Genetic Heritability of Common Non-Hodgkin Lymphoma Subtypes. S. I. Berndt1, L. M. Morton1, S. S. Wang2, L. R. Teras3, S. L. Slager4, J. Vijai5, K. Smedby6, G. M. Ferri7, L. Miligi8, C. Magnani7, D. Albanes1, A. R. Brooks-Wilson9, E. Roman10, A. Monnereau11, P. Vineis12, A. Nieters13, B. M. Birmann14, G. G. Giles15, M. P. Purdue1, B. K. Link16, C. M. Vajdic17, A. Zeleniuch-Jacquotte18, C. F. Skibola19, Y. Zhang20, J. R. Cerhan4, Z. Wang1, N. Rothman1, S. J. Chanock1, J. Sampson1 on behalf of the NHL GWAS Project 1) Division of Cancer Epidemiology & Genetics, National Cancer Institute, Rockville, MD, USA; 2) Department of Cancer Etiology, City of Hope Beckman Research Institute, Duarte, CA, USA; 3) Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA; 4) Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA; 5) Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; 6) Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 7) Interdisciplinary Department of Medicine, University of Bari, Policlinico - Piazza G. Cesare 11, Bari, Italy; 8) Environmental and Occupational Epidemiology Unit, Cancer Prevention and Research Institute (ISPO), Via delle Oblate 2, Florence, Italy; 9) Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada; 10) Department of Health Sciences, University of York, York, United Kingdom; 11) Environmental epidemiology of Cancer Group, Inserm, Centre for research in Epidemiology and Population Health (CESP), U1018, Villejuif, France; 12) Human Genetics Foundation, Turin, Italy; 13) Center of Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany; 14) Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; 15) Cancer Epidemiology Centre, Cancer Council Victoria, Carlton, Victoria, Australia; 16) Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA; 17) Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia; 18) Department of Population Health, New York University School of Medicine, New York, New York, USA; 19) Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, Birmingham, Alabama, USA; 20) Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA.

   Non-Hodgkin lymphoma (NHL) is comprised of multiple subtypes with distinct morphologic and clinical features. Although these subtypes are hypothesized to be etiologically distinct and common variants for specific subtypes have been identified, no studies have comprehensively evaluated the contribution of common genetic variants to the heritability of individual subtypes. We, therefore, used genome-wide association data from a large, multicenter study of the four most common subtypes of NHL to estimate the contribution of common SNPs to the heritability of NHL. Participants were genotyped using the Illumina OmniExpress, and data were available from 2,179 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 2,142 cases of follicular lymphoma (FL), 2,661 cases of diffuse large B-cell lymphoma (DLBCL), 825 cases of marginal zone lymphoma (MZL) and 6,221 controls of European ancestry. We utilized genome-wide complex trait analysis (GCTA) to estimate the proportion of phenotypic variance explained on a liability scale and to estimate the shared heritability between subtypes, adjusting for age, sex, study, and principal components. The proportion of variance explained for the four NHL subtypes combined was estimated to be 11.9% (95% CI: 8-17%) with substantial heterogeneity among NHL subtypes: 35.5% (95% CI: 24-50%) for CLL/SLL, 20.8% (95% CI: 12-32%) for FL, 10.4% (95% CI: 4-18%) for DLBCL, and 8.3% (95% CI: 0-23%) for MZL. Small but non-significant differences were observed by sex for the individual subtypes. Although the precision in the estimates was limited, an examination of the shared heritability between subtypes showed modest genetic correlations ranging from 0.20-0.86. FL and DLBCL, for example, showed a genetic correlation of 0.57 (0.28). Exclusion of the HLA region, did not substantially affect the estimates for the individual subtypes or the shared heritability observed between subtypes, suggesting that the HLA region captures only a small portion of the variance explained. Overall, this study indicates that although there is some shared heritability across NHL subtypes, the genetic architecture of individual NHL subtypes is distinct and consideration of NHL subtypes is essential for discovering new variants associated with susceptibility.

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