Inherited myeloproliferative neoplasm risk impacts hematopoietic stem cells

Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells, which result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs). Epidemiologic studies indicate a substantial disease heritability that is among the highest known for cancers(1). However, only a limited set of genetic risk loci have been identified, and the underlying biological mechanisms leading to MPN acquisition remain unexplained. Here, we conducted a large-scale genome-wide association study (3,797 cases and 1,152,977 controls) to identify 17 MPN risk loci (p < 5.0 × 10(−8)), seven of which have not been previously reported. We find a shared genetic architecture between MPN risk and several hematopoietic traits spanning distinct lineages, an enrichment for risk variants mapping to accessible chromatin in HSCs, and associations of increased MPN risk with longer leukocyte telomere length and other clonal hematopoietic states, collectively implicating HSC function and self-renewal. Gene mapping identifies modulators of HSC biology and targeted variant-to-function assays suggest likely roles for CHEK2 and GFI1B in altering HSC function to confer disease risk. Overall, we demonstrate the power of human genetic studies to illuminate a previously unappreciated mechanism for inherited MPN risk through modulation of HSC function.