title: Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms.
abstract: We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n = 1223) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line JAK2 46/1 haplotype (rs59384377: odds ratio [OR] = 2.4, P = 6.6 × 10(-89)), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR = 1.8, P = 1.1 × 10(-32)), in SH2B3 (rs7310615: OR = 1.4, P = 3.1 × 10(-14)), and upstream of TET2 (rs1548483: OR = 2.0, P = 2.0 × 10(-9)). These associations were confirmed in a separate replication cohort of 446 V617F carriers vs 169 021 noncarriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B All SNP ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.
authors.affiliation: 23andMe, Inc, Mountain View, CA;
authors.forename: David A
authors.initials: DA
authors.lastname: Hinds
authors.affiliation: 23andMe, Inc, Mountain View, CA;
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Barnholt
authors.affiliation: Division of Hematology & Medical Oncology, Mayo Clinic, Scottsdale, AZ;
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
authors.affiliation: 23andMe, Inc, Mountain View, CA;
authors.forename: Amy K
authors.initials: AK
authors.lastname: Kiefer
authors.affiliation: 23andMe, Inc, Mountain View, CA;
authors.forename: Chuong B
authors.initials: CB
authors.lastname: Do
authors.affiliation: 23andMe, Inc, Mountain View, CA;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Eriksson
authors.affiliation: 23andMe, Inc, Mountain View, CA;
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Mountain
authors.affiliation: 23andMe, Inc, Mountain View, CA;
authors.forename: Uta
authors.initials: U
authors.lastname: Francke
authors.affiliation: 23andMe, Inc, Mountain View, CA;
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Tung
authors.affiliation: Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
authors.forename: Huong Marie
authors.initials: HM
authors.lastname: Nguyen
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Haiyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Linda
authors.initials: L
authors.lastname: Gojenola
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA; and Division of Hematology, Department of Medicine, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA.
authors.forename: James L
authors.initials: JL
authors.lastname: Zehnder
authors.affiliation: Division of Hematology, Department of Medicine, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003710:Demography; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005854:Germ Cells / Q000378:metabolism*; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D007223:Infant; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2