title: Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia.
abstract: Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada, Section of Genetics, International Agency for Research on Cancer, 69372 Lyon, France, Department of Cancer Epidemiology and Prevention Research, Cancer Control Alberta, Alberta Health Services, Calgary, Alberta T2T 5C7, Canada.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Brenner
authors.affiliation: Department of Community and Family Medicine, Center for Genomic Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03766, USA.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada.
authors.forename: Yonathan
authors.initials: Y
authors.lastname: Brhane
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, UK.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Timofeeva
authors.affiliation: Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Caporaso
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Environmental Health and Epidemiology, Harvard University School of Public Health, Boston, MA 02115, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.affiliation: Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Bickeböller
authors.affiliation: Division of Health Sciences, Cancer Center and College of Medicine, Mayo Clinic, Rochester, NY 55905, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.affiliation: Epidemiology Research Program, American Cancer Society, Epidemiology and Surveillance Research, Atlanta, GA 30301, USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Stevens
authors.affiliation: Epidemiology Research Program, American Cancer Society, Epidemiology and Surveillance Research, Atlanta, GA 30301, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Gapstur
authors.affiliation: Section of Genetics, International Agency for Research on Cancer, 69372 Lyon, France.
authors.forename: James
authors.initials: J
authors.lastname: McKay
authors.affiliation: Population Sciences, Tisch Cancer Center and Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.affiliation: Institute of Carcinogenesis, Russian N.N.Blokhin Cancer Research Centre, 115478 Moscow, Russia.
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.affiliation: Department of Epidemiology, Institute of Occupational Medicine, 91348 Lodz, Poland.
authors.forename: Neonilia
authors.initials: N
authors.lastname: Szeszenia-Dabrowska
authors.affiliation: Department of Epidemiology and Cancer Prevention, The M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02781, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.affiliation: National Institute of Environmental Health, Budapest 1097, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Rudnai
authors.affiliation: Department of Health Risk Assessment, Regional Authority of Public Health, Banská Bystrica 97556, Slovak Republic.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Fabianova
authors.affiliation: National Institute of Public Health, Bucharest 050463, Romania.
authors.forename: Dana
authors.initials: D
authors.lastname: Mates
authors.affiliation: Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University in Prague, 128 00 Prague 2, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bencko
authors.affiliation: Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno 65653, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Foretova
authors.affiliation: Department of Preventive Medicine, Palacky University, Olomouc 77515, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Janout
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Krokan
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine and.
authors.forename: Frank
authors.initials: F
authors.lastname: Skorpen
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine and.
authors.forename: Maiken E
authors.initials: ME
authors.lastname: Gabrielsen
authors.affiliation: Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim 7489, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Vatten
authors.affiliation: Department of Community Medicine, University of Tromso, Tromso N-9037, Norway.
authors.forename: Inger
authors.initials: I
authors.lastname: Njølstad
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Chu
authors.initials: C
authors.lastname: Chen
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Goodman
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montréal, Quebec, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Vooder
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen 5009, Norway.
authors.forename: Kristjan
authors.initials: K
authors.lastname: Välk
authors.affiliation: Institute of Molecular and Cell Biology, Estonian Biocentre, Genotyping Core Facility, Tartu 51010, Estonia.
authors.forename: Mari
authors.initials: M
authors.lastname: Nelis
authors.affiliation: Institute of Molecular and Cell Biology, Estonian Biocentre, Genotyping Core Facility, Tartu 51010, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.affiliation: Department of Oncology, Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Eisen
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Genetics, U.T. M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.affiliation: Departments of Environmental Health and Epidemiology, Harvard University School of Public Health, Boston, MA 02115, USA.
authors.forename: Yongyue
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Departments of Environmental Health and Epidemiology, Harvard University School of Public Health, Boston, MA 02115, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.affiliation: Division of Health Sciences, Cancer Center and College of Medicine, Mayo Clinic, Rochester, NY 55905, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Xie
authors.affiliation: Division of Health Sciences, Cancer Center and College of Medicine, Mayo Clinic, Rochester, NY 55905, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: She
authors.affiliation: Department of Preventive Medicine, Kyushu University Graduate School of Medicine, Fukuoka City 819-0395, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.affiliation: Department of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Chikusa-ku Nagoya 464-0021, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ, 69121 Heidelberg, Germany, Division of Epigenomics and Cancer Risk Factors, Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), 69121 Heidelberg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Risch
authors.affiliation: Unit of Environmental Epidemiology, Helmholtz Zentrum Munchen, 85764 Neuherberg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Heinrich
authors.affiliation: Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Rosenberger
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), 69121 Heidelberg, Germany, Translational Research Unit and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Muley
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), 69121 Heidelberg, Germany, Department of Thoracic Surgery, Thoraxklinik am Universitätsklinikum Heidelberg, 69117 Heidelberg, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Dienemann
authors.affiliation: Roy Castle Lung Cancer Research Programme, The University of Liverpool Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.affiliation: Roy Castle Lung Cancer Research Programme, The University of Liverpool Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Olaide
authors.initials: O
authors.lastname: Raji
authors.affiliation: Roy Castle Lung Cancer Research Programme, The University of Liverpool Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Roy Castle Lung Cancer Research Programme, The University of Liverpool Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: John
authors.initials: J
authors.lastname: Gosney
authors.affiliation: Roy Castle Lung Cancer Research Programme, The University of Liverpool Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Triantafillos
authors.initials: T
authors.lastname: Liloglou
authors.affiliation: Roy Castle Lung Cancer Research Programme, The University of Liverpool Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Michael P A
authors.initials: MP
authors.lastname: Davies
authors.affiliation: Roy Castle Lung Cancer Research Programme, The University of Liverpool Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Marcus
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada.
authors.forename: John
authors.initials: J
authors.lastname: McLaughlin
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Orlow
authors.affiliation: Department of Community and Family Medicine, Center for Genomic Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03766, USA.
authors.forename: Younghun
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Community and Family Medicine, Center for Genomic Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03766, USA.
authors.forename: Yafang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada.
authors.forename: Xuchen
authors.initials: X
authors.lastname: Zong
authors.affiliation: Section of Genetics, International Agency for Research on Cancer, 69372 Lyon, France.
authors.forename: Mattias
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Medical Oncology and Haematology, Department of Medicine, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shelley S
authors.initials: SS
authors.lastname: Tworoger
authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Keck School of Medicine, University of South California, Los Angeles, CA 90089-0911, USA and.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Wilkens
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Juncheng
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.affiliation: Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Landi
authors.affiliation: Section of Genetics, International Agency for Research on Cancer, 69372 Lyon, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada, rayjean.hung@lunenfeld.ca.
authors.forename: Rayjean J
authors.initials: RJ
authors.lastname: Hung
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D001499:Bayes Theorem; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology