panadero, Maria Ángeles; Mayordomo, José I.; Christiani, David C.; Kiemeney, Lambertus; Andreassen, O. A.; Houlston, Richard; Amos, Christopher I.; Chatterjee, Nilanjan; Laird-Offringa, Ite A.; Mills, Ian G.; Landi, Maria Teresa
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Notes:
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Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10-6) and blood triglycerides (P = 1.39x10-5). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 × 10-4) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21,Pcombined = 5.20x10-9). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer.
This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD.
Transdisciplinary Research for Cancer of Lung (TRICL): National Institute of Health U19 CA148127-01 (PI: Amos), Canadian Cancer Society Research Institute (No. 020214, PI: Hung). The Environment and Genetics in Lung Cancer Etiology (EAGLE), Prostate, Lung, Colon, Ovary Screening Trial (PLCO), and Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) studies were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. ATBC was also supported by US Public Health Service contracts (N01-CN-45165, N01-RC-45035, and N01-RC-37004) from the NCI.
PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN-25522), the Pacific Health Research Institute (NO1-CN-25515), the Henry Ford Health System (NO1-CN-25512), the University of Minnesota (NO1-CN-25513), Washington University (NO1-CN-25516), the University of Pittsburgh (NO1-CN-25511), the University of Utah (NO1-CN-25524), the Marshfield Clinic Research Foundation (NO1-CN-25518), the University of Alabama at Birmingham (NO1-CN-75022), Westat, Inc. (NO1-CN-25476), and the University of California, Los Angeles (NO1-CN-25404). The Cancer Prevention Study-II (CPS-II) Nutrition Cohort was supported by the American Cancer Society. Funding for the Lung Cancer and Smoking study was provided by the National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. Harvard Lung Study: The Harvard Lung Cancer Study is supported by the National Institutes of Health (R01 CA092824, P50 CA090578, and R01 CA074386). Lung eQTL study: The lung eQTL study at Laval University was supported by the Chaire de pneumologie de la Fondation JD Bégin de l’Université Laval, the Fondation de l’Institut universitaire de cardiologie et de pneumologie de Québec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP - 123369), and the Cancer Research Society and Read for the Cure. Y. Bossé is the recipient of a Junior 2 Research Scholar award from the Fonds de recherche Québec – Santé (FRQS).
Lung meQTL study: The meQTL study based on the environment and Genetics in Lung Cancer Etiology (EAGLE) study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services.
Epigenetics: This study was supported by NIH grant 1 R01 HL114094 to IAL-O and ZB, NIH grants 1 P30 H101258 and R37HL062569-13 to ZB. ZB is supported by the Ralph Edgington Chair in Medicine. CNM was supported in part by the department of Surgery, University of Southern California. Generation of epigenetic data was supported in part by a Norris Comprehensive Cancer Center core grant, award number P30CA014089, from the National Cancer Institute. |
