TY - JOUR
T1 - Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells
AU - FinnGen
AU - 23andMe Research Team
AU - Bao, Erik L.
AU - Nandakumar, Satish K.
AU - Liao, Xiaotian
AU - Bick, Alexander G.
AU - Karjalainen, Juha
AU - Tabaka, Marcin
AU - Gan, Olga I.
AU - Havulinna, Aki S.
AU - Kiiskinen, Tuomo T.J.
AU - Lareau, Caleb A.
AU - de Lapuente Portilla, Aitzkoa L.
AU - Li, Bo
AU - Emdin, Connor
AU - Codd, Veryan
AU - Nelson, Christopher P.
AU - Walker, Christopher J.
AU - Churchhouse, Claire
AU - de la Chapelle, Albert
AU - Klein, Daryl E.
AU - Nilsson, Björn
AU - Wilson, Peter W.F.
AU - Cho, Kelly
AU - Partanen, Jukka
AU - Savinainen, Kimmo
AU - Kosma, Veli Matti
AU - Schleutker, Johanna
AU - Laaksonen, Reijo
AU - Peltola, Jukka
AU - Jussila, Airi
AU - Isomäki, Pia
AU - Laitinen, Tarja
AU - Kankaanranta, Hannu
AU - Kähönen, Mika
AU - Auranen, Annika
AU - Uusitalo, Hannu
AU - Uusitalo-Järvinen, Hannele
AU - Salmi, Teea
AU - Wahlfors, Tiina
AU - Mannermaa, Arto
AU - Kononen, Juha
AU - Laivuori, Hannele
AU - Shcherban, Anastasia
AU - Siirtola, Harri
AU - Tabuenca, Javier Gracia
N1 - Funding Information:
Acknowledgements We thank members of the Sankaran laboratory for comments; W. Zhou for technical guidance on the implementation of SAIGE; and the research participants and employees of 23andMe, UKBB, FinnGen and the Million Veteran Program. This research has been conducted using the UKBB Resource under application 31063. E.L.B. received support from the Howard Hughes Medical Institute Medical Research Fellowship. S.K.N. received support through a Scholar Award from the American Society of Hematology. This work was supported by the Claudia Adams Barr Program for Innovative Cancer Research, the New York Stem Cell Foundation, the MPN Research Foundation, the Leukemia & Lymphoma Society, and National Institutes of Health grants (R01 DK103794 and R01 HL146500 to V.G.S.). V.G.S. is a New York Stem Cell Foundation-Robertson Investigator.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10
Y1 - 2020/10
N2 - Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers1. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs remain unclear. Here, by conducting a large-scale genome-wide association study (3,797 cases and 1,152,977 controls), we identify 17 MPN risk loci (P < 5.0 × 10−8), 7 of which have not been previously reported. We find that there is a shared genetic architecture between MPN risk and several haematopoietic traits from distinct lineages; that there is an enrichment for MPN risk variants within accessible chromatin of HSCs; and that increased MPN risk is associated with longer telomere length in leukocytes and other clonal haematopoietic states—collectively suggesting that MPN risk is associated with the function and self-renewal of HSCs. We use gene mapping to identify modulators of HSC biology linked to MPN risk, and show through targeted variant-to-function assays that CHEK2 and GFI1B have roles in altering the function of HSCs to confer disease risk. Overall, our results reveal a previously unappreciated mechanism for inherited MPN risk through the modulation of HSC function.
AB - Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers1. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs remain unclear. Here, by conducting a large-scale genome-wide association study (3,797 cases and 1,152,977 controls), we identify 17 MPN risk loci (P < 5.0 × 10−8), 7 of which have not been previously reported. We find that there is a shared genetic architecture between MPN risk and several haematopoietic traits from distinct lineages; that there is an enrichment for MPN risk variants within accessible chromatin of HSCs; and that increased MPN risk is associated with longer telomere length in leukocytes and other clonal haematopoietic states—collectively suggesting that MPN risk is associated with the function and self-renewal of HSCs. We use gene mapping to identify modulators of HSC biology linked to MPN risk, and show through targeted variant-to-function assays that CHEK2 and GFI1B have roles in altering the function of HSCs to confer disease risk. Overall, our results reveal a previously unappreciated mechanism for inherited MPN risk through the modulation of HSC function.
U2 - 10.1038/s41586-020-2786-7
DO - 10.1038/s41586-020-2786-7
M3 - Article
C2 - 33057200
AN - SCOPUS:85092577991
SN - 0028-0836
VL - 586
SP - 769
EP - 775
JO - Nature
JF - Nature
IS - 7831
ER -
