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 M 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

Abstract

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 (US)
JournalLeukemia
DOIs
StateAccepted/In press - 2022

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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