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.

Cancer Control Research BC Cancer Agency Vancouver British Columbia Canada V5Z1L3

Cancer Epidemiology Centre Cancer Council Victoria Melbourne Victoria 3004 Australia

Cancer Epidemiology Research Programme Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona 08908 Spain

Cancer Epidemiology Unit University of Oxford Oxford OX3 7LF UK

Cancer Genomics Research Laboratory Division of Cancer Epidemiology and Genetics National Cancer Institute Gaithersburg Maryland 20877 USA

Carolina Center for Genome Sciences University of North Carolina at Chapel Hill Chapel Hill North Carolina 27599 USA

Center for Chronic Immunodeficiency University Medical Center Freiburg Freiburg 79108 Baden Württemberg Germany

Center for Epidemiology and Computational Biology Health Sciences Exponent Inc Menlo Park California 94025 USA

Center for Lymphoid Cancer BC Cancer Agency Vancouver British Columbia Canada V5Z1L3

Centre for Big Data Research in Health University of New South Wales Sydney New South Wales 2052 Australia

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health University of Melbourne Melbourne Victoria 3010 Australia

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts 02115 USA

Chronic Disease Prevention Unit National Institute for Health and Welfare FI 00271 Helsinki Finland

CIBER de Epidemiología y Salud Pública 08036 Barcelona Spain

CIBER Epidemiología y Salud Pública 28029 Madrid Spain

College of Information Science and Technology Dalian Maritime University Dalian Liaoning Province 116026 China

Departamento de Biologia Geral Instituto de Ciências Biológicas Universidade Federal de Minas Gerais Belo Horizonte 31270 901 Brazil

Department of Biomedical Physiology and Kinesiology Simon Fraser University Burnaby British Columbia Canada V5A1S6

Department of Biomedical Science University of Cagliari Monserrato 09042 Cagliari Italy

Department of Biostatistics Harvard School of Public Health Boston Massachusetts 02115 USA

Department of Biostatistics University of Alabama at Birmingham Birmingham Alabama 35233 USA

Department of Biostatistics Yale School of Public Health New Haven Connecticut 06520 USA

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute and MF MU 656 53 Brno Czech Republic

Department of Community Medicine Faculty of Health Sciences University of Tromsø The Arctic University of Norway N 9037 Tromsø Norway

Department of Environmental and Occupational Health Drexel University School of Public Health Philadelphia Pennsylvania 19104 USA

Department of Environmental Health Sciences Yale School of Public Health New Haven Connecticut 06520 USA

Department of Environmental Medicine New York University School of Medicine New York New York 10016 USA

Department of Epidemiology and Biostatistics University of California San Francisco San Francisco California 94118 USA

Department of Epidemiology Harvard School of Public Health Boston Massachusetts 02115 USA

Department of Epidemiology MD Anderson Cancer Center Houston Texas 77030 USA

Department of Epidemiology Murcia Regional Health Authority E30008 Murcia Spain

Department of Epidemiology Research Division of Health Surveillance and Research Statens Serum Institut 2300 Copenhagen Denmark

Department of Epidemiology School of Public Health and Comprehensive Cancer Center University of Alabama at Birmingham Birmingham Alabama 35233 USA

Department of Epidemiology University of North Carolina at Chapel Hill Chapel Hill North Carolina 27599 USA

Department of Family Medicine and Public Health Sciences Wayne State University Detroit Michigan 48201 USA

Department of Haematology Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital Sheffield South Yorkshire S10 2TN UK

Department of Health Sciences Research Mayo Clinic Rochester Minnesota 55905 USA

Department of Health Sciences University of York York YO10 5DD UK

Department of Histopathology Douglass Hanly Moir Pathology Sydney New South Wales 2113 Australia

Department of Immunology Genetics and Pathology Uppsala University 75105 Uppsala Sweden

Department of Internal Medicine Carver College of Medicine The University of Iowa Iowa City Iowa 52242 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 Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota 55905 USA

Department of Medical Epidemiology and Biostatistics Karolinska Institutet 17177 Stockholm Sweden

Department of Medicine Duke University and VA Medical Centers Durham North Carolina 27710 USA

Department of Medicine Mayo Clinic Rochester Minnesota 55905 USA

Department of Medicine Memorial Sloan Kettering Cancer Center New York New York 10065 USA

Department of Medicine Solna Karolinska Institutet Karolinska University Hospital Stockholm 17176 Sweden

Department of Medicine Stanford University School of Medicine Stanford California 94305 USA

Department of Medicine University of British Columbia Vancouver British Columbia Canada V6T1Z3

Department of Nutrition Harvard School of Public Health Boston Massachusetts 02115 USA

Department of Oncology University of Sheffield Sheffield South Yorkshire S10 1NS UK

Department of Pathology University of British Columbia Vancouver British Columbia Canada V6T1Z3

Department of Population Health New York University School of Medicine New York New York 10016 USA

Department of Preventive Medicine USC Keck School of Medicine University of Southern California Los Angeles California 90033 USA

Department of Public Health Clinical and Molecular Medicine University of Cagliari Monserrato 09042 Cagliari Italy

Department of Research Cancer Registry of Norway Institute of Population Based Cancer Research N 0304 Oslo Norway

Department of Statistics Dongguk University Seoul 100 715 Republic of Korea

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda Maryland 20892 USA

Division of Cancer Epidemiology German Cancer Research Center Heidelberg 69120 Baden Württemberg Germany

Division of Cancer Etiology City of Hope Beckman Research Institute Duarte California 91030 USA

Division of Endocrinology Diabetes and Metabolism The Ohio State University Columbus Ohio 43210 USA

Division of Environmental Health Sciences University of California Berkeley School of Public Health Berkeley California 94720 USA

Division of Epidemiology Department of Health Research and Policy Stanford University School of Medicine Stanford California 94305 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

Division of Hematology Mayo Clinic Rochester Minnesota 55905 USA

Division of Hematology Oncology Mayo Clinic Phoenix Arizona 85054 USA

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle Washington 98117 USA

EA 4184 Registre des Hémopathies Malignes de Côte d'Or University of Burgundy and Dijon University Hospital 21070 Dijon France

Environmental and Occupational Epidemiology Unit Cancer Prevention and Research Institute 50139 Florence Italy

Epidemiology of Childhood and Adolescent Cancers Group INSERM Center of Research in Epidemiology and Statistics Sorbonne Paris Cité F 94807 Paris France

Epidemiology Research Program American Cancer Society Atlanta Georgia 30303 USA

Faculty of Medicine and Health Sciences Macquarie University Sydney New South Wales 2109 Australia

Genetic Epidemiology Group Folkhälsan Research Center FI 00250 Helsinki Finland

Genetic Epidemiology Laboratory Department of Pathology University of Melbourne Melbourne Victoria 3010 Australia

Genome Sciences Centre BC Cancer Agency Vancouver British Columbia Canada V5Z1L3

George E Wahlen Department of Veterans Affairs Medical Center Salt Lake City Utah 84148 USA

Human Genetics Foundation 10126 Turin Italy

Institute for Risk Assessment Sciences Utrecht University Utrecht 3508 TD The Netherlands

Interdisciplinary Department of Medicine University of Bari 70124 Bari Italy

International Agency for Research on Cancer 69372 Lyon France

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht 3584 CX Utrecht The Netherlands

Molecular and Nutritional Epidemiology Unit Cancer Research and Prevention Institute 50139 Florence Italy

MRC PHE Centre for Environment and Health School of Public Health Imperial College London London W2 1PG UK

Norris Comprehensive Cancer Center USC Keck School of Medicine University of Southern California Los Angeles California 90033 USA

Ontario Health Study Toronto Ontario Canada M5G 0A3

Perlmutter Cancer Center NYU Langone Medical Center New York New York 10016 USA

Registre des hémopathies malignes de la Gironde Institut Bergonié 33076 Bordeaux Cedex France

School of Nursing and Human Sciences Dublin City University Dublin 9 Ireland

School of Population and Public Health University of British Columbia Vancouver British Columbia Canada V6T1Z3

School of Public Health Imperial College London London W2 1PG UK

Sydney School of Public Health The University of Sydney Sydney New South Wales 2006 Australia

The Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York New York 10029 USA

Translational Research Laboratory Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat 08908 Barcelona Spain

Unit of Infections and Cancer Cancer Epidemiology Research Programme Institut Catala d'Oncologia IDIBELL 08908L'Hospitalet de Llobregat 08908 Barcelona Spain

Unit of Nutrition Environment and Cancer Cancer Epidemiology Research Program Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat 08908 Barcelona Spain

Université Paris Descartes 75270 Paris France

Westat Rockville Maryland 20850 USA

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