Open AccessInherited causes of clonal haematopoiesis in 97,691 whole genomes
Author(s) -
Alexander G. Bick,
Joshua S. Weinstock,
Satish K. Nandakumar,
Charles P. Fulco,
Erik L. Bao,
Seyedeh M. Zekavat,
Mindy D Szeto,
Xiaotian Liao,
Matthew Leventhal,
Joseph Nasser,
Kyle Chang,
Cecelia Laurie,
Bala Bharathi Burugula,
Christopher J. Gibson,
Abhishek Niroula,
Amy Lin,
Margaret A. Taub,
François 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,
Deborah A. Meyers,
Stephen T. McGarvey,
Ida Yii-Der Chen,
M. Benjamin Shoemaker,
Patricia A. Peyser,
Jai 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 LaskySu,
Donald W. Bowden,
L. Adrienne Cupples,
Angel C. Y. 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,
D. C. Rao,
Dawood Darbar,
JeeYoung Moon,
Russell P. Tracy,
Erin Buth,
Nicholas Rafaels,
Ruth J. F. 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,
Éster Cerdeira Sabino,
John Blangero,
Lawrence K. Williams,
Bruce D. Levy,
Wayne HueyHerng Sheu,
Dan M. Roden,
Eric Boerwinkle,
JoAnn E. Manson,
Rasika A. Mathias,
Pinkal Desai,
Kent D. Taylor,
Andrew D. Johnson,
Namiko Abe,
Christine M. Albert,
Laura Almasy,
Alvaro Alonso,
Seth A. Ament,
Peter Anderson,
Pramod Anugu,
Deborah ApplebaumBowden,
Dan Arking,
Allison E. AshleyKoch,
Tim Assimes,
Dimitrios Avramopoulos,
John Barnard,
R. Graham Barr,
Emily BarronCasella,
Lucas Barwick,
Terri Beaty,
Gerald J. Beck,
Diane M. Becker,
Rebecca Beer,
Amber L. Beitelshees,
Emelia J. Benjamin,
P.V. Benos,
Marcos Bezerra,
Larry Bielak,
Russell P. Bowler,
Jennifer A. Brody,
Ulrich Broeckel,
Karen Bunting,
Carlos D. Bustamante,
Jonathan Cardwell,
Vincent J. Carey,
Cara L. Carty,
Richard Casaburi,
James F. Casella,
Peter J. Castaldi,
Mark Chaffin,
Christy Chang,
YiCheng Chang,
Daniel I. Chasman,
Sameer Chavan,
Bo-Juen Chen,
WeiMin Chen,
Seung Hoan Choi,
LeeMing Chuang,
Mina K. Chung,
RenHua Chung,
Clary B. Clish,
Suzy Comhair,
Elaine Cornell,
Carolyn Crandall,
James D. Crapo,
Jeffrey L. Curtis,
Coleen Damcott,
Sayantan Das,
Sean P. David,
Colleen Davis,
Michael R. DeBaun,
Ranjan Deka,
Dawn L. DeMeo,
Scott E. Devine,
Qing Duan,
Ravi Duggirala,
Susan K. Dutcher,
Charles B. Eaton,
Lynette Ekunwe,
Adel Boueiz,
Leslie Emery,
Serpil C. Erzurum,
Charles R. Farber,
Matthew Flickinger,
Nora Franceschini,
Chris Frazar,
Mao Fu,
Stephanie M. Fullerton,
Lucinda A. Fulton,
Stacey Gabriel,
Weiniu Gan,
Shanshan Gao,
Yan Gao,
Margery Gass,
Bruce D. Gelb,
Xiaoqi Geng,
Mark W. Geraci,
Søren Germer,
Robert E. Gerszten,
Auyon Ghosh,
Richard A. Gibbs,
Chris Gignoux,
Mark T. Gladwin,
David C. Glahn,
DaWei Gong,
Harald H.H. Göring,
Sharon Graw,
Daniel Grine,
C. Charles Gu,
Yue Guan,
Namrata Gupta,
Jeff Haessler,
Michael E. Hall,
Daniel Harris,
Nicola L. Hawley,
Ben Heavner,
Ryan D. Hernandez,
David Herrington,
Craig P. Hersh,
Bertha Hidalgo,
Brian D. Hobbs,
John E. Hokanson,
Elliott Hong,
Karin F. Hoth,
Chao A. Hsiung,
YiJen Hung,
Haley Huston,
Chii Min Hwu,
Rebecca D. Jackson,
Deepti Jain,
Cashell E. Jaquish,
Min A. Jhun,
Craig Johnson,
Rich Johnston,
Kimberly Jones,
Hyun Min Kang,
Shan Kelly,
Michael Kessler,
Alyna Khan,
Wonji Kim,
Gregory L. Kinney,
Holly Kramer,
Christoph Lange,
Meryl S. LeBoff,
Seunggeun Shawn Lee,
WenJane Lee,
Jonathon LeFaive,
David Levine,
Joshua P. Lewis,
Xiaohui Li,
Yun Li,
Henry J. Lin,
Honghuang Lin,
Keng Han Lin,
Xihong Lin,
Simin Liu,
Yu Liu,
Kathryn L. Lunetta,
James Luo,
Michael C. Mahaney,
Barry J. Make,
Ani Manichaikul,
Lauren Margolin,
Lisa Martin,
Susan K. Mathai,
Susanne May,
Patrick F. McArdle,
MerryLynn McDonald,
Sean McFarland,
Daniel McGoldrick,
Caitlin McHugh,
Hao Mei,
Luisa Mestroni,
Julie Mikulla,
YuanI Min,
Mollie Minear,
Ryan L. Minster,
Matt Moll,
Courtney G. Montgomery,
Solomon K. Musani,
Stanford Mwasongwe,
Josyf C. Mychaleckyj,
Girish N. Nadkarni,
Rakhi P. Naik,
Take Naseri,
Sergeï Nekhai,
Sarah C. Nelson,
Bonnie Neltner,
Deborah A. Nickerson,
Jeff O’Connell,
Tim O’Connor,
Heather M. OchsBalcom,
David T. Paik,
James S. Pankow,
George Papanicolaou,
Afshin Parsa,
Marco Perez,
James A. Perry,
Annette Peters,
Lawrence S. Phillips,
Toni I. Pollin,
Wendy S. Post,
Julia Powers Becker,
Meher Preethi Boorgula,
Michael Preuß,
Pankaj Qasba,
Dandi Qiao,
Zhaohui Qin,
Laura J. RasmussenTorvik,
Aakrosh Ratan,
Robert D. Reed,
Elizabeth A. Regan,
Muagututi‘a Sefuiva Reupena,
Kenneth Rice,
Carolina Roselli,
Ingo Ruczinski,
Pamela Russell,
Sarah Ruuska,
Kathleen A. Ryan,
Danish Saleheen,
Shabnam Salimi,
Steven L. Salzberg,
Kevin Sandow,
Christopher Scheller,
Ellen M. Schmidt,
Karen Schwander,
Frank C. Sciurba,
Christine E. Seidman,
Jonathan G. Seidman,
Vivien A. Sheehan,
Stephanie L. Sherman,
Amol C. Shetty,
Aniket Shetty,
Brian Silver,
Josh Smith,
Tanja Smith,
Sylvia Smoller,
Beverly M. Snively,
M Snyder,
Tamar Sofer,
a Sotoodehnia,
Adrienne M. Stilp,
Garrett Storm,
Elizabeth A. Streeten,
Yan V. Sun,
Jody Sylvia,
Adam A. Szpiro,
Carole Sztalryd,
Daniel Taliun,
Hua Tang,
Matthew R.G. Taylor,
Simeon I. Taylor,
Marilyn J. Telen,
Timothy A. Thornton,
Machiko Threlkeld,
Lesley Tinker,
David Tirschwell,
Sarah A. Tishkoff,
Hemant Tiwari,
Catherine Tong,
Michael Tsai,
Dhananjay Vaidya,
David Van Den Berg,
Peter VandeHaar,
Scott Vrieze,
Tarik Walker,
Robert B. Wallace,
Avram Walts,
Heming Wang,
Karol Watson,
Bruce S. Weir,
LuChen Weng,
Jennifer Wessel,
Cristen J. Willer,
Kayleen Williams,
Carla G. Wilson,
Joseph C. Wu,
Huichun Xu,
Lisa R. Yanek,
Rongze Yang,
Norann A. Zaghloul,
Yingze Zhang,
Snow Xueyan Zhao,
Wei Zhao,
Degui Zhi,
Xiang Zhou,
Xiaofeng Zhu,
Michael C. Zody,
Sebastian Zoellner,
Paul L. Auer,
Charles Kooperberg,
Cathy C. Laurie,
Thomas W. Blackwell,
Albert V. Smith,
Hongyu Zhao,
Ethan M. Lange,
Leslie Lange,
Stephen S. Rich,
Jerome I. Rotter,
James Wilson,
Paul Scheet,
Jacob O. Kitzman,
Eric S. Lander,
J Engreitz,
Benjamin L. Ebert,
Alexander P. Reiner,
Siddhartha Jaiswal,
Gonçalo R. Abecasis,
Vijay G. Sankaran,
Sekar Kathiresan,
Pradeep Natarajan
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-020-2819-2
Subject(s) - biology , germline , somatic cell , genetics , haematopoiesis , germline mutation , genome wide association study , stem cell , genome , gene , mutation , single nucleotide polymorphism , genotype
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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