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      Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

      research-article
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          Abstract

          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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          Most cited references46

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          Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1.

          To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 x 10(-17)) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.
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            A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.

            Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
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              Parental origin of sequence variants associated with complex diseases.

              Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                21 May 2014
                01 June 2014
                July 2014
                01 January 2015
                : 46
                : 7
                : 736-741
                Affiliations
                [1 ]Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK
                [2 ]International Agency for Research on Cancer (IARC/WHO), Lyon, France
                [3 ]deCODE genetics/Amgen, Sturlugata 8, 101 Reykjavik, Iceland
                [4 ]Division of Cancer Epidemiology and Genetics, National Cancer institute, NIH, DHHS, Bethesda, MD 20892-9769, USA
                [5 ]Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital. Toronto, Canada
                [6 ]Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [7 ]Department of Environmental Health, Harvard School of Public Health, Boston, MA, 617-432-1641, USA
                [8 ]Center for Genomic Medicine Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, 46 Centerra Parkway, Suite 330, Lebanon, NH 03766
                [9 ]Information Management Services, Inc., Rockville, MD 20852, USA
                [10 ]Princess Margaret Hospital, University Health Network, Toronto, Canada
                [11 ]Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [12 ]Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
                [13 ]Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30301, USA
                [14 ]Department of Genetics, U.T. M.D. Anderson Cancer Center, Houston, TX 77030
                [15 ]Institute of Carcinogenesis, Russian N.N. Blokhin Cancer Research Centre, 115478 Moscow, Russia
                [16 ]Department of Epidemiology, Institute of Occupational Medicine, 91348 Lodz, Poland
                [17 ]The M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02781, Poland
                [18 ]National Institute of Environmental Health, Budapest 1097, Hungary
                [19 ]Regional Authority of Public Health, Banska’ Bystrica 97556, Slovak Republic
                [20 ]National Institute of Public Health, Bucharest 050463, Romania
                [21 ]1st Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University in Prague, 12800 Prague 2, Czech Republic
                [22 ]Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno 65653, Czech Republic
                [23 ]Palacky University, Olomouc 77515, Czech Republic
                [24 ]Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim 7489, Norway
                [25 ]Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine
                [26 ]Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim 7489, Norway
                [27 ]Department of Community Medicine, University of Tromso, Tromso 9037, Norway
                [28 ]Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
                [29 ]INSERM U946, Paris 75010, France
                [30 ]Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia
                [31 ]Competence Centre on Reproductive Medicine and Biology, 50410 Tartu, Estonia
                [32 ]Estonian Genome Center, Institute of Molecular and Cell Biology, Tartu 51010, Estonia
                [33 ]Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
                [34 ]Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
                [35 ]Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK
                [36 ]HuGeF Foundation, Torino, Italy
                [37 ]Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain
                [38 ]INSERM, Centre for research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women’s Health team, F-94805, Villejuif, France
                [39 ]Université Paris Sud, UMRS 1018, F-94805, Villejuif, France
                [40 ]IGR, F-94805, Villejuif, France
                [41 ]National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
                [42 ]Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands
                [43 ]Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA
                [44 ]Bureau of Epidemiologic Research, Academy of Athens, 23 Alexandroupoleos Street, Athens, GR-115 27, Greece
                [45 ]Hellenic Health Foundation, 13 Kaisareias Street, Athens, GR-115 27, Greece
                [46 ]University of Cambridge School of Clinical Medicine, Clinical Gerontology Unit Box 251, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK
                [47 ]Department of Radiation Sciences, Umeå universitet, SE-901 87 Umeå, Sverige, Sweden
                [48 ]Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
                [49 ]Department of Research, Cancer Registry of Norway, Oslo, Norway
                [50 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
                [51 ]Samfundet Folkhälsan, Helsinki, Finland
                [52 ]Danish Cancer Society Research Center, Strandboulevarden 49, DK 2100 Copenhagen Ø, Denmark
                [53 ]Centre d’Etude du Polymorphisme Humain (CEPH), Paris 75010, France
                [54 ]Department of Epidemiology, U.T. M.D. Anderson Cancer Center, Houston, TX 77030, USA
                [55 ]Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
                [56 ]Department of Thoracic Surgery, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany
                [57 ]Department of Genetic Epidemiology, University of Göttingen, Göttingen, Germany
                [58 ]Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, UK
                [59 ]Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
                [60 ]Addenbrooke’s Hospital, Cambridge Biomedical Campus, Hill’s Road Cambridge CB2 0QQ, UK
                Author notes
                Correspondence to: Richard S Houlston ( richard.houlston@ 123456icr.ac.uk ) or Maria Teresa Landi ( landim@ 123456mail.nih.gov )
                [*]

                These individuals should be considered as having equal authorship status

                [¥]

                These individuals jointly directed research

                AUTHOR CONTRIBUTIONS: RSH and YW conceived the study and provided overall project management and drafted the paper. In the UK: YW performed statistics and bioinformatics of UK data and conducted all meta-analyses; additional support was provided by MH; PB oversaw genotyping and sequencing; AL and BK performed genotyping and Sanger sequencing; AM, TE and RSH were responsible for the development and operation of the GELCAPS study; DC and PB formed next generation sequencing. At IARC JDM, PB provided overall project management; MT, MDS, VG, MV performed statistics and bioinformatics of IARC data and conducted meta-analysis; JDM, FLK oversaw genotyping and sequencing; GS, DZ, N S-D, JL, PR, EF, DM, VB, LF, VJ, H E. K, M E G, F S, LV, IN, CC, GG, ML,S B, TV, KV, MN, AM, ML, JL provided samples and data. For the Dartmouth/MDACC component, CIA provided overall project management and obtained support for genotyping and contributed to statistical analyses, WVC performed imputation analysis, YH performed statistical analyses, MRS oversaw sample collection and development of the epidemiological studies. MRS was also responsible for collecting samples that are a part of this research. XW provided ongoing support for the research protocol and supported large laboratory management of samples. YY and JG performed genotyping. At NCI, MTL was responsible for the overall project and managed the EAGLE study; NEC managed the PLCO study; DA managed the ATBC study; SMG and VLS managed the CPS-II study; NC and WW performed statistical analyses; ZW performed genotyping and imputation analysis; SC oversaw genotyping and imputation analysis. At deCODE TR and KS were responsible for the development and operation of deCODE’s lung cancer study; GT and PS performed the imputations and statistical analysis of the Icelandic data. At Harvard DCC was responsible for the overall conduct of the project; LS was responsible for sample management, genotyping and laboratory quality control; YW performed data management and statistical analyses. For Heidelberg-EPIC replication: ML managed DNA samples and performed genotyping; ARo managed genotype and phenotype information; ARi supervised genotyping and data analysis; RK, ARi and HD conceived and managed studies which contributed samples. For Toronto replication: RH and GL provided overall supervision of the study conduct, including study design, field recruitment, genotyping and statistical analysis; XZ performed the statistical analysis.

                Article
                EMS58504
                10.1038/ng.3002
                4074058
                24880342
                f1b29820-521d-465f-9eff-f749ac9d12fb
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                Genetics
                Genetics

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