Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.

Sonja I Berndt, Nicola J Camp, Christine F Skibola, Joseph Vijai, Zhaoming Wang, Jian Gu, Alexandra Nieters, Rachel S Kelly, Karin E Smedby, Alain Monnereau, Wendy Cozen, Angela Cox, Sophia S Wang, Qing Lan, Lauren R Teras, Moara Machado, Meredith Yeager, Angela R Brooks-Wilson, Patricia Hartge, Mark P Purdue, Brenda M Birmann, Claire M Vajdic, Pierluigi Cocco, Yawei Zhang, Graham G Giles, Anne Zeleniuch-Jacquotte, Charles Lawrence, Rebecca Montalvan, Laurie Burdett, Amy Hutchinson, Yuanqing Ye, Timothy G Call, Tait D Shanafelt, Anne J Novak, Neil E Kay, Mark Liebow, Julie M Cunningham, Cristine Allmer, Henrik Hjalgrim, Hans-Olov Adami, Mads Melbye, Bengt Glimelius, Ellen T Chang, Martha Glenn, Karen Curtin, Lisa A Cannon-Albright, W Ryan Diver, Brian K Link, George J Weiner, Lucia Conde, Paige M Bracci, Jacques Riby, Donna K Arnett, Degui Zhi, Justin M Leach, Elizabeth A Holly, Rebecca D Jackson, Lesley F Tinker, Yolanda Benavente, Núria Sala, Delphine Casabonne, Nikolaus Becker, Paolo Boffetta, Paul Brennan, Lenka Foretova, Marc Maynadie, James McKay, Anthony Staines, Kari G Chaffee, Sara J Achenbach, Celine M Vachon, Lynn R Goldin, Sara S Strom, Jose F Leis, J Brice Weinberg, Neil E Caporaso, Aaron D Norman, Anneclaire J De Roos, Lindsay M Morton, Richard K Severson, Elio Riboli, Paolo Vineis, Rudolph Kaaks, Giovanna Masala, Elisabete Weiderpass, María-Dolores Chirlaque, Roel C H Vermeulen, Ruth C Travis, Melissa C Southey, Roger L Milne, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Jacqueline Clavel, Tongzhang Zheng, Theodore R Holford, Danylo J Villano, Ann Maria, John J Spinelli, Randy D Gascoyne, Joseph M Connors, Kimberly A Bertrand, Edward Giovannucci, Peter Kraft, Anne Kricker, Jenny Turner, Maria Grazia Ennas, Giovanni M Ferri, Lucia Miligi, Liming Liang, Baoshan Ma, Jinyan Huang, Simon Crouch, Ju-Hyun Park, Nilanjan Chatterjee, Kari E North, John A Snowden, Josh Wright, Joseph F Fraumeni, Kenneth Offit, Xifeng Wu, Silvia de Sanjose, James R Cerhan, Stephen J Chanock, Nathaniel Rothman, Susan L Slager

Journal: Nature communications 2016;7():10933

PMID: 26956414

Abstract

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

Address: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.; Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute and University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.; Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.; Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, California 94720, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.; Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, Maryland 20877, USA.; Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas 77030, USA.; Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, 79108 Baden-Württemberg, Germany.; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.; MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.; Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm 17176, Sweden.; Epidemiology of Childhood and Adolescent Cancers Group, INSERM, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), F-94807 Paris, France.; Université Paris Descartes, 75270 Paris, France.; Registre des hémopathies malignes de la Gironde, Institut Bergonié, 33076 Bordeaux Cedex, France.; Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.; Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.; Department of Oncology, University of Sheffield, Sheffield, South Yorkshire S10 1NS, UK.; Division of Cancer Etiology, City of Hope Beckman Research Institute, Duarte, California 91030, USA.; Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA.; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.; Departamento de Biologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.; Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z1L3.; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada V5A1S6.; Ontario Health Study, Toronto, Ontario, Canada M5G 0A3.; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.; Centre for Big Data Research in Health, University of New South Wales, Sydney, New South Wales 2052, Australia.; Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Monserrato, 09042 Cagliari, Italy.; Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut 06520, USA.; Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia.; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria 3010, Australia.; Department of Population Health, New York University School of Medicine, New York, New York 10016, USA.; Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016, USA.; Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York 10016, USA.; Westat, Rockville, Maryland 20850, USA.; Division of Hematology, Mayo Clinic, Rochester, Minnesota 55905, USA.; Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.; Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.; Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, 2300 Copenhagen, Denmark.; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.; Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, 2300 Copenhagen, Denmark.; Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.; Department of Immunology, Genetics and Pathology, Uppsala University, 75105 Uppsala, Sweden.; Center for Epidemiology and Computational Biology, Health Sciences, Exponent, Inc., Menlo Park, California 94025, USA.; Division of Epidemiology, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California 94305, USA.; Department of Internal Medicine, Huntsman Cancer Institute, Salt Lake City, Utah 84112, USA.; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA.; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA.; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah 84148, USA.; Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94118, USA.; Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.; Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.; Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA.; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98117, USA.; Cancer Epidemiology Research Programme, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona 08908, Spain.; CIBER de Epidemiología y Salud Pública (CIBERESP), 08036 Barcelona, Spain.; Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.; Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.; Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Programme, Institut Catala d'Oncologia, IDIBELL, 08908L'Hospitalet de Llobregat, 08908 Barcelona, Spain.; CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain.; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120 Baden-Württemberg, Germany.; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.; International Agency for Research on Cancer (IARC), 69372 Lyon, France.; Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, 656 53 Brno, Czech Republic.; EA 4184, Registre des Hémopathies Malignes de Côte d'Or, University of Burgundy and Dijon University Hospital, 21070 Dijon, France.; School of Nursing and Human Sciences, Dublin City University, Dublin 9, Ireland.; Division of Hematology/Oncology, Mayo Clinic, Phoenix, Arizona 85054, USA.; Department of Medicine, Duke University and VA Medical Centers, Durham, North Carolina 27710, USA.; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98117, USA.; Department of Environmental and Occupational Health, Drexel University School of Public Health, Philadelphia, Pennsylvania 19104, USA.; Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan 48201, USA.; School of Public Health, Imperial College London, London W2 1PG, UK.; MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.; Human Genetics Foundation, 10126 Turin, Italy.; Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), 50139 Florence, Italy.; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.; Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, N-9037 Tromsø, Norway.; Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, N-0304 Oslo, Norway.; Genetic Epidemiology Group, Folkhälsan Research Center, FI-00250 Helsinki, Finland.; CIBER de Epidemiología y Salud Pública (CIBERESP), 08036 Barcelona, Spain.; Department of Epidemiology, Murcia Regional Health Authority, E30008 Murcia, Spain.; Institute for Risk Assessment Sciences, Utrecht University, Utrecht, 3508, TD, The Netherlands.; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.; Cancer Epidemiology Unit, University of Oxford, Oxford OX3 7LF, UK.; Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.; Chronic Disease Prevention Unit, National Institute for Health and Welfare, FI-00271 Helsinki, Finland.; Epidemiology of Childhood and Adolescent Cancers Group, INSERM, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), F-94807 Paris, France.; Université Paris Descartes, 75270 Paris, France.; Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut 06520, USA.; Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z1L3.; School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada V6T1Z3.; Center for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z1L3.; Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada V6T1Z3.; Center for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z1L3.; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T1Z3.; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.; Sydney School of Public Health, The University of Sydney, Sydney, New South Wales 2006, Australia.; Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.; Department of Histopathology, Douglass Hanly Moir Pathology, Sydney, New South Wales 2113, Australia.; Department of Biomedical Science, University of Cagliari, Monserrato, 09042 Cagliari, Italy.; Interdisciplinary Department of Medicine, University of Bari, 70124 Bari, Italy.; Environmental and Occupational Epidemiology Unit, Cancer Prevention and Research Institute (ISPO), 50139 Florence, Italy.; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.; College of Information Science and Technology, Dalian Maritime University, Dalian, Liaoning Province 116026, China.; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.; Department of Health Sciences, University of York, York YO10 5DD, UK.; Department of Statistics, Dongguk University, Seoul 100-715, Republic of Korea.; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Department of Oncology, University of Sheffield, Sheffield, South Yorkshire S10 1NS, UK.; Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, South Yorkshire S10 2TN, UK.
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