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Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology
By
Erik L. Bao,
Satish K Nandakumar,
Xiaotian Liao,
Alexander G Bick,
Juha Karjalainen,
Marcin Tabaka,
Olga I Gan,
Aki Havulinna,
Tuomo Kiiskinen,
Caleb A. Lareau,
Aitzkoa L de Lapuente Portilla,
Bo Li,
Connor Emdin,
Veryan Codd,
Christopher P Nelson,
Pradeep Natarajan,
Claire Churchhouse,
23andMe Research Team,
Björn Nilsson,
Peter WF Wilson,
Kelly Cho,
Saiju Pyarajan,
J. Michael Gaziano,
Nilesh J. Samani,
Million Veteran Program,
Aviv Regev,
Aarno Palotie,
Benjamin Neale,
John E Dick,
Christopher J. O’Donnell,
Mark Daly,
Michael Milyavsky,
Sekar Kathiresan,
Vijay G. Sankaran
Posted 08 Oct 2019
bioRxiv DOI: 10.1101/790626
Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells that result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs). While substantial progress has been made to define the causal somatic mutation profile for MPNs, epidemiologic studies indicate a significant heritable component for the disease that is among the highest known for all cancers. However, only a limited set of genetic risk loci have been identified, and the underlying biological mechanisms leading to MPN acquisition remain unexplained. Here, to define the inherited risk profile, we conducted the largest genome-wide association study of MPNs to date (978,913 individuals with 3,224 cases) and identified 14 genome-wide significant loci, as well as a polygenic signature that increases the odds for disease acquisition by nearly 3-fold between the top and median deciles. Interestingly, we find a shared genetic architecture between MPN risk and several hematopoietic traits spanning distinct lineages, as well as an association between increased MPN risk and longer leukocyte telomere length, collectively implicating HSC function and self-renewal. Strikingly, we find a significant enrichment for risk variants mapping to accessible chromatin in HSCs compared with other hematopoietic populations. Finally, gene mapping identifies modulators of HSC biology and targeted variant-to-function analyses 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 MPN risk through modulation of HSC function.
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