Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Sonja I. Berndt, Joseph Vijai, Yolanda Benavente, Nicola J. Camp, Alexandra Nieters, Zhaoming Wang, Karin E. Smedby, Geffen Kleinstern, Henrik Hjalgrim, Caroline Besson, Christine F. Skibola, Lindsay M. Morton, Angela R. Brooks-Wilson, Lauren R. Teras, Charles Breeze, Joshua Arias, Hans Olov Adami, Demetrius Albanes, Kenneth C. Anderson, Stephen M. AnsellBryan Bassig, Nikolaus Becker, Parveen Bhatti, Brenda M. Birmann, Paolo Boffetta, Paige M. Bracci, Paul Brennan, Elizabeth E. Brown, Laurie Burdett, Lisa A. Cannon-Albright, Ellen T. Chang, Brian C.H. Chiu, Charles C. Chung, Jacqueline Clavel, Pierluigi Cocco, Graham Colditz, Lucia Conde, David V. Conti, David G. Cox, Karen Curtin, Delphine Casabonne, Immaculata De Vivo, W. Ryan Diver, Ahmet Dogan, Christopher K. Edlund, Lenka Foretova, Joseph F. Fraumeni, Attilio Gabbas, Hervé Ghesquières, Graham G. Giles, Sally Glaser, Martha Glenn, Bengt Glimelius, Jian Gu, Thomas M. Habermann, Christopher A. Haiman, Corinne Haioun, Jonathan N. Hofmann, Theodore R. Holford, Elizabeth A. Holly, Amy Hutchinson, Aalin Izhar, Rebecca D. Jackson, Ruth F. Jarrett, Rudolph Kaaks, Eleanor Kane, Laurence N. Kolonel, Yinfei Kong, Peter Kraft, Anne Kricker, Annette Lake, Qing Lan, Charles Lawrence, Dalin Li, Mark Liebow, Brian K. Link, Corrado Magnani, Marc Maynadie, James McKay, Mads Melbye, Lucia Miligi, Roger L. Milne, Thierry J. Molina, Alain Monnereau, Rebecca Montalvan, Kari E. North, Anne J. Novak, Kenan Onel, Mark P. Purdue, Kristin A. Rand, Elio Riboli, Jacques Riby, Eve Roman, Gilles Salles, Douglas W. Sborov, Richard K. Severson, Tait D. Shanafelt, Martyn T. Smith, Alexandra Smith, Kevin W. Song, Lei Song, Melissa C. Southey, John J. Spinelli, Anthony Staines, Deborah Stephens, Heather J. Sutherland, Kaitlyn Tkachuk, Carrie A. Thompson, Hervé Tilly, Lesley F. Tinker, Ruth C. Travis, Jenny Turner, Celine M. Vachon, Claire M. Vajdic, Anke Van Den Berg, David J. Van Den Berg, Roel C.H. Vermeulen, Paolo Vineis, Sophia S. Wang, Elisabete Weiderpass, George J. Weiner, Stephanie Weinstein, Nicole Wong Doo, Yuanqing Ye, Meredith Yeager, Kai Yu, Anne Zeleniuch-Jacquotte, Yawei Zhang, Tongzhang Zheng, Elad Ziv, Joshua Sampson, Nilanjan Chatterjee, Kenneth Offit, Wendy Cozen, Xifeng Wu, James R. Cerhan, Stephen J. Chanock, Susan L. Slager, Nathaniel Rothman

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Number of pages10
Issue number12
StatePublished - Dec 2022

Bibliographical note

Funding Information:
TS received research support to his institution from Genetech, Pharacyclics, AbbVie, Cephalon, Hospira, GlaxoSmithKline, Polyphenon E International, Merck, and Celgene and holds a patent (US14/292,075) on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia. KS received research funding from Janssen Pharmaceuticals AB for research unrelated to this project. CH received honoraria from Novartis, Amgen, Servier/Pfizer, and Gilead Sciences, acted as a consultant or advisor to Roche, Celgene, Janssen-Cilag, Gilead Sciences, Takeda, Miltenyi Biotec, Abbvie, and ADC Therapeutics, and received travel, accommodations and/or expenses from Roche, Celgene, and Amgen. KO is currently a full-time employee at Sema4. TH is on the data monitoring boards for Seagen and Tessa Therapeutics, scientific advisory boards for Eli Lilly, Morpohsys, Incyte, Biegene, and Loxo Oncology, and received research support from Genentech and Sorrento Therapeutics. The other authors declare no competing interests.

Funding Information:
This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. The authors thank Mr. William Wheeler (Information Management Services, Inc.) for his analytic support. A complete list of funding sources and acknowledgements for individual studies is listed in the Supplementary Material.

Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.


  • Humans
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Risk Factors
  • Lymphoma, Non-Hodgkin/genetics
  • Germ Cells
  • Case-Control Studies
  • Polymorphism, Single Nucleotide

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research


Dive into the research topics of 'Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes'. Together they form a unique fingerprint.

Cite this