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

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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 & 63 more 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

Original languageEnglish
Article number6233
Number of pages1
JournalNature Communications
Volume12
Issue number1
DOIs
Published1 Oct 2021

Bibliographical 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’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).

King's Authors

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).

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