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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.

Original publication




Journal article


Nat Commun

Publication Date





Adult, Aged, Alleles, Calreticulin, Case-Control Studies, Cohort Studies, DNA-Binding Proteins, Female, GTP-Binding Proteins, Gene Frequency, Genes, myb, Genetic Predisposition to Disease, Genetic Variation, Genotype, HSP70 Heat-Shock Proteins, Humans, Janus Kinase 2, MDS1 and EVI1 Complex Locus Protein, Male, Middle Aged, Mutation, Myeloproliferative Disorders, Peptide Elongation Factors, Polycythemia Vera, Polymorphism, Single Nucleotide, Proto-Oncogenes, Receptors, Thrombopoietin, Telomerase, Thrombocythemia, Essential, Transcription Factors