Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Wei Yu Lin; Sarah E. Fordham; Eric Hungate; Nicola J. Sunter; Claire Elstob; Yaobo Xu; Catherine Park; Anne Quante; Konstantin Strauch; Christian Gieger; Andrew Skol; Thahira Rahman; Lara Sucheston-Campbell; Junke Wang; Theresa Hahn; Alyssa I. Clay-Gilmour; Gail L. Jones; Helen J. Marr; Graham H. Jackson; Tobias Menne; Mathew Collin; Adam Ivey; Robert K. Hills; Alan K. Burnett; Nigel H. Russell; Jude Fitzgibbon; Richard A. Larson; Michelle M. Le Beau; Wendy Stock; Olaf Heidenreich; Abrar Alharbi; David J. Allsup; Richard S. Houlston; Jean Norden; Anne M. Dickinson; Elisabeth Douglas; Clare Lendrem; Ann K. Daly; Louise Palm; Kim Piechocki; Sally Jeffries; Martin Bornhäuser; Christoph Röllig; Heidi Altmann; Leo Ruhnke; Desiree Kunadt; Lisa Wagenführ; Heather J. Cordell; Rebecca Darlay; Mette K. Andersen; Maria C. Fontana; Giovanni Martinelli; Giovani Marconi; Miguel A. Sanz; José Cervera; Inés Gómez-Seguí; Thomas Cluzeau; Chimène Moreilhon; Sophie Raynaud; Heinz Sill; Maria Teresa Voso; Francesco Lo-Coco; Hervé Dombret; Meyling Cheok; Claude Preudhomme; Rosemary E. Gale; David Linch; Julia Gaal-Wesinger; Andras Masszi; Daniel Nowak; Wolf Karsten Hofmann; Amanda Gilkes; Kimmo Porkka; Jelena D. Milosevic Feenstra; Robert Kralovics; David Grimwade; Manja Meggendorfer; Torsten Haferlach; Szilvia Krizsán; Csaba Bödör; Friedrich Stölzel; Kenan Onel; James M. Allan

doi:10.1038/s41467-021-26551-x

Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Wei Yu Lin, Sarah E. Fordham, Eric Hungate, Nicola J. Sunter, Claire Elstob, Yaobo Xu, Catherine Park, Anne Quante, Konstantin Strauch, Christian Gieger, Andrew Skol, Thahira Rahman, Lara Sucheston-Campbell, Junke Wang, Theresa Hahn, Alyssa I. Clay-Gilmour, Gail L. Jones, Helen J. Marr, Graham H. Jackson, Tobias MenneMathew Collin, Adam Ivey, Robert K. Hills, Alan K. Burnett, Nigel H. Russell, Jude Fitzgibbon, Richard A. Larson, Michelle M. Le Beau, Wendy Stock, Olaf Heidenreich, Abrar Alharbi, David J. Allsup, Richard S. Houlston, Jean Norden, Anne M. Dickinson, Elisabeth Douglas, Clare Lendrem, Ann K. Daly, Louise Palm, Kim Piechocki, Sally Jeffries, Martin Bornhäuser, Christoph Röllig, Heidi Altmann, Leo Ruhnke, Desiree Kunadt, Lisa Wagenführ, Heather J. Cordell, Rebecca Darlay, Mette K. Andersen, Maria C. Fontana, Giovanni Martinelli, Giovani Marconi, Miguel A. Sanz, José Cervera, Inés Gómez-Seguí, Thomas Cluzeau, Chimène Moreilhon, Sophie Raynaud, Heinz Sill, Maria Teresa Voso, Francesco Lo-Coco, Hervé Dombret, Meyling Cheok, Claude Preudhomme, Rosemary E. Gale, David Linch, Julia Gaal-Wesinger, Andras Masszi, Daniel Nowak, Wolf Karsten Hofmann, Amanda Gilkes, Kimmo Porkka, Jelena D. Milosevic Feenstra, Robert Kralovics, David Grimwade, Manja Meggendorfer, Torsten Haferlach, Szilvia Krizsán, Csaba Bödör, Friedrich Stölzel, Kenan Onel, James M. Allan^*

^*Corresponding author for this work

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

19 Citations (Scopus)

Abstract

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10⁻⁸; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10⁻¹⁰; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

Original language	English
Article number	6233
Number of pages	1
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26551-x
Publication status	Published - 1 Oct 2021

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10.1038/s41467-021-26551-x

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Lin, W. Y., Fordham, S. E., Hungate, E., Sunter, N. J., Elstob, C., Xu, Y., Park, C., Quante, A., Strauch, K., Gieger, C., Skol, A., Rahman, T., Sucheston-Campbell, L., Wang, J., Hahn, T., Clay-Gilmour, A. I., Jones, G. L., Marr, H. J., Jackson, G. H., ... Allan, J. M. (2021). Genome-wide association study identifies susceptibility loci for acute myeloid leukemia. Nature Communications, 12(1), Article 6233. https://doi.org/10.1038/s41467-021-26551-x

@article{e01329c10d0b49259d45a53d45ef85a6,

title = "Genome-wide association study identifies susceptibility loci for acute myeloid leukemia",

abstract = "Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).",

author = "Lin, {Wei Yu} and Fordham, {Sarah E.} and Eric Hungate and Sunter, {Nicola J.} and Claire Elstob and Yaobo Xu and Catherine Park and Anne Quante and Konstantin Strauch and Christian Gieger and Andrew Skol and Thahira Rahman and Lara Sucheston-Campbell and Junke Wang and Theresa Hahn and Clay-Gilmour, {Alyssa I.} and Jones, {Gail L.} and Marr, {Helen J.} and Jackson, {Graham H.} and Tobias Menne and Mathew Collin and Adam Ivey and Hills, {Robert K.} and Burnett, {Alan K.} and Russell, {Nigel H.} and Jude Fitzgibbon and Larson, {Richard A.} and {Le Beau}, {Michelle M.} and Wendy Stock and Olaf Heidenreich and Abrar Alharbi and Allsup, {David J.} and Houlston, {Richard S.} and Jean Norden and Dickinson, {Anne M.} and Elisabeth Douglas and Clare Lendrem and Daly, {Ann K.} and Louise Palm and Kim Piechocki and Sally Jeffries and Martin Bornh{\"a}user and Christoph R{\"o}llig and Heidi Altmann and Leo Ruhnke and Desiree Kunadt and Lisa Wagenf{\"u}hr and Cordell, {Heather J.} and Rebecca Darlay and Andersen, {Mette K.} and Fontana, {Maria C.} and Giovanni Martinelli and Giovani Marconi and Sanz, {Miguel A.} and Jos{\'e} Cervera and In{\'e}s G{\'o}mez-Segu{\'i} and Thomas Cluzeau and Chim{\`e}ne Moreilhon and Sophie Raynaud and Heinz Sill and Voso, {Maria Teresa} and Francesco Lo-Coco and Herv{\'e} Dombret and Meyling Cheok and Claude Preudhomme and Gale, {Rosemary E.} and David Linch and Julia Gaal-Wesinger and Andras Masszi and Daniel Nowak and Hofmann, {Wolf Karsten} and Amanda Gilkes and Kimmo Porkka and {Milosevic Feenstra}, {Jelena D.} and Robert Kralovics and David Grimwade and Manja Meggendorfer and Torsten Haferlach and Szilvia Krizs{\'a}n and Csaba B{\"o}d{\"o}r and Friedrich St{\"o}lzel and Kenan Onel and Allan, {James M.}",

note = "Funding Information: This work was funded by Blood Cancer UK (to JMA; #06002 and #13044). The Hungarian AML study was funded by the Hungarian National Research, Development and Innovation Office (NKFIH) (NVKP_16-1-2016-0004), a Momentum grant (LP-95021) from the Hungarian Academy of Sciences and EU{\textquoteright}s Horizon 2020 research and innovation program under grant agreement No. 739593. The KORA study was initiated and financed by the Helmholtz Zentrum M{\"u}nchen—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universit{\"a}t, as part of LMUinnovativ. The recruitment of cases via the Catholic University of Rome was funded by Progetto AIRC 5permille Mynerva. DN is an endowed Professor of the Deutsche Jose Carreras Leukaemie Stiftung (DJCLS H 03/01) and is funded by the H.W. & J. Hector fund, Baden Wuerttemberg and the Dr. Rolf M. Schwiete Fund, Mannheim. MM is employed by the Munich Leukemia Laboratory and TH is part owner of the Munich Leukemia Laboratory. We are grateful to the Newcastle University Biobank (https://www.ncl.ac.uk/biobanks/) for providing samples. Funding Information: Collection of patient samples and associated clinico-pathological information was undertaken with written informed consent. All studies were conducted in accordance with the Declaration of Helsinki and received local institutional review board or national research ethics approval (Supplementary Table 9). Specifically, this research has been conducted using the UK Biobank Resource (Application #16583, James Allan). MRC/NCRI AML 11 trial, AML 12 trial and the UK Leukaemia Research Fund (LLR) population-based case–control study of adult acute leukemia received multicenter research ethics committee approval54,55,75. Research ethics committee approval was given to the Newcastle Haematology Biobank (07/H0906/109 + 5) and the AML genome-wide association study in the UK (06/q1108/92, BH136664 (7078)). AML cases and controls for Samples from the Hungarian AML patients were obtained during the standard diagnostic workup at the Hematology Divisions of the 1st and 3rd Department of Internal Medicine, Semmelweis University, Budapest, following ethical approval from the Local Ethical Committee (REF TUKEB-1552012) and the Hungarian Medical Research Council (REF 45371-2/2016/EKU). Saliva and fibroblast samples from Austrian AML patients were collected at the Division of Hematology, Medical University of Graz, Graz, Austria76. The diagnosis of AML was made in accordance with World Health Organisation guidelines. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = oct,

day = "1",

doi = "10.1038/s41467-021-26551-x",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Lin, WY, Fordham, SE, Hungate, E, Sunter, NJ, Elstob, C, Xu, Y, Park, C, Quante, A, Strauch, K, Gieger, C, Skol, A, Rahman, T, Sucheston-Campbell, L, Wang, J, Hahn, T, Clay-Gilmour, AI, Jones, GL, Marr, HJ, Jackson, GH, Menne, T, Collin, M, Ivey, A, Hills, RK, Burnett, AK, Russell, NH, Fitzgibbon, J, Larson, RA, Le Beau, MM, Stock, W, Heidenreich, O, Alharbi, A, Allsup, DJ, Houlston, RS, Norden, J, Dickinson, AM, Douglas, E, Lendrem, C, Daly, AK, Palm, L, Piechocki, K, Jeffries, S, Bornhäuser, M, Röllig, C, Altmann, H, Ruhnke, L, Kunadt, D, Wagenführ, L, Cordell, HJ, Darlay, R, Andersen, MK, Fontana, MC, Martinelli, G, Marconi, G, Sanz, MA, Cervera, J, Gómez-Seguí, I, Cluzeau, T, Moreilhon, C, Raynaud, S, Sill, H, Voso, MT, Lo-Coco, F, Dombret, H, Cheok, M, Preudhomme, C, Gale, RE, Linch, D, Gaal-Wesinger, J, Masszi, A, Nowak, D, Hofmann, WK, Gilkes, A, Porkka, K, Milosevic Feenstra, JD, Kralovics, R, Grimwade, D, Meggendorfer, M, Haferlach, T, Krizsán, S, Bödör, C, Stölzel, F, Onel, K & Allan, JM 2021, 'Genome-wide association study identifies susceptibility loci for acute myeloid leukemia', Nature Communications, vol. 12, no. 1, 6233. https://doi.org/10.1038/s41467-021-26551-x

TY - JOUR

T1 - Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

AU - Lin, Wei Yu

AU - Fordham, Sarah E.

AU - Hungate, Eric

AU - Sunter, Nicola J.

AU - Elstob, Claire

AU - Xu, Yaobo

AU - Park, Catherine

AU - Quante, Anne

AU - Strauch, Konstantin

AU - Gieger, Christian

AU - Skol, Andrew

AU - Rahman, Thahira

AU - Sucheston-Campbell, Lara

AU - Wang, Junke

AU - Hahn, Theresa

AU - Clay-Gilmour, Alyssa I.

AU - Jones, Gail L.

AU - Marr, Helen J.

AU - Jackson, Graham H.

AU - Menne, Tobias

AU - Collin, Mathew

AU - Ivey, Adam

AU - Hills, Robert K.

AU - Burnett, Alan K.

AU - Russell, Nigel H.

AU - Fitzgibbon, Jude

AU - Larson, Richard A.

AU - Le Beau, Michelle M.

AU - Stock, Wendy

AU - Heidenreich, Olaf

AU - Alharbi, Abrar

AU - Allsup, David J.

AU - Houlston, Richard S.

AU - Norden, Jean

AU - Dickinson, Anne M.

AU - Douglas, Elisabeth

AU - Lendrem, Clare

AU - Daly, Ann K.

AU - Palm, Louise

AU - Piechocki, Kim

AU - Jeffries, Sally

AU - Bornhäuser, Martin

AU - Röllig, Christoph

AU - Altmann, Heidi

AU - Ruhnke, Leo

AU - Kunadt, Desiree

AU - Wagenführ, Lisa

AU - Cordell, Heather J.

AU - Darlay, Rebecca

AU - Andersen, Mette K.

AU - Fontana, Maria C.

AU - Martinelli, Giovanni

AU - Marconi, Giovani

AU - Sanz, Miguel A.

AU - Cervera, José

AU - Gómez-Seguí, Inés

AU - Cluzeau, Thomas

AU - Moreilhon, Chimène

AU - Raynaud, Sophie

AU - Sill, Heinz

AU - Voso, Maria Teresa

AU - Lo-Coco, Francesco

AU - Dombret, Hervé

AU - Cheok, Meyling

AU - Preudhomme, Claude

AU - Gale, Rosemary E.

AU - Linch, David

AU - Gaal-Wesinger, Julia

AU - Masszi, Andras

AU - Nowak, Daniel

AU - Hofmann, Wolf Karsten

AU - Gilkes, Amanda

AU - Porkka, Kimmo

AU - Milosevic Feenstra, Jelena D.

AU - Kralovics, Robert

AU - Grimwade, David

AU - Meggendorfer, Manja

AU - Haferlach, Torsten

AU - Krizsán, Szilvia

AU - Bödör, Csaba

AU - Stölzel, Friedrich

AU - Onel, Kenan

AU - Allan, James M.

N1 - Funding Information: This work was funded by Blood Cancer UK (to JMA; #06002 and #13044). The Hungarian AML study was funded by the Hungarian National Research, Development and Innovation Office (NKFIH) (NVKP_16-1-2016-0004), a Momentum grant (LP-95021) from the Hungarian Academy of Sciences and EU’s Horizon 2020 research and innovation program under grant agreement No. 739593. The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The recruitment of cases via the Catholic University of Rome was funded by Progetto AIRC 5permille Mynerva. DN is an endowed Professor of the Deutsche Jose Carreras Leukaemie Stiftung (DJCLS H 03/01) and is funded by the H.W. & J. Hector fund, Baden Wuerttemberg and the Dr. Rolf M. Schwiete Fund, Mannheim. MM is employed by the Munich Leukemia Laboratory and TH is part owner of the Munich Leukemia Laboratory. We are grateful to the Newcastle University Biobank (https://www.ncl.ac.uk/biobanks/) for providing samples. Funding Information: Collection of patient samples and associated clinico-pathological information was undertaken with written informed consent. All studies were conducted in accordance with the Declaration of Helsinki and received local institutional review board or national research ethics approval (Supplementary Table 9). Specifically, this research has been conducted using the UK Biobank Resource (Application #16583, James Allan). MRC/NCRI AML 11 trial, AML 12 trial and the UK Leukaemia Research Fund (LLR) population-based case–control study of adult acute leukemia received multicenter research ethics committee approval54,55,75. Research ethics committee approval was given to the Newcastle Haematology Biobank (07/H0906/109 + 5) and the AML genome-wide association study in the UK (06/q1108/92, BH136664 (7078)). AML cases and controls for Samples from the Hungarian AML patients were obtained during the standard diagnostic workup at the Hematology Divisions of the 1st and 3rd Department of Internal Medicine, Semmelweis University, Budapest, following ethical approval from the Local Ethical Committee (REF TUKEB-1552012) and the Hungarian Medical Research Council (REF 45371-2/2016/EKU). Saliva and fibroblast samples from Austrian AML patients were collected at the Division of Hematology, Medical University of Graz, Graz, Austria76. The diagnosis of AML was made in accordance with World Health Organisation guidelines. Publisher Copyright: © 2021, The Author(s).

PY - 2021/10/1

Y1 - 2021/10/1

N2 - Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

AB - Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

UR - http://www.scopus.com/inward/record.url?scp=85118442520&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-26551-x

DO - 10.1038/s41467-021-26551-x

M3 - Article

AN - SCOPUS:85118442520

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6233

ER -

Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

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