AIM: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk. METHODS: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis. RESULTS: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. CONCLUSION: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

Basic Science Program Frederick National Laboratory for Cancer Research in the Laboratory of Integrative Cancer Immunology National Cancer Institute Bethesda MD 20892 USA

Bill Lyons Informatics Centre UCL Cancer Institute University College London London WC1E 6DD UK

Cancer Control Research BC Cancer Agency Vancouver British Columbia V5Z1L3 Canada

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria 3004 Australia

Cancer Epidemiology Research Programme Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona 08908 Spain

Cancer Epidemiology Unit University of Oxford Oxford OX3 7LF UK

Cancer Genomics Research Laboratory Division of Cancer Epidemiology and Genetics National Cancer Institute Gaithersburg MD 20877 USA

Carolina Center for Genome Sciences University of North Carolina at Chapel Hill Chapel Hill NC 27599 USA

Center for Chronic Immunodeficiency University Medical Center Freiburg Freiburg Baden Württemberg 79108 Germany

Center of Research in Epidemiology and Statistics Sorbonne Paris Cité UMR1153 INSERM Villejuif 75004 France

Centre for Big Data Research in Health University of New South Wales Sydney New South Wales 2052 Australia

Centre for Epidemiology and Biostatistics School of Population and Global Health The University of Melbourne Melbourne Victoria 3010 Australia

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA 02115 USA

Concord Clinical School University of Sydney Concord New South Wales 2139 Australia

Consortium for Biomedical Research in Epidemiology and Public Health Barcelona 08036 Spain

Departamento de Biologia Geral Instituto de Ciências Biológicas Universidade Federal de Minas Gerais Belo Horizonte 31270 901 Brazil

Department of Biomedical Physiology and Kinesiology Simon Fraser University Burnaby British Columbia V5A1S6 Canada

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno 656 53 Czech Republic

Department of Environmental Health Sciences Yale School of Public Health New Haven CT 06520 USA

Department of Epidemiology and Biostatistics University of California San Francisco San Francisco CA 94118 USA

Department of Epidemiology Brown University Providence RI 02903 USA

Department of Epidemiology Harvard T H Chan School of Public Health Boston MA 02115 USA

Department of Epidemiology Research Division of Health Surveillance and Research Statens Serum Institut Copenhagen 2300 Denmark

Department of Epidemiology University of North Carolina at Chapel Hill Chapel Hill NC 27599 USA

Department of Family Medicine and Public Health Sciences Wayne State University Detroit MI 48201 USA

Department of Health Sciences Research Mayo Clinic Rochester MN 55905 USA

Department of Health Sciences University of York York YO10 5DD UK

Department of Hematology and Medical Oncology Emory University School of Medicine Atlanta GA 30322 USA

Department of Hematology Centre Léon Bérard Lyon 69008 France

Department of Hematology Hospices Civils de Lyon Pierre Benite Cedex 69495 France

Department of Hematology Université Lyon 1 Pierre Benite Cedex 69495 France

Department of Immunology Genetics and Pathology Uppsala University Uppsala 75105 Sweden

Department of Internal Medicine and Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City UT 84112 USA

Department of Internal Medicine Carver College of Medicine The University of Iowa Iowa City IA 52242 USA

Department of Internal Medicine Mayo Clinic Rochester MN 55905 USA

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

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm 17176 Sweden

Department of Medicine Memorial Sloan Kettering Cancer Center New York NY 10065 USA

Department of Medicine Solna Karolinska Institutet Stockholm 17176 Sweden

Department of Medicine Stanford University School of Medicine Stanford CA 94305 USA

Department of Obstetrics and Gynecology New York University School of Medicine New York NY 10016 USA

Department of Pathology AP HP Necker Enfants Malades Université Paris Descartes EA 7324 Sorbonne Paris Cité 75015 France

Department of Population Health New York University School of Medicine New York NY 10016 USA

Department of Population Science American Cancer Society Atlanta GA 30303 USA

Department of Preventive Medicine USC Keck School of Medicine University of Southern California Los Angeles CA 90033 USA

Department of Public Health Clinical and Molecular Medicine University of Cagliari Monserrato Cagliari 09042 Italy

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD 20892 USA

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Baden Württemberg 69120 Germany

Division of Endocrinology Diabetes and Metabolism The Ohio State University Columbus OH 43210 USA

Division of Health Analytics City of Hope Beckman Research Institute Duarte CA 91010 USA

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA 98117 USA

Environmental and Occupational Epidemiology Branch Cancer Risk Factors and Lifestyle Epidemiology Unit Institute for Cancer Research Prevention and Clinical Network Florence 50139 Italy

Genetic Epidemiology Laboratory Department of Pathology University of Melbourne Melbourne Victoria 3010 Australia

Genome Sciences Centre BC Cancer Agency Vancouver British Columbia V5Z1L3 Canada

Genomic Epidemiology Group German Cancer Research Center Heidelberg 69120 Germany

Hematology Center Karolinska University Hospital Stockholm 17176 Sweden

INSERM U1052 Cancer Research Center of Lyon Centre Léon Bérard Lyon 69008 France

INSERM U1052 Cancer Research Center of Lyon Lyon 1 University Pierre Bénite Cedex 69008 France

Institute for Risk Assessment Sciences Utrecht University Utrecht 3584 CG The Netherlands

Institute of Health and Society Clinical Effectiveness Research Group University of Oslo Oslo 0315 Norway

International Agency for Research on Cancer Lyon 69372 France

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht 3584 CX The Netherlands

Norris Comprehensive Cancer Center USC Keck School of Medicine University of Southern California Los Angeles CA 90033 USA

Perlmutter Comprehensive Cancer Center NYU Langone Health New York NY 10016 USA

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton Victoria 3800 Australia

Ragon Institute of MGH Cambridge MA 02139 USA

Regional Cancer Prevention Laboratory Institute for Cancer Research Prevention and Clinical Network Florence 50139 Italy

Registre des Hémopathies Malignes de la Gironde Institut Bergonié Bordeaux Cedex 33076 France

School of Nursing Psychotherapy and Community Health Dublin City University Dublin 9 Ireland

School of Population and Public Health University of British Columbia Vancouver British Columbia V6T1Z3 Canada

School of Public Health Imperial College London London W2 1PG UK

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

U1231 Registre des Hémopathies Malignes de Côte d'Or University of Burgundy and Dijon University Hospital Dijon 21070 France

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