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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  JAK2  V617F -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  JAK2  V617F -positive cases. rs9376092 has a stronger effect in  JAK2  V617F -negative cases with  CALR  and/or  MPL  mutations (Breslow–Day  P =4.5 × 10 −7 ), whereas in  JAK2  V617F -positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic  χ  2   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.

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