Inherited causes of clonal haematopoiesis in 97,691 whole genomes
Journal
Nature
Journal Volume
586
Journal Issue
7831
Pages
763-768
Date Issued
2020
Author(s)
Weinstock J.S.
Nandakumar S.K.
Fulco C.P.
Bao E.L.
Zekavat S.M.
Szeto M.D.
Liao X.
Leventhal M.J.
Nasser J.
Chang K.
Laurie C.
Burugula B.B.
Gibson C.J.
Lin A.E.
Taub M.A.
Aguet F.
Ardlie K.
Mitchell B.D.
Barnes K.C.
Moscati A.
Fornage M.
Redline S.
Psaty B.M.
Silverman E.K.
Weiss S.T.
Palmer N.D.
Vasan R.S.
Burchard E.G.
Kardia S.L.R.
He J.
Kaplan R.C.
Smith N.L.
Arnett D.K.
Schwartz D.A.
Correa A.
de Andrade M.
Guo X.
Konkle B.A.
Custer B.
Peralta J.M.
Gui H.
Meyers D.A.
McGarvey S.T.
Chen I.Y.-D.
Shoemaker M.B.
Peyser P.A.
Broome J.G.
Gogarten S.M.
Wang F.F.
Wong Q.
Montasser M.E.
Daya M.
Kenny E.E.
North K.E.
Launer L.J.
Cade B.E.
Bis J.C.
Cho M.H.
Lasky-Su J.
Bowden D.W.
Cupples L.A.
Mak A.C.Y.
Becker L.C.
Smith J.A.
Kelly T.N.
Aslibekyan S.
Heckbert S.R.
Tiwari H.K.
Yang I.V.
Heit J.A.
Lubitz S.A.
Johnsen J.M.
Curran J.E.
Wenzel S.E.
Weeks D.E.
Rao D.C.
Darbar D.
Moon J.-Y.
Tracy R.P.
Buth E.J.
Rafaels N.
Loos R.J.F.
Durda P.
Liu Y.
Hou L.
Lee J.
Kachroo P.
Freedman B.I.
Levy D.
Bielak L.F.
Hixson J.E.
Floyd J.S.
Whitsel E.A.
Ellinor P.T.
Irvin M.R.
Fingerlin T.E.
Raffield L.M.
Armasu S.M.
Wheeler M.M.
Sabino E.C.
Blangero J.
Williams L.K.
Levy B.D.
Sheu W.H.-H.
Roden D.M.
Boerwinkle E.
Manson J.A.E.
Mathias R.A.
Desai P.
Taylor K.D.
Johnson A.D.
Abe N.
Albert C.
Almasy L.
Alonso A.
Ament S.
Anderson P.
Anugu P.
Applebaum-Bowden D.
Arking D.
Ashley-Koch A.
Aslibekyan S.
Assimes T.
Avramopoulos D.
Barnard J.
Barr R.G.
Barron-Casella E.
Barwick L.
Beaty T.
Beck G.
Becker D.
Beer R.
Beitelshees A.
Benjamin E.
Benos P.
Bezerra M.
Bielak L.
Bowler R.
Brody J.
Broeckel U.
Bunting K.
Bustamante C.
Cardwell J.
Carey V.
Carty C.
Casaburi R.
Casella J.
Castaldi P.
Chaffin M.
Chang C.
Chasman D.
Chavan S.
Chen B.-J.
Chen W.-M.
Choi S.H.
Chung M.
Chung R.-H.
Clish C.
Comhair S.
Cornell E.
Crandall C.
Crapo J.
Curtis J.
Damcott C.
Das S.
David S.
Davis C.
DeBaun M.
Deka R.
DeMeo D.
Devine S.
Duan Q.
Duggirala R.
Dutcher S.
Eaton C.
Ekunwe L.
Boueiz A.E.
Emery L.
Erzurum S.
Farber C.
Flickinger M.
Franceschini N.
Frazar C.
Fu M.
Fullerton S.M.
Fulton L.
Gabriel S.
Gan W.
Gao S.
Gao Y.
Gass M.
Gelb B.
(Priscilla) Geng X.
Geraci M.
Germer S.
Gerszten R.
Ghosh A.
Gibbs R.
Gignoux C.
Gladwin M.
Glahn D.
Gong D.-W.
Goring H.
Graw S.
Grine D.
Gu C.C.
Guan Y.
Gupta N.
Haessler J.
Hall M.
Harris D.
Hawley N.L.
Heavner B.
Hernandez R.
Herrington D.
Hersh C.
Hidalgo B.
Hobbs B.
Hokanson J.
Hong E.
Hoth K.
(Agnes) Hsiung C.
Hung Y.-J.
Huston H.
Hwu C.M.
Jackson R.
Jain D.
Jaquish C.
Jhun M.A.
Johnson C.
Johnston R.
Jones K.
Kang H.M.
Kelly S.
Kessler M.
Khan A.
Kim W.
Kinney G.
Kramer H.
Lange C.
LeBoff M.
Lee S.S.
Lee W.-J.
LeFaive J.
Levine D.
Lewis J.
Li X.
Li Y.
Lin H.
Lin H.
Lin K.H.
Lin X.
Liu S.
Liu Y.
Lunetta K.
Luo J.
Mahaney M.
Make B.
Manichaikul A.
Margolin L.
Martin L.
Mathai S.
May S.
McArdle P.
McDonald M.-L.
McFarland S.
McGoldrick D.
McHugh C.
Mei H.
Mestroni L.
Mikulla J.
Min N.
Minear M.
Minster R.L.
Moll M.
Montgomery C.
Musani S.
Mwasongwe S.
Mychaleckyj J.C.
Nadkarni G.
Naik R.
Naseri T.
Nekhai S.
Nelson S.C.
Neltner B.
Nickerson D.
O’Connell J.
O’Connor T.
Ochs-Balcom H.
Paik D.
Pankow J.
Papanicolaou G.
Parsa A.
Perez M.
Perry J.
Peters U.
Peyser P.
Phillips L.S.
Pollin T.
Post W.
Becker J.P.
Boorgula M.P.
Preuss M.
Qasba P.
Qiao D.
Qin Z.
Rasmussen-Torvik L.
Ratan A.
Reed R.
Regan E.
Sefuiva Reupena M.
Rice K.
Roselli C.
Ruczinski I.
Russell P.
Ruuska S.
Ryan K.
Saleheen D.
Salimi S.
Salzberg S.
Sandow K.
Scheller C.
Schmidt E.
Schwander K.
Sciurba F.
Seidman C.
Seidman J.
Sheehan V.
Sherman S.L.
Shetty A.
Shetty A.
Silver B.
Smith J.
Smith T.
Smoller S.
Snively B.
Snyder M.
Sofer T.
Sotoodehnia N.
Stilp A.M.
Storm G.
Streeten E.
Su J.L.
Sung Y.J.
Sylvia J.
Szpiro A.
Sztalryd C.
Taliun D.
Tang H.
Taylor M.
Taylor S.
Telen M.
Thornton T.A.
Threlkeld M.
Tinker L.
Tirschwell D.
Tishkoff S.
Tiwari H.
Tong C.
Tsai M.
Vaidya D.
Berg D.V.D.
VandeHaar P.
Vrieze S.
Walker T.
Wallace R.
Walts A.
Wang H.
Watson K.
Weir B.
Weng L.-C.
Wessel J.
Willer C.
Williams K.
Wilson C.
Wu J.
Xu H.
Yanek L.
Yang R.
Zaghloul N.
Zhang Y.
Zhao S.X.
Zhao W.
Zhi D.
Zhou X.
Zhu X.
Zody M.
Zoellner S.
Auer P.L.
Kooperberg C.
Laurie C.C.
Blackwell T.W.
Smith A.V.
Zhao H.
Lange E.
Lange L.
Rich S.S.
Rotter J.I.
Wilson J.G.
Scheet P.
Kitzman J.O.
Lander E.S.
Engreitz J.M.
Ebert B.L.
Reiner A.P.
Jaiswal S.
Abecasis G.
Sankaran V.G.
Kathiresan S.
Natarajan P.
NHLBI Trans-Omics for Precision Medicine Consortium
Abstract
Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. 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 cancer2–4 and coronary heart disease5—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. ? 2020, The Author(s), under exclusive licence to Springer Nature Limited.
SDGs
Other Subjects
age; blood; cardiovascular disease; cell; chronic wasting disease; genetic variation; genome; laboratory method; lipid; mutation; risk factor; African; Article; Black person; cell function; CHEK2 gene; gene; gene expression; gene locus; genetic analysis; genetic risk; genetic variability; genetic variation; hematopoiesis; hematopoietic stem cell; human; in vitro study; priority journal; RNA sequencing; somatic mutation; TET2 gene; whole genome sequencing; adult; Africa; aged; cell self-renewal; cytology; ethnology; female; genetic predisposition; genetics; germline mutation; human genome; male; metabolism; middle aged; national health organization; personalized medicine; phenotype; United States; very elderly; DNA binding protein; karyopherin alpha; KPNA4 protein, human; oncoprotein; signal peptide; TET2 protein, human; TRIM59 protein, human; tripartite motif protein; Adult; Africa; African Continental Ancestry Group; Aged; Aged, 80 and over; alpha Karyopherins; Cell Self Renewal; Clonal Hematopoiesis; DNA-Binding Proteins; Female; Genetic Predisposition to Disease; Genome, Human; Germ-Line Mutation; Hematopoietic Stem Cells; Humans; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; National Heart, Lung, and Blood Institute (U.S.); Phenotype; Precision Medicine; Proto-Oncogene Proteins; Tripartite Motif Proteins; United States; Whole Genome Sequencing
Publisher
Nature Research
Type
journal article