Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.
Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10-13), 1q42.13 (rs41271473, P=1.06 × 10-10), 4q24 (rs71597109, P=1.37 × 10-10), 4q35.1 (rs57214277, P=3.69 × 10-8), 6p21.31 (rs3800461, P=1.97 × 10-8), 11q23.2 (rs61904987, P=2.64 × 10-11), 18q21.1 (rs1036935, P=3.27 × 10-8), 19p13.3 (rs7254272, P=4.67 × 10-8) and 22q13.33 (rs140522, P=2.70 × 10-9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
Philip J
0000-0001-9663-4611
PJ
Law
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Sonja I
SI
Berndt
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
Helen E
HE
Speedy
Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
Nicola J
NJ
Camp
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
Georgina P
GP
Sava
Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
Christine F
CF
Skibola
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
Amy
A
Holroyd
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Vijai
0000-0002-7933-151X
V
Joseph
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Nicola J
NJ
Sunter
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Baden-Württemberg 79108, Germany.
Alexandra
A
Nieters
Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Hospital Clínic, Barcelona 08036, Spain.
Silvia
S
Bea
Registre des hémopathies malignes de la Gironde, Institut Bergonié, Inserm U1219 EPICENE, 33076 Bordeaux, France.|Epidemiology of Childhood and Adolescent Cancers Group, Inserm, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité, Paris, F-94807, France.|Université Paris Descartes, Paris 75270, France.
Alain
A
Monnereau
Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Hospital Clínic, Barcelona 08036, Spain.
David
D
Martin-Garcia
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Lynn R
LR
Goldin
Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Hospital Clínic, Barcelona 08036, Spain.
Guillem
G
Clot
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA.
Lauren R
LR
Teras
Grupo de Medicina Xenomica, Universidade de Santiago de Compostela, Centro Nacional de Genotipado (CeGen-PRB2-ISCIII), CIBERER, 15782 Santiago de Compostela, Spain.
Inés
I
Quintela
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Brenda M
BM
Birmann
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester LE2 7LX, UK.
Sandrine
S
Jayne
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.
Wendy
W
Cozen
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester LE2 7LX, UK.
Aneela
A
Majid
Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Hematology Center, Karolinsak University Hospital, Stockholm 17176, Sweden.
Karin E
KE
Smedby
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Qing
Q
Lan
The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.
Claire
C
Dearden
Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z1L3.|Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia V5A1S6, Canada.
Angela R
AR
Brooks-Wilson
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Andrew G
AG
Hall
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Mark P
MP
Purdue
Haematological Sciences, Medical School, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK.
Tryfonia
T
Mainou-Fowler
Centre for Big Data Research in Health, University of New South Wales, Sydney, New South Wales 2052, Australia.
Claire M
0000-0002-3612-8298
CM
Vajdic
Department of Haematology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
Graham H
GH
Jackson
Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Monserrato, Cagliari 09042, Italy.
Pierluigi
P
Cocco
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Helen
H
Marr
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut 06520, USA.
Yawei
Y
Zhang
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut 06520, USA.
Tongzhang
T
Zheng
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.
Graham G
GG
Giles
Westat, Rockville, Maryland 20850, USA.
Charles
C
Lawrence
Division of Hematology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Timothy G
TG
Call
Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Mark
M
Liebow
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.
Mads
M
Melbye
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75105 Uppsala, Sweden.
Bengt
B
Glimelius
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75105 Uppsala, Sweden.
Larry
L
Mansouri
Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
Martha
M
Glenn
Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
Karen
K
Curtin
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA.
W Ryan
WR
Diver
Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
Brian K
BK
Link
Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
Lucia
L
Conde
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94118, USA.
Paige M
PM
Bracci
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94118, USA.
Elizabeth A
EA
Holly
Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, Ohio 43210, USA.
Rebecca D
RD
Jackson
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98117, USA.
Lesley F
LF
Tinker
Cancer Epidemiology Research Programme, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona 08908, Spain.|CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona 08036, Spain.
Yolanda
Y
Benavente
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Paolo
P
Boffetta
International Agency for Research on Cancer, Lyon 69372, France.
Paul
P
Brennan
Registre des Hémopathies Malignes de Côte d'Or, University of Burgundy and Dijon University Hospital, Dijon 21070, France.
Marc
M
Maynadie
International Agency for Research on Cancer, Lyon 69372, France.
James
J
McKay
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Demetrius
D
Albanes
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Stephanie
S
Weinstein
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Zhaoming
Z
Wang
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Neil E
NE
Caporaso
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Lindsay M
LM
Morton
Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan 48201, USA.
Richard K
RK
Severson
School of Public Health, Imperial College London, London W2 1PG, UK.
Elio
E
Riboli
MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.|Human Genetics Foundation, 10126 Turin, Italy.
Paolo
P
Vineis
Institute for Risk Assessment Sciences, Utrecht University, Utrecht 3508 TD, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
Roel C H
RC
Vermeulen
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
Melissa C
MC
Southey
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.
Roger L
0000-0001-5764-7268
RL
Milne
Epidemiology of Childhood and Adolescent Cancers Group, Inserm, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), Paris F-94807, France.|Université Paris Descartes, 75270 Paris, France.
Jacqueline
J
Clavel
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Sabine
S
Topka
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.
John J
JJ
Spinelli
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.|Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
Peter
P
Kraft
Department of Biomedical Science, University of Cagliari, Monserrato, Cagliari 09042, Italy.
Maria Grazia
MG
Ennas
Department of Haematology, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK.
Geoffrey
G
Summerfield
Interdisciplinary Department of Medicine, University of Bari, Bari 70124, Italy.
Giovanni M
GM
Ferri
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK.
Robert J
RJ
Harris
Environmental and Occupational Epidemiology Unit, Cancer Prevention and Research Institute (ISPO), Florence 50139, Italy.
Lucia
L
Miligi
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK.
Andrew R
AR
Pettitt
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.
Kari E
KE
North
Queens Centre for Haematology and Oncology, Castle Hill Hospital, Hull and East Yorkshire NHS Trust, Cottingham HU16 5JQ, UK.
David J
0000-0001-6159-6109
DJ
Allsup
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Joseph F
JF
Fraumeni
Queens Centre for Haematology and Oncology, Castle Hill Hospital, Hull and East Yorkshire NHS Trust, Cottingham HU16 5JQ, UK.
James R
JR
Bailey
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Kenneth
K
Offit
Department of Haematology, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK.
Guy
G
Pratt
Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, 2300 Copenhagen, Denmark.
Henrik
H
Hjalgrim
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Chris
C
Pepper
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Stephen J
SJ
Chanock
Cardiff and Vale National Health Service Trust, Heath Park, Cardiff CF14 4XW, UK.
Chris
C
Fegan
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75105 Uppsala, Sweden.
Richard
R
Rosenquist
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|International Agency for Research on Cancer, Lyon 69372, France.
Silvia
S
de Sanjose
Grupo de Medicina Xenomica, Universidade de Santiago de Compostela, Centro Nacional de Genotipado (CeGen-PRB2-ISCIII), CIBERER, 15782 Santiago de Compostela, Spain.|Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, KSA.
Angel
A
Carracedo
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester LE2 7LX, UK.
Martin J S
MJ
Dyer
Division of Molecular Pathology, The Institute of Cancer Research, London SW7 3RP, UK.
Daniel
D
Catovsky
Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Hospital Clínic, Barcelona 08036, Spain.|Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona 08036, Spain.
Elias
0000-0001-9850-9793
E
Campo
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
James R
JR
Cerhan
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
James M
JM
Allan
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Nathanial
N
Rothman
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
Richard
R
Houlston
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
Susan
S
Slager
D000328:Adult; D000917:Antibody Formation / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult