Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Philip J. Law; Sonja I. Berndt; Helen E. Speedy; Nicola J. Camp; Georgina P. Sava; Christine F. Skibola; Amy Holroyd; Vijai Joseph; Nicola J. Sunter; Alexandra Nieters; Silvia Bea; Alain Monnereau; David Martin-Garcia; Lynn R. Goldin; Guillem Clot; Lauren R. Teras; Inés Quintela; Brenda M. Birmann; Sandrine Jayne; Wendy Cozen; Aneela Majid; Karin E. Smedby; Qing Lan; Claire Dearden; Angela R. Brooks-Wilson; Andrew G. Hall; Mark P. Purdue; Tryfonia Mainou-Fowler; Claire M. Vajdic; Graham H. Jackson; Pierluigi Cocco; Helen Marr; Yawei Zhang; Tongzhang Zheng; Graham G. Giles; Charles Lawrence; Timothy G. Call; Mark Liebow; Mads Melbye; Bengt Glimelius; Larry Mansouri; Martha Glenn; Karen Curtin; W. Ryan Diver; Brian K. Link; Lucia Conde; Paige M. Bracci; Elizabeth A. Holly; Rebecca D. Jackson; Lesley F. Tinker; Yolanda Benavente; Paolo Boffetta; Paul Brennan; Marc Maynadie; James McKay; Demetrius Albanes; Stephanie Weinstein; Zhaoming Wang; Neil E. Caporaso; Lindsay M. Morton; Richard K. Severson; Elio Riboli; Paolo Vineis; Roel C.H. Vermeulen; Melissa C. Southey; Roger L. Milne; Jacqueline Clavel; Sabine Topka; John J. Spinelli; Peter Kraft; Maria Grazia Ennas; Geoffrey Summerfield; Giovanni M. Ferri; Robert J. Harris; Lucia Miligi; Andrew R. Pettitt; Kari E. North; David J. Allsup; Joseph F. Fraumeni; James R. Bailey; Kenneth Offit; Guy Pratt; Henrik Hjalgrim; Chris Pepper; Stephen J. Chanock; Chris Fegan; Richard Rosenquist; Silvia De Sanjose; Angel Carracedo; Martin J.S. Dyer; Daniel Catovsky; Elias Campo; James R. Cerhan; James M. Allan; Nathanial Rothman; Richard Houlston; Susan Slager

doi:10.1038/ncomms14175

Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Philip J. Law, Sonja I. Berndt, Helen E. Speedy, Nicola J. Camp, Georgina P. Sava, Christine F. Skibola, Amy Holroyd, Vijai Joseph, Nicola J. Sunter, Alexandra Nieters, Silvia Bea, Alain Monnereau, David Martin-Garcia, Lynn R. Goldin, Guillem Clot, Lauren R. Teras, Inés Quintela, Brenda M. Birmann, Sandrine Jayne, Wendy CozenAneela Majid, Karin E. Smedby, Qing Lan, Claire Dearden, Angela R. Brooks-Wilson, Andrew G. Hall, Mark P. Purdue, Tryfonia Mainou-Fowler, Claire M. Vajdic, Graham H. Jackson, Pierluigi Cocco, Helen Marr, Yawei Zhang, Tongzhang Zheng, Graham G. Giles, Charles Lawrence, Timothy G. Call, Mark Liebow, Mads Melbye, Bengt Glimelius, Larry Mansouri, Martha Glenn, Karen Curtin, W. Ryan Diver, Brian K. Link, Lucia Conde, Paige M. Bracci, Elizabeth A. Holly, Rebecca D. Jackson, Lesley F. Tinker, Yolanda Benavente, Paolo Boffetta, Paul Brennan, Marc Maynadie, James McKay, Demetrius Albanes, Stephanie Weinstein, Zhaoming Wang, Neil E. Caporaso, Lindsay M. Morton, Richard K. Severson, Elio Riboli, Paolo Vineis, Roel C.H. Vermeulen, Melissa C. Southey, Roger L. Milne, Jacqueline Clavel, Sabine Topka, John J. Spinelli, Peter Kraft, Maria Grazia Ennas, Geoffrey Summerfield, Giovanni M. Ferri, Robert J. Harris, Lucia Miligi, Andrew R. Pettitt, Kari E. North, David J. Allsup, Joseph F. Fraumeni, James R. Bailey, Kenneth Offit, Guy Pratt, Henrik Hjalgrim, Chris Pepper, Stephen J. Chanock, Chris Fegan, Richard Rosenquist, Silvia De Sanjose, Angel Carracedo, Martin J.S. Dyer, Daniel Catovsky, Elias Campo, James R. Cerhan, James M. Allan, Nathanial Rothman, Richard Houlston, Susan Slager

Research output: Contribution to journal › Article › peer-review

70 Scopus citations

Abstract

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.

Original language	English
Article number	14175
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14175
State	Published - 6 Feb 2017

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10.1038/ncomms14175

Cite this

Law, P. J., Berndt, S. I., Speedy, H. E., Camp, N. J., Sava, G. P., Skibola, C. F., Holroyd, A., Joseph, V., Sunter, N. J., Nieters, A., Bea, S., Monnereau, A., Martin-Garcia, D., Goldin, L. R., Clot, G., Teras, L. R., Quintela, I., Birmann, B. M., Jayne, S., ... Slager, S. (2017). Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia. Nature Communications, 8, Article 14175. https://doi.org/10.1038/ncomms14175

@article{6ba625af149c4a339300b59069d4571d,

title = "Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia",

abstract = "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.",

author = "Law, {Philip J.} and Berndt, {Sonja I.} and Speedy, {Helen E.} and Camp, {Nicola J.} and Sava, {Georgina P.} and Skibola, {Christine F.} and Amy Holroyd and Vijai Joseph and Sunter, {Nicola J.} and Alexandra Nieters and Silvia Bea and Alain Monnereau and David Martin-Garcia and Goldin, {Lynn R.} and Guillem Clot and Teras, {Lauren R.} and In{\'e}s Quintela and Birmann, {Brenda M.} and Sandrine Jayne and Wendy Cozen and Aneela Majid and Smedby, {Karin E.} and Qing Lan and Claire Dearden and Brooks-Wilson, {Angela R.} and Hall, {Andrew G.} and Purdue, {Mark P.} and Tryfonia Mainou-Fowler and Vajdic, {Claire M.} and Jackson, {Graham H.} and Pierluigi Cocco and Helen Marr and Yawei Zhang and Tongzhang Zheng and Giles, {Graham G.} and Charles Lawrence and Call, {Timothy G.} and Mark Liebow and Mads Melbye and Bengt Glimelius and Larry Mansouri and Martha Glenn and Karen Curtin and Diver, {W. Ryan} and Link, {Brian K.} and Lucia Conde and Bracci, {Paige M.} and Holly, {Elizabeth A.} and Jackson, {Rebecca D.} and Tinker, {Lesley F.} and Yolanda Benavente and Paolo Boffetta and Paul Brennan and Marc Maynadie and James McKay and Demetrius Albanes and Stephanie Weinstein and Zhaoming Wang and Caporaso, {Neil E.} and Morton, {Lindsay M.} and Severson, {Richard K.} and Elio Riboli and Paolo Vineis and Vermeulen, {Roel C.H.} and Southey, {Melissa C.} and Milne, {Roger L.} and Jacqueline Clavel and Sabine Topka and Spinelli, {John J.} and Peter Kraft and Ennas, {Maria Grazia} and Geoffrey Summerfield and Ferri, {Giovanni M.} and Harris, {Robert J.} and Lucia Miligi and Pettitt, {Andrew R.} and North, {Kari E.} and Allsup, {David J.} and Fraumeni, {Joseph F.} and Bailey, {James R.} and Kenneth Offit and Guy Pratt and Henrik Hjalgrim and Chris Pepper and Chanock, {Stephen J.} and Chris Fegan and Richard Rosenquist and {De Sanjose}, Silvia and Angel Carracedo and Dyer, {Martin J.S.} and Daniel Catovsky and Elias Campo and Cerhan, {James R.} and Allan, {James M.} and Nathanial Rothman and Richard Houlston and Susan Slager",

note = "Funding Information: In the United Kingdom, Bloodwise provided funding for the study (LRF05001, LRF06002 and LRF13044) with additional support from Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and the Arbib Fund. G.P.S. is in receipt of a PhD studentship from The Institute of Cancer Research. The NCI/InterLymph NHL GWAS initiative was supported by the intramural programme of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health. ATBC-This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. In addition, this research was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services. BC-Canadian Institutes for Health Research (CIHR); Canadian Cancer Society; Michael Smith Foundation for Health Research. CPS-II-The Cancer Prevention Study-II (CPS-II) Nutrition Cohort is supported by the American Cancer Society. Genotyping for all CPS-II samples was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. We also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. ELCCS-Leukemia and Lymphoma Research. ENGELA-Association pour la Recherche contre le Cancer (ARC), Institut National du Cancer (INCa), Fondation de France, Fondation contre la Leucemie, Agence nationale de securite sanitaire de l'alimentation, de l'environnement et du travail (ANSES). EPIC-Coordinated Action (Contract #006438, SP23-CT-2005-006438); HuGeF (Human Genetics Foundation), Torino, Italy; Cancer Research UK. EpiLymph- European Commission (grant references QLK4-CT-2000-00422 and FOOD-CT-2006- 023103); the Spanish Ministry of Health (grant references CIBERESP, PI11/01810, PI14/01219, RCESP C03/09, RTICESP C03/10 and RTIC RD06/0020/0095), the Marato de TV3 Foundation (grant reference 051210), the Agencia de Gestiod'AjutsUniversitarisi de Recerca-Generalitat de Catalunya (grant reference 2014SRG756), who had no role in the data collection, analysis or interpretation of the results; the NIH (contract NO1- CO-12400); the Compagnia di San Paolo-Programma Oncologia; the Federal Office for Radiation Protection grants StSch4261 and StSch4420, the Jose Carreras Leukemia Foundation grant DJCLS-R12/23, the German Federal Ministry for Education and Research (BMBF-01-EO-1303); the Health Research Board, Ireland, and Cancer Research Ireland; Czech Republic supported by MH CZ-DRO (MMCI, 00209805) and RECAMO, CZ.1.05/2.1.00/03.0101; Fondation de France and Association de Recherche Contre le Cancer. GEC/Mayo GWAS-National Institutes of Health (CA118444, CA148690, CA92153). Intramural Research Program of the NIH, National Cancer Institute. Veterans Affairs Research Service. Data collection for Duke University was supported by a Leukemia and Lymphoma Society Career Development Award, the Bernstein Family Fund for Leukemia and Lymphoma Research and the National Institutes of Health (K08CA134919), National Center for Advancing Translational Science (UL1 TR000135). HPFS-The HPFS was supported in part by National Institutes of Health grants CA167552, CA149445 and CA098122. We would like to thank the participants and staff of the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. We assume full responsibility for analyses and interpretation of these data. Iowa-Mayo SPORE-NCI Specialized Programs of Research Excellence (SPORE) in Human Cancer (P50 CA97274); National Cancer Institute (P30 CA086862, P30 CA15083); Henry J. Predolin Foundation. Italian GxE-Italian Association for Cancer Research (AIRC, Investigator Grant 11855; PC); Fondazione Banco di Sardegna 2010-2012 and Regione Autonoma della Sardegna (LR7 CRP-59812/2012; MGE). Mayo Clinic Case-Control-National Institutes of Health (R01 CA92153); National Cancer Institute (P30 CA015083). MCCS-The Melbourne Collaborative Cohort Study recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR). MD Anderson-Institutional support to the Center for Translational and Public Health Genomics. MSKCC-Geoffrey Beene Cancer Research Grant, Lymphoma Foundation (LF5541); Barbara K. Lipman Lymphoma Research Fund (74419); Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative (57470); U01 HG007033; ENCODE; U01 HG007033. R21 CA178800. NCI-SEER-Intramural Research Program of the National Cancer Institute, National Institutes of Health and Public Health Service (N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105). NHS-The NHS was supported in part by National Institutes of Health grants CA186107, CA87969, CA49449, CA149445 and CA098122. We would like to thank the participants and staff of the Nurses' Health Study for their valuable contributions as well as the following state cancer registries for their help: A.L., A.Z., A.R., C.A., C.O., C.T., D.E., F.L., G.A., I.D., I.L., I.N., I.A., K.Y., L.A., M.E., M.D., M.A., M.I., N.E., N.H., N.J., N.Y., N.C., N.D., O.H., O.K., O.R., P.A., R.I., S.C., T.N., T.X., V.A., W.A. and W.Y. The authors assume full responsibility for analyses and interpretation of these data. NSW-NSW was supported by grants from the Australian National Health and Medical Research Council (ID990920), the Cancer Council NSW and the University of Sydney Faculty of Medicine. NYU-WHS-National Cancer Institute (R01 CA098661, P30 CA016087); National Institute of Environmental Health Sciences (ES000260). PLCO-This research was supported by the Intramural Research Program of the National Cancer Institute and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. SCALE-Swedish Cancer Society (2009/659). Stockholm County Council (20110209) and the Strategic Research Program in Epidemiology at Karolinska Institute. Swedish Cancer Society grant (02 6661). National Institutes of Health (5R01 CA69669-02); Plan Denmark. UCSF2-The UCSF studies were supported by the NCI, National Institutes of Health, CA1046282, CA154643, CA45614, CA89745, CA87014. The collection of cancer incidence data used in this study was supported by the California Department of Health Services as part of the statewide cancer reporting programme mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement #1U58 DP000807-01 awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the authors, and endorsement by the State of California, the California Department of Health Services, the National Cancer Institute or the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended nor should be inferred. Utah-National Institutes of Health CA134674. Partial support for data collection at the Utah site was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all data sets within the UPDB is provided by the Huntsman Cancer Institute (HCI) and the HCI Comprehensive Cancer Center Support grant, P30 CA42014. The UCR is supported in part by NIH contract HHSN261201000026C from the National Cancer Institute SEER Program with additional support from the Utah State Department of Health and the University of Utah. WHI-WHI investigators are: Program Office (National Heart, Lung, and Blood Institute, Bethesda, Maryland)- Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford and Nancy Geller; Clinical Coordinating Center (Fred Hutchinson Cancer Research Center, Seattle, WA)-Garnet Anderson, Ross Prentice, Andrea LaCroix and Charles Kooperberg; Investigators and Academic Centers (Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA)-JoAnn E. Manson; (MedStar Health Research Institute/ Howard University, Washington, DC, USA) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA, USA) Marcia L. Stefanick (The Ohio State University, Columbus, OH, USA); Rebecca Jackson (University of Arizona, Tucson/Phoenix, AZ, USA); Cynthia A. Thomson; (University at Buffalo, Buffalo, NY, USA); Jean Wactawski- Wende (University of Florida, Gainesville/Jacksonville, FL, USA); Marian Limacher (University of Iowa, Iowa City/Davenport, IA, USA); Robert Wallace (University of Pittsburgh, Pittsburgh, PA, USA); Lewis Kuller (Wake Forest University School of Medicine, Winston-Salem, NC, USA); Sally Shumaker WHI Memory Study (Wake Forest University School of Medicine, Winston-Salem, NC, USA) Sally Shumaker. The WHI programme is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. YALE- National Cancer Institute (CA62006); National Cancer Institute (CA165923). The Spanish replication study was supported by the Spanish Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III (FIS PI13/01136; International Cancer Genome Consortium-Chronic Lymphocytic Leukemia Genome Project). We thank L. Padyukov (Karolinska Institutet) and the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) group for providing control samples from the Swedish population for the Swedish replication study. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available in www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. We are grateful to all investigators and all the patients and individuals for their participation. We also thank the clinicians, other hospital staff and study staff that contributed to the blood sample and data collection for this study",

year = "2017",

month = feb,

day = "6",

doi = "10.1038/ncomms14175",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Law, PJ, Berndt, SI, Speedy, HE, Camp, NJ, Sava, GP, Skibola, CF, Holroyd, A, Joseph, V, Sunter, NJ, Nieters, A, Bea, S, Monnereau, A, Martin-Garcia, D, Goldin, LR, Clot, G, Teras, LR, Quintela, I, Birmann, BM, Jayne, S, Cozen, W, Majid, A, Smedby, KE, Lan, Q, Dearden, C, Brooks-Wilson, AR, Hall, AG, Purdue, MP, Mainou-Fowler, T, Vajdic, CM, Jackson, GH, Cocco, P, Marr, H, Zhang, Y, Zheng, T, Giles, GG, Lawrence, C, Call, TG, Liebow, M, Melbye, M, Glimelius, B, Mansouri, L, Glenn, M, Curtin, K, Diver, WR, Link, BK, Conde, L, Bracci, PM, Holly, EA, Jackson, RD, Tinker, LF, Benavente, Y, Boffetta, P, Brennan, P, Maynadie, M, McKay, J, Albanes, D, Weinstein, S, Wang, Z, Caporaso, NE, Morton, LM, Severson, RK, Riboli, E, Vineis, P, Vermeulen, RCH, Southey, MC, Milne, RL, Clavel, J, Topka, S, Spinelli, JJ, Kraft, P, Ennas, MG, Summerfield, G, Ferri, GM, Harris, RJ, Miligi, L, Pettitt, AR, North, KE, Allsup, DJ, Fraumeni, JF, Bailey, JR, Offit, K, Pratt, G, Hjalgrim, H, Pepper, C, Chanock, SJ, Fegan, C, Rosenquist, R, De Sanjose, S, Carracedo, A, Dyer, MJS, Catovsky, D, Campo, E, Cerhan, JR, Allan, JM, Rothman, N, Houlston, R & Slager, S 2017, 'Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia', Nature Communications, vol. 8, 14175. https://doi.org/10.1038/ncomms14175

TY - JOUR

T1 - Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

AU - Law, Philip J.

AU - Berndt, Sonja I.

AU - Speedy, Helen E.

AU - Camp, Nicola J.

AU - Sava, Georgina P.

AU - Skibola, Christine F.

AU - Holroyd, Amy

AU - Joseph, Vijai

AU - Sunter, Nicola J.

AU - Nieters, Alexandra

AU - Bea, Silvia

AU - Monnereau, Alain

AU - Martin-Garcia, David

AU - Goldin, Lynn R.

AU - Clot, Guillem

AU - Teras, Lauren R.

AU - Quintela, Inés

AU - Birmann, Brenda M.

AU - Jayne, Sandrine

AU - Cozen, Wendy

AU - Majid, Aneela

AU - Smedby, Karin E.

AU - Lan, Qing

AU - Dearden, Claire

AU - Brooks-Wilson, Angela R.

AU - Hall, Andrew G.

AU - Purdue, Mark P.

AU - Mainou-Fowler, Tryfonia

AU - Vajdic, Claire M.

AU - Jackson, Graham H.

AU - Cocco, Pierluigi

AU - Marr, Helen

AU - Zhang, Yawei

AU - Zheng, Tongzhang

AU - Giles, Graham G.

AU - Lawrence, Charles

AU - Call, Timothy G.

AU - Liebow, Mark

AU - Melbye, Mads

AU - Glimelius, Bengt

AU - Mansouri, Larry

AU - Glenn, Martha

AU - Curtin, Karen

AU - Diver, W. Ryan

AU - Link, Brian K.

AU - Conde, Lucia

AU - Bracci, Paige M.

AU - Holly, Elizabeth A.

AU - Jackson, Rebecca D.

AU - Tinker, Lesley F.

AU - Benavente, Yolanda

AU - Boffetta, Paolo

AU - Brennan, Paul

AU - Maynadie, Marc

AU - McKay, James

AU - Albanes, Demetrius

AU - Weinstein, Stephanie

AU - Wang, Zhaoming

AU - Caporaso, Neil E.

AU - Morton, Lindsay M.

AU - Severson, Richard K.

AU - Riboli, Elio

AU - Vineis, Paolo

AU - Vermeulen, Roel C.H.

AU - Southey, Melissa C.

AU - Milne, Roger L.

AU - Clavel, Jacqueline

AU - Topka, Sabine

AU - Spinelli, John J.

AU - Kraft, Peter

AU - Ennas, Maria Grazia

AU - Summerfield, Geoffrey

AU - Ferri, Giovanni M.

AU - Harris, Robert J.

AU - Miligi, Lucia

AU - Pettitt, Andrew R.

AU - North, Kari E.

AU - Allsup, David J.

AU - Fraumeni, Joseph F.

AU - Bailey, James R.

AU - Offit, Kenneth

AU - Pratt, Guy

AU - Hjalgrim, Henrik

AU - Pepper, Chris

AU - Chanock, Stephen J.

AU - Fegan, Chris

AU - Rosenquist, Richard

AU - De Sanjose, Silvia

AU - Carracedo, Angel

AU - Dyer, Martin J.S.

AU - Catovsky, Daniel

AU - Campo, Elias

AU - Cerhan, James R.

AU - Allan, James M.

AU - Rothman, Nathanial

AU - Houlston, Richard

AU - Slager, Susan

N1 - Funding Information: In the United Kingdom, Bloodwise provided funding for the study (LRF05001, LRF06002 and LRF13044) with additional support from Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and the Arbib Fund. G.P.S. is in receipt of a PhD studentship from The Institute of Cancer Research. The NCI/InterLymph NHL GWAS initiative was supported by the intramural programme of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health. ATBC-This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. In addition, this research was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services. BC-Canadian Institutes for Health Research (CIHR); Canadian Cancer Society; Michael Smith Foundation for Health Research. CPS-II-The Cancer Prevention Study-II (CPS-II) Nutrition Cohort is supported by the American Cancer Society. Genotyping for all CPS-II samples was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. We also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. ELCCS-Leukemia and Lymphoma Research. ENGELA-Association pour la Recherche contre le Cancer (ARC), Institut National du Cancer (INCa), Fondation de France, Fondation contre la Leucemie, Agence nationale de securite sanitaire de l'alimentation, de l'environnement et du travail (ANSES). EPIC-Coordinated Action (Contract #006438, SP23-CT-2005-006438); HuGeF (Human Genetics Foundation), Torino, Italy; Cancer Research UK. EpiLymph- European Commission (grant references QLK4-CT-2000-00422 and FOOD-CT-2006- 023103); the Spanish Ministry of Health (grant references CIBERESP, PI11/01810, PI14/01219, RCESP C03/09, RTICESP C03/10 and RTIC RD06/0020/0095), the Marato de TV3 Foundation (grant reference 051210), the Agencia de Gestiod'AjutsUniversitarisi de Recerca-Generalitat de Catalunya (grant reference 2014SRG756), who had no role in the data collection, analysis or interpretation of the results; the NIH (contract NO1- CO-12400); the Compagnia di San Paolo-Programma Oncologia; the Federal Office for Radiation Protection grants StSch4261 and StSch4420, the Jose Carreras Leukemia Foundation grant DJCLS-R12/23, the German Federal Ministry for Education and Research (BMBF-01-EO-1303); the Health Research Board, Ireland, and Cancer Research Ireland; Czech Republic supported by MH CZ-DRO (MMCI, 00209805) and RECAMO, CZ.1.05/2.1.00/03.0101; Fondation de France and Association de Recherche Contre le Cancer. GEC/Mayo GWAS-National Institutes of Health (CA118444, CA148690, CA92153). Intramural Research Program of the NIH, National Cancer Institute. Veterans Affairs Research Service. Data collection for Duke University was supported by a Leukemia and Lymphoma Society Career Development Award, the Bernstein Family Fund for Leukemia and Lymphoma Research and the National Institutes of Health (K08CA134919), National Center for Advancing Translational Science (UL1 TR000135). HPFS-The HPFS was supported in part by National Institutes of Health grants CA167552, CA149445 and CA098122. We would like to thank the participants and staff of the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. We assume full responsibility for analyses and interpretation of these data. Iowa-Mayo SPORE-NCI Specialized Programs of Research Excellence (SPORE) in Human Cancer (P50 CA97274); National Cancer Institute (P30 CA086862, P30 CA15083); Henry J. Predolin Foundation. Italian GxE-Italian Association for Cancer Research (AIRC, Investigator Grant 11855; PC); Fondazione Banco di Sardegna 2010-2012 and Regione Autonoma della Sardegna (LR7 CRP-59812/2012; MGE). Mayo Clinic Case-Control-National Institutes of Health (R01 CA92153); National Cancer Institute (P30 CA015083). MCCS-The Melbourne Collaborative Cohort Study recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR). MD Anderson-Institutional support to the Center for Translational and Public Health Genomics. MSKCC-Geoffrey Beene Cancer Research Grant, Lymphoma Foundation (LF5541); Barbara K. Lipman Lymphoma Research Fund (74419); Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative (57470); U01 HG007033; ENCODE; U01 HG007033. R21 CA178800. NCI-SEER-Intramural Research Program of the National Cancer Institute, National Institutes of Health and Public Health Service (N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105). NHS-The NHS was supported in part by National Institutes of Health grants CA186107, CA87969, CA49449, CA149445 and CA098122. We would like to thank the participants and staff of the Nurses' Health Study for their valuable contributions as well as the following state cancer registries for their help: A.L., A.Z., A.R., C.A., C.O., C.T., D.E., F.L., G.A., I.D., I.L., I.N., I.A., K.Y., L.A., M.E., M.D., M.A., M.I., N.E., N.H., N.J., N.Y., N.C., N.D., O.H., O.K., O.R., P.A., R.I., S.C., T.N., T.X., V.A., W.A. and W.Y. The authors assume full responsibility for analyses and interpretation of these data. NSW-NSW was supported by grants from the Australian National Health and Medical Research Council (ID990920), the Cancer Council NSW and the University of Sydney Faculty of Medicine. NYU-WHS-National Cancer Institute (R01 CA098661, P30 CA016087); National Institute of Environmental Health Sciences (ES000260). PLCO-This research was supported by the Intramural Research Program of the National Cancer Institute and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. SCALE-Swedish Cancer Society (2009/659). Stockholm County Council (20110209) and the Strategic Research Program in Epidemiology at Karolinska Institute. Swedish Cancer Society grant (02 6661). National Institutes of Health (5R01 CA69669-02); Plan Denmark. UCSF2-The UCSF studies were supported by the NCI, National Institutes of Health, CA1046282, CA154643, CA45614, CA89745, CA87014. The collection of cancer incidence data used in this study was supported by the California Department of Health Services as part of the statewide cancer reporting programme mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement #1U58 DP000807-01 awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the authors, and endorsement by the State of California, the California Department of Health Services, the National Cancer Institute or the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended nor should be inferred. Utah-National Institutes of Health CA134674. Partial support for data collection at the Utah site was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all data sets within the UPDB is provided by the Huntsman Cancer Institute (HCI) and the HCI Comprehensive Cancer Center Support grant, P30 CA42014. The UCR is supported in part by NIH contract HHSN261201000026C from the National Cancer Institute SEER Program with additional support from the Utah State Department of Health and the University of Utah. WHI-WHI investigators are: Program Office (National Heart, Lung, and Blood Institute, Bethesda, Maryland)- Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford and Nancy Geller; Clinical Coordinating Center (Fred Hutchinson Cancer Research Center, Seattle, WA)-Garnet Anderson, Ross Prentice, Andrea LaCroix and Charles Kooperberg; Investigators and Academic Centers (Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA)-JoAnn E. Manson; (MedStar Health Research Institute/ Howard University, Washington, DC, USA) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA, USA) Marcia L. Stefanick (The Ohio State University, Columbus, OH, USA); Rebecca Jackson (University of Arizona, Tucson/Phoenix, AZ, USA); Cynthia A. Thomson; (University at Buffalo, Buffalo, NY, USA); Jean Wactawski- Wende (University of Florida, Gainesville/Jacksonville, FL, USA); Marian Limacher (University of Iowa, Iowa City/Davenport, IA, USA); Robert Wallace (University of Pittsburgh, Pittsburgh, PA, USA); Lewis Kuller (Wake Forest University School of Medicine, Winston-Salem, NC, USA); Sally Shumaker WHI Memory Study (Wake Forest University School of Medicine, Winston-Salem, NC, USA) Sally Shumaker. The WHI programme is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. YALE- National Cancer Institute (CA62006); National Cancer Institute (CA165923). The Spanish replication study was supported by the Spanish Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III (FIS PI13/01136; International Cancer Genome Consortium-Chronic Lymphocytic Leukemia Genome Project). We thank L. Padyukov (Karolinska Institutet) and the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) group for providing control samples from the Swedish population for the Swedish replication study. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available in www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. We are grateful to all investigators and all the patients and individuals for their participation. We also thank the clinicians, other hospital staff and study staff that contributed to the blood sample and data collection for this study

PY - 2017/2/6

Y1 - 2017/2/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85012025522&partnerID=8YFLogxK

U2 - 10.1038/ncomms14175

DO - 10.1038/ncomms14175

M3 - Article

C2 - 28165464

AN - SCOPUS:85012025522

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 14175

ER -

Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

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