Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia

Mary L. McMaster, Sonja I. Berndt, Jianqing Zhang, Susan L. Slager, Shengchao Alfred Li, Claire M. Vajdic, Karin E. Smedby, Huihuang Yan, Brenda M. Birmann, Elizabeth E. Brown, Alex Smith, Geffen Kleinstern, Mervin M. Fansler, Christine Mayr, Bin Zhu, Charles C. Chung, Ju Hyun Park, Laurie Burdette, Belynda D. Hicks, Amy HutchinsonLauren R. Teras, Hans Olov Adami, Paige M. Bracci, James McKay, Alain Monnereau, Brian K. Link, Roel C.H. Vermeulen, Stephen M. Ansell, Ann Maria, W. Ryan Diver, Mads Melbye, Akinyemi I. Ojesina, Peter Kraft, Paolo Boffetta, Jacqueline Clavel, Edward Giovannucci, Caroline M. Besson, Federico Canzian, Ruth C. Travis, Paolo Vineis, Elisabete Weiderpass, Rebecca Montalvan, Zhaoming Wang, Meredith Yeager, Nikolaus Becker, Yolanda Benavente, Paul Brennan, Lenka Foretova, Marc Maynadie, Alexandra Nieters, Silvia de Sanjose, Anthony Staines, Lucia Conde, Jacques Riby, Bengt Glimelius, Henrik Hjalgrim, Nisha Pradhan, Andrew L. Feldman, Anne J. Novak, Charles Lawrence, Bryan A. Bassig, Qing Lan, Tongzhang Zheng, Kari E. North, Lesley F. Tinker, Wendy Cozen, Richard K. Severson, Jonathan N. Hofmann, Yawei Zhang, Rebecca D. Jackson, Lindsay M. Morton, Mark P. Purdue, Nilanjan Chatterjee, Kenneth Offit, James R. Cerhan, Stephen J. Chanock, Nathaniel Rothman, Joseph Vijai, Lynn R. Goldin, Christine F. Skibola, Neil E. Caporaso

Research output: Contribution to journalArticlepeer-review

Abstract

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10−54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10−19). Both risk alleles are observed at a low frequency among controls (~2–3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.

Original languageEnglish
Article number4182
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2018
Externally publishedYes

Bibliographical note

Funding Information:
We wish to thank Seth A. Brodie, PhD, for his critical reading of the manuscript and his intellectual contributions to the functional experimental approach. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 03/07/2018. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. Further acknowledgements are provided in Supplementary Note 1.

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Physics and Astronomy (all)

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