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

      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 6 , 5 , 6 , 5 , 11 , 4 , 3 , 3 , 12 , 13 , 6 , 6 , 5 , 5 , 14 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 25 , 26 , 27 , 28 , 29 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 35 , 5 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ,   43 , 44 , 45 , 46 , 5 , 4 , 4 , 47 , 47 , 47 , 48 , 49 , 50 , 9 , 51 , 52 , 3 , 53 , 4 , 9 , 7 , 5 , 54 , 55 , 56
      Nature genetics
      Springer Nature

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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 BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10(-20)) and CHEK2 p.Ile157Thr (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 that had been previously reported only 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 with substantive effects on cancer risk from preexisting genome-wide association study 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
                Nat. Genet.
                Nature genetics
                Springer Nature
                1546-1718
                1061-4036
                Jul 2014
                : 46
                : 7
                Affiliations
                [1 ] 1] Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK. [2].
                [2 ] 1] International Agency for Research on Cancer (IARC, World Health Organization (WHO)), Lyon, France. [2] [3].
                [3 ] deCODE Genetics, Amgen, Reykjavik, Iceland.
                [4 ] Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
                [5 ] International Agency for Research on Cancer (IARC, World Health Organization (WHO)), Lyon, France.
                [6 ] Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.
                [7 ] Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
                [8 ] Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [9 ] Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.
                [10 ] Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, USA.
                [11 ] Information Management Services, Inc., Rockville, Maryland, USA.
                [12 ] Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
                [13 ] 1] Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany. [2] Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
                [14 ] Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
                [15 ] Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
                [16 ] Institute of Carcinogenesis, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia.
                [17 ] Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland.
                [18 ] The M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
                [19 ] National Institute of Environmental Health, Budapest, Hungary.
                [20 ] Regional Authority of Public Health, Banská Bystrica, Slovak Republic.
                [21 ] National Institute of Public Health, Bucharest, Romania.
                [22 ] 1st Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University in Prague, Prague, Czech Republic.
                [23 ] Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
                [24 ] Palacky University, Olomouc, Czech Republic.
                [25 ] Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
                [26 ] Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
                [27 ] Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
                [28 ] Department of Community Medicine, University of Tromsø, Tromsø, Norway.
                [29 ] Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
                [30 ] INSERM U946, Paris, France.
                [31 ] Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
                [32 ] Department of Biomedicine, University of Bergen, Bergen, Norway.
                [33 ] 1] Estonian Genome Center, Institute of Molecular and Cell Biology, Tartu, Estonia. [2] Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
                [34 ] Estonian Genome Center, Institute of Molecular and Cell Biology, Tartu, Estonia.
                [35 ] Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
                [36 ] 1] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK. [2] Unit of Molecular and Genetic Epidemiology, HuGeF Foundation, Torino, Italy.
                [37 ] Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain.
                [38 ] 1] INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, Villejuif, France. [2] Université Paris Sud, UMRS 1018, Villejuif, France. [3] Institut Gustave Roussy, Villejuif, France.
                [39 ] 1] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK. [2] National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. [3] Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.
                [40 ] 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. [3] Hellenic Health Foundation, Athens, Greece.
                [41 ] University of Cambridge School of Clinical Medicine, Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge, UK.
                [42 ] Department of Radiation Sciences, Umeå Universitet, Umeå, Sverige, Sweden.
                [43 ] 1] Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway. [2] Department of Research, Cancer Registry of Norway, Oslo, Norway. [3] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. [4] Samfundet Folkhälsan, Helsinki, Finland.
                [44 ] Danish Cancer Society Research Center, Copenhagen, Denmark.
                [45 ] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.
                [46 ] Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France.
                [47 ] Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
                [48 ] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
                [49 ] 1] Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany. [2] Department of Thoracic Surgery, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
                [50 ] Department of Genetic Epidemiology, University of Göttingen, Göttingen, Germany.
                [51 ] Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
                [52 ] 1] Department of Oncology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK. [2] Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK.
                [53 ] 1] Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2] Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
                [54 ] 1] Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA. [2] [3].
                [55 ] 1] Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK. [2] [3].
                [56 ] 1] Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, USA. [2] [3].
                Article
                ng.3002 EMS58504
                10.1038/ng.3002
                4074058
                24880342
                f1b29820-521d-465f-9eff-f749ac9d12fb
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