Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10-8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10-9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10-8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

Bill Lyons Informatics Centre UCL Cancer Institute University College London London United Kingdom

Cancer Control Research BC Cancer Agency Vancouver BC Canada

Cancer Epidemiology Division Cancer Council Victoria Melbourne VC Australia

Cancer Epidemiology Program University of Hawaii Cancer Center Honolulu HI USA

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

Cancer Epidemiology Unit University of Oxford Oxford United Kingdom

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

Cancer Prevention Institute of California Fremont CA USA

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

Center for Cancer Research National Cancer Institute Frederick MA USA

Center for Health Sciences Exponent Inc Menlo Park CA USA

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

Centre for Occupational and Environmental Health Division of Population Science Health Services Research and Primary Care University of Manchester Manchester United Kingdom

Centre Henri Becquerel Université de Rouen Rouen France

Centre Hospitalier de Versailles Le Chesnay France

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

Chao Family Comprehensive Cancer Center University of California Irvine Irvine CA USA

CIBER de Epidemiología y Salud Pública Barcelona Spain

CIRI Centre International de Recherche en Infectiologie Team Lymphoma Immuno Biology Univ Lyon Inserm U1111 Université Claude Bernard Lyon 1 CNRS UMR5308 ENS de Lyon Lyon France

Concord Clinical School University of Sydney Concord NSW Australia

CPO Piemonte and Unit of Medical Statistics and Epidemiology Department Translational Medicine University of Piemonte Orientale Novara Italy

CRESS UMR1153 INSERM Villejuif France

Danish Cancer Society Research Center Copenhagen Denmark

Danish Cancer Society Research Center Danish Cancer Society Copenhagen Denmark

Department of Biomedical Physiology and Kinesiology Simon Fraser University Burnaby BC Canada

Department of Biostatistics Bloomberg School of Public Health Johns Hopkins University Baltimore MA USA

Department of Biostatistics Harvard T H Chan School of Public Health Boston MA USA

Department of Biostatistics Yale School of Public Health New Haven CT USA

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Clinical Pathology Melbourne Medical School The University of Melbourne VC 3010 Australia

Department of Environmental Health Sciences Yale School of Public Health New Haven CT USA

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

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

Department of Epidemiology and Cancer Control St Jude Children's Research Hospital Memphis TN USA

Department of Epidemiology Brown University Providence RI USA

Department of Epidemiology Harvard T H Chan School of Public Health Boston MA USA

Department of Epidemiology MD Anderson Cancer Center Houston TX USA

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

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

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

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

Department of Genetics Stanford University Medical School Stanford CA USA

Department of Haematology Rigshospitalet Copenhagen Denmark

Department of Health Sciences Research Mayo Clinic Rochester MN USA

Department of Health Sciences University of York York United Kingdom

Department of Hematology and Medical Oncology Emory University School of Medicine Atlanta GA USA

Department of Hematology Hospices Civils de Lyon Lyon Sud Hospital Pierre Benite France

Department of Histopathology Douglass Hanly Moir Pathology Sydney NSW Australia

Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Department of Internal Medicine and Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City UT USA

Department of Internal Medicine Carver College of Medicine The University of Iowa Iowa City IA USA

Department of Internal Medicine Mayo Clinic Rochester MN USA

Department of Medical and Surgical Sciences University of Bologna Bologna 41026 Italy

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Oncology Dana Farber Cancer Institute Harvard Medical School Boston MA USA

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

Department of Medicine Solna Karolinska Institutet Stockholm Sweden

Department of Medicine Stanford University School of Medicine Stanford CA USA

Department of Medicine University of British Columbia Vancouver BC Canada

Department of Oncology School of Medicine Johns Hopkins University Baltimore MA USA

Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen Groningen The Netherlands

Department of Pathology APHP Necker and Robert Debré Université Paris Cité Institut Imagine INSERM U1163 Paris France

Department of Pathology University of Alabama at Birmingham Birmingham AL USA

Department of Population and Public Health Sciences USC Keck School of Medicine University of Southern California Los Angeles CA USA

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

Department of Population Science American Cancer Society Atlanta GA USA

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

Department of Public Health Sciences University of Chicago Chicago IL USA

Department of Quantitative Health Sciences Mayo Clinic Rochester MN USA

Departments of Laboratory Medicine and Pathology Memorial Sloan Kettering Cancer Center New York NY USA

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda Md USA

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

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

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

Division of General Internal Medicine Department of Medicine Institute of Human Genetics Helen Diller Family Comprehensive Cancer Center University of California San Francisco San Francisco CA USA

Division of Health Analytics City of Hope Beckman Research Institute Duarte CA USA

Division of Public Health Sciences Department of Surgery Washington University School of Medicine St Louis MO USA

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

Donald and Barbara Zucker School of Medicine Hofstra Northwell Hempstead New York NY USA

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

F Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute Cedars Sinai Medical Center Los Angeles CA USA

Faculty of Medicine and Health Sciences Macquarie University Sydney NSW Australia

Genome Sciences Centre BC Cancer Agency Vancouver BC Canada

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

Hematology Center Karolinska University Hospital Stockholm Sweden

Human Genetics Foundation Turin Italy

Information Systems and Decision Sciences California State University Fullerton Fullerton CA USA

INSERM U1052 Cancer Research Center of Lyon Centre Léon Bérard Lyon France

INSERM U1231 EA 4184 Registre des Hémopathies Malignes de Côte d'Or University of Burgundy and Dijon University Hospital Dijon France

Institute for Immunodeficiency University Medical Center Freiburg Freiburg Germany

Institute for Risk Assessment Sciences Utrecht University Utrecht The Netherlands

Institute of Health and Society Clinical Effectiveness Research Group University of Oslo Oslo Norway

International Agency for Research on Cancer Lyon France

Jebsen Center for Genetic epidemiology NTNU Trondheim Norway

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

Laboratory of Translational Genomics Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Leukemia Bone Marrow Transplantation Program BC Cancer Agency Vancouver BC Canada

Lymphoid Malignancies Unit Henri Mondor Hospital and University Paris Est Créteil France

MRC PHE Centre for Environment and Health School of Public Health Imperial College London London United Kingdom

MRC University of Glasgow Centre for Virus Research Glasgow United Kingdom

Perlmutter Cancer Center NYU Langone Medical Center New York NY USA

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton VC Australia

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

School of Nursing Psychotherapy and Community Health Dublin City University Dublin Ireland

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

School of Public Health Imperial College London London United Kingdom

School of Public Health University of Haifa Haifa Israel

Stanford Cancer Institute Stanford CA USA

Stony Brook Cancer Center Stony Brook University Stony Brook New York 11794 NY USA

Sydney School of Public Health The University of Sydney Sydney NSW Australia

The Kirby Institute University of New South Wales Sydney NSW Australia

Université de Paris Cité Villejuif France

Université Paris Saclay UVSQ Inserm Équipe Exposome et Hérédité CESP Villejuif France

Westat Rockville MA USA

Erratum v

Leukemia. 2023 Oct;37(10):2142. doi: 10.1038/s41375-023-01978-x. PubMed

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