Inherited causes of clonal haematopoiesis in 97,691 whole genomes


Alexander G. Bick
Joshua S. Weinstock
Satish K. Nandakumar
Charles P. Fulco
Erik L. Bao
Seyedeh M. Zekavat
Mindy D. Szeto
Xiaotian Liao
Matthew J. Leventhal
Joseph Nasser
Kyle Chang
Cecelia Laurie
Bala Bharathi Burugula
Christopher J. Gibson
Amy E. Lin
Margaret A. Taub
Francois Aguet
Kristin Ardlie
Braxton D. Mitchell
Kathleen C. Barnes
Arden Moscati
Myriam Fornage
Susan Redline
Bruce M. Psaty
Edwin K. Silverman
Scott T. Weiss
Nicholette D. Palmer
Ramachandran S. Vasan
Esteban G. Burchard
Sharon L R Kardia
Jiang He
Robert C. Kaplan
Nicholas L. Smith
Donna K. Arnett
David A. Schwartz
Adolfo Correa
Mariza de Andrade
Xiuqing Guo
Barbara A. Konkle
Brian Custer
Juan M. Peralta
Hongsheng Gui, Henry Ford Health SystemFollow
Deborah A. Meyers
Stephen T. McGarvey
Ida Yii-Der Chen
M. Benjamin Shoemaker
Patricia A. Peyser
Jai G. Broome
Stephanie M. Gogarten
Fei Fei Wang
Quenna Wong
May E. Montasser
Michelle Daya
Eimear E. Kenny
Kari E. North
Lenore J. Launer
Brian E. Cade
Joshua C. Bis
Michael H. Cho
Jessica Lasky-Su
Donald W. Bowden
L. Adrienne Cupples
Angel CY Mak
Lewis C. Becker
Jennifer A. Smith
Tanika N. Kelly
Stella Aslibekyan
Susan R. Heckbert
Hemant K. Tiwari
Ivana V. Yang
John A. Heit
Steven A. Lubitz
Jill M. Johnsen
Joanne E. Curran
Sally E. Wenzel
Daniel E. Weeks
Dabeeru C. Rao
Dawood Darbar
Jee-Young Moon
Russell P. Tracy
Erin J. Buth
Nicholas Rafaels
Ruth JF Loos
Peter Durda
Yongmei Liu
Lifang Hou
Jiwon Lee
Priyadarshini Kachroo
Barry I. Freedman
Daniel Levy
Lawrence F. Bielak
James E. Hixson
James S. Floyd
Eric A. Whitsel
Patrick T. Ellinor
Marguerite R. Irvin
Tasha E. Fingerlin
Laura M. Raffield
Sebastian M. Armasu
Marsha M. Wheeler
Ester C. Sabino
John Blangero
Keoki L. Williams, Henry Ford Health SystemFollow
Bruce D. Levy
Wayne Huey-Herng Sheu
Dan M. Roden
Eric Boerwinkle
JoAnn E. Manson
Rasika A. Mathias
Pinkal Desai
Kent D. Taylor
Andrew D. Johnson
Paul L. Auer
Charles Kooperberg
Cathy C. Laurie
Thomas W. Blackwell
Albert V. Smith
Hongyu Zhao
Ethan Lange
Leslie Lange
Stephen S. Rich
Jerome I. Rotter
James G. Wilson
Paul Scheet
Jacob O. Kitzman
Eric S. Lander
Jesse M. Engreitz
Benjamin L. Ebert
Alexander P. Reiner
Siddhartha Jaiswal
Gonçalo Abecasis
Vijay G. Sankaran
Sekar Kathiresan
Pradeep Natarajan

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Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown(1). The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer(2-4) and coronary heart disease(5)-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)(6). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

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ePub ahead of print





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