Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

William Tapper, Amy V. Jones, Robert Kralovics, Ashot S. Harutyunyan, Katerina Zoi, William Leung, Anna L. Godfrey, Paola Guglielmelli, Alison Callaway, Daniel Ward, Paula Aranaz, Helen E. White, Katherine Waghorn, Feng Lin, Andrew Chase, E. Joanna Baxter, Cathy MacLean, Jyoti Nangalia, Edwin Chen, Paul EvansMichael Short, Andrew Jack, Louise Wallis, David Oscier, Andrew S. Duncombe, Anna Schuh, Adam J. Mead, Michael Griffiths, Joanne Ewing, Rosemary E. Gale, Susanne Schnittger, Torsten Haferlach, Frank Stegelmann, Konstanze Döhner, Harald Grallert, Konstantin Strauch, Toshiko Tanaka, Stefania Bandinelli, Andreas Giannopoulos, Lisa Pieri, Carmela Mannarelli, Heinz Gisslinger, Giovanni Barosi, Mario Cazzola, Andreas Reiter, Claire Harrison, Peter Campbell, Anthony R. Green, Alessandro Vannucchi, Nicholas C P Cross

Research output: Contribution to journalArticlepeer-review


Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F -negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10-10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10-9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10-7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic x2 P=7.3 × 10-7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.

Original languageEnglish
Article number6691
JournalNature Communications
Publication statusPublished - Apr 13 2015

ASJC Scopus subject areas

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


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