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      Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

      research-article
      1 , 2 , 3 , 2 , 1 , 4 , 5 , 1 , 3 , 3 , 3 , 6 , 6 , 3 , 3 , 2 , 1 , 7 , 8 , 9 , 10 , 11 , 5 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 29 , 10 , 4 , 4 , 4 , 2 , 30 , 31 , 31 , 16 , 32 , 11 , 15 , 15 , 19 , 33 , 25 , 25 , 18 , 18 , 34 , 35 , 35 , 36 ,   37 , 38 , 39 , 24 , 40 , 41 , 42 , 40 , 40 , 43 , 44 , 44 , 44 , 45 , 45 , 46 , 47 , 48 , 49 , 50 , 48 , 49 , 50 , 51 , 52 , 12 , 53 , 54 , 55 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 1 , 66 , 63 , 67 , 21 , 21 , 68 , 27 , 69 , 70 , 71 , 72 , 73 , 74 , 74 , 75 , 76 , 77 , 5 , 5 , 2 , 78 , 79 , 78 , 79 , 78 , 79 , SpiroMeta Consortium 80 , 81 , 81 , 81 , 81 , 82 , 83 , 84 , 85 , 86 , 5 , 87 , 3 , 3 , 3 , 88 , 89 , 90 , 91 , 92 , 92 , 74 , 93 , 5 , 1 , 5 , 3
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          Summary

          While several lung cancer susceptibility loci have been identified, much of lung cancer heritability remains unexplained. Here, 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated GWAS analysis of lung cancer on 29,266 patients and 56,450 controls. We identified 18 susceptibility loci achieving genome wide significance, including 10 novel loci. The novel loci highlighted the striking heterogeneity in genetic susceptibility across lung cancer histological subtypes, with four loci associated with lung cancer overall and six with lung adenocarcinoma. Gene expression quantitative trait analysis (eQTL) in 1,425 normal lung tissues highlighted RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes, OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

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          Most cited references20

          • Record: found
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          Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

          We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants of BRCA2-K3326X (rs11571833; odds ratio [OR]=2.47, P=4.74×10−20) and of CHEK2-I157T (rs17879961; OR=0.38 P=1.27×10−13). We also showed an association between common variation at 3q28 (TP63; rs13314271; OR=1.13, P=7.22×10−10) and lung adenocarcinoma previously only reported in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants having substantive effects on cancer risk from pre-existing GWAS data.
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            A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma.

            Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR]=1.23, 95% confidence interval [CI]=1.13-1.33, p=3.02x10(-7)), but not with other histologic types (OR=1.01, p=0.84 and OR=1.00, p=0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95% CI=1.17-1.31, p=3.74x10(-14) for AD; OR=0.99, p=0.69 and OR=0.97, p=0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.
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              • Article: not found

              Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease.

              Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                11 May 2017
                12 June 2017
                July 2017
                12 December 2017
                : 49
                : 7
                : 1126-1132
                Affiliations
                [1 ]International Agency for Research on Cancer, World Health Organization, Lyon, France
                [2 ]Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto, Toronto, Canada
                [3 ]Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover NH
                [4 ]Department of Environmental Health, Harvard TH Chan School of Public Health, and Massachusetts General Hospital/Harvard Medical School, Boston, MA. 02115
                [5 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
                [6 ]Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom
                [7 ]Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark
                [8 ]Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [9 ]Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark
                [10 ]Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX USA
                [11 ]Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
                [12 ]Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Germany
                [13 ]Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center
                [14 ]Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH
                [15 ]University of Oviedo and CIBERESP, Faculty of Medicine, Campus del Cristo s/n, 33006 Oviedo, Spain
                [16 ]Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
                [17 ]School of Health and Related Research, University of Sheffield, England, UK
                [18 ]Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
                [19 ]Radboud University Medical Center, Nijmegen, The Netherlands
                [20 ]Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington, USA
                [21 ]National Institute of Occupational Health, Oslo, Norway
                [22 ]British Columbia Cancer Agency, Vancouver, Canada
                [23 ]Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
                [24 ]Department of Epidemiology, Geisel School of Medicine, Hanover, NH
                [25 ]Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, P.R. China
                [26 ]Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
                [27 ]University of Pittsburgh Cancer Institute, Pittsburgh, USA
                [28 ]Department of Preventive Medicine, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
                [29 ]Department of Clinical Sciences and Community Health – DISCCO, University of Milan, Milan, Italy
                [30 ]University Health Network- The Princess Margaret Cancer Centre, Toronto, CA
                [31 ]Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark
                [32 ]Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA
                [33 ]Department of Integrative Bioscience & Biotechnology, Sejong University, Gwangjin-gu, Seoul, Republic of Korea
                [34 ]Dept. of Pathology, Lund University, Lund, Sweden
                [35 ]Faculty of Medicine, Lund University, Lund, Sweden
                [36 ]School of Public Health, St Mary’s Campus, Imperial College London, UK
                [37 ]Section for Epidemiology, Department of Public Health, Aarhus University, Denmark
                [38 ]Hellenic Health Foundation, Athens, GR
                [39 ]Tumino. Molecular and Nutritional Epidemiology Unit CSPO (Cancer Research and Prevention Centre), Scientific Institute of Tuscany, Florence, Italy
                [40 ]Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
                [41 ]Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112
                [42 ]Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
                [43 ]Swedish Medical Group, Seattle, WA, USA
                [44 ]Department of Oncology, University of Sheffield, Sheffield, UK
                [45 ]Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [46 ]Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany
                [47 ]Institute of Medical Statistics and Epidemiology, Technical University Munich, Germany
                [48 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [49 ]Thoraxklinik at University Hospital Heidelberg
                [50 ]Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany
                [51 ]German Center for Lung Research (DZL), Heidelberg, Germany
                [52 ]University of Salzburg and Cancer Cluster Salzburg, Austria
                [53 ]Department of Medical Biosciences, Umeå University, Umeå, Sweden
                [54 ]Department of Radiation Sciences, Umeå University, Umeå, Sweden
                [55 ]Princess Margaret Cancer Centre, Toronto, Canada
                [56 ]University of Kentucky, Markey Cancer Center, Lexington, Kentucky, USA
                [57 ]Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
                [58 ]Institute of Pneumology “Marius Nasta”, Bucharest, Romania
                [59 ]2nd Faculty of Medicine, Charles University, Prague, Czech Republic
                [60 ]Faculty of Medicine, University of Ostrava, Czech Republic
                [61 ]Clinical Center of Serbia, Belgrade. School of Medicine, University of Belgrade
                [62 ]M. Sklodowska-Curie Cancer Center, Institute of Oncology, Warsaw, Poland
                [63 ]Department of Epidemiology and Prevention, Russian N.N.Blokhin Cancer Research Centre, Moscow, Russian Federation
                [64 ]International Organization for Cancer Prevention and Research, Belgrade, Serbia
                [65 ]Department of Surgery, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland
                [66 ]Nofer Institute of Occupational Medicine, Department of Environmental Epidemiology, Lodz, Poland
                [67 ]Department of Clinical Science, University of Bergen, Bergen, Norway
                [68 ]Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
                [69 ]Duke-National University of Singapore Medical School, Singapore, Singapore
                [70 ]Department of Epidemiology, Shanghai Cancer Institute, China
                [71 ]The Institute of Cancer Research, London, England
                [72 ]Public Health Ontario, Canada
                [73 ]American Cancer Society, Inc., Atlanta, Georgia, USA
                [74 ]Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada
                [75 ]Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, MA, USA
                [76 ]The University of British Columbia Centre for Heart Lung Innovation, St Paul’s Hospital, Vancouver, BC, Canada
                [77 ]University of Groningen, Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, The Netherlands
                [78 ]Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK
                [79 ]National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK
                [80 ]SpiroMeta Consortium see Supplemental Materials for full list of participating members
                [81 ]deCODE Genetics, Amgen Inc., Reykjavik, Iceland
                [82 ]Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, North Carolina, USA
                [83 ]Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA
                [84 ]Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030
                [85 ]Research Computing Division, RTI International, Research Triangle Park, North Carolina, USA
                [86 ]Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
                [87 ]Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, North Carolina, USA
                [88 ]Department of Epidemiology, University of Washington, 1959 NE Pacific Street, Health Sciences Bldg., F-247B, Box 357236, Seattle, WA 98195
                [89 ]Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115
                [90 ]Departments of Pharmacology and Toxicology & Psychiatry, Toronto, Ontario, Canada
                [91 ]Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
                [92 ]Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
                [93 ]Department of Molecular Medicine, Laval University, Québec, Canada
                Author notes
                Corresponding author: Christopher I. Amos Christopher.I.Amos@ 123456dartmouth.edu
                [*]

                these authors have equal contributions

                Article
                NIHMS875731
                10.1038/ng.3892
                5510465
                28604730
                6a80f36f-31fc-4930-a481-a772e6244438

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