Journal article
Inherited causes of clonal haematopoiesis in 97,691 whole genomes
Nature (London), Vol.586(7831), pp.763-768
10/2020
DOI: 10.1038/s41586-020-2819-2
PMCID: PMC7944936
PMID: 33057201
Abstract
Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown
. 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
and coronary heart disease
-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)
. 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.
Details
- Title: Subtitle
- Inherited causes of clonal haematopoiesis in 97,691 whole genomes
- Creators
- Alexander G Bick - Vanderbilt University Medical CenterJoshua S Weinstock - University of MichiganSatish K Nandakumar - Broad InstituteCharles P Fulco - Broad InstituteErik L Bao - Broad InstituteSeyedeh M Zekavat - Yale UniversityMindy D Szeto - University of Colorado Anschutz Medical CampusXiaotian Liao - Broad InstituteMatthew J Leventhal - Broad InstituteJoseph Nasser - Broad InstituteKyle Chang - The University of Texas MD Anderson Cancer CenterCecelia Laurie - University of WashingtonBala Bharathi Burugula - University of MichiganChristopher J Gibson - Harvard UniversityAmy E Lin - Brigham and Women's HospitalMargaret A Taub - Johns Hopkins UniversityFrancois Aguet - Broad InstituteKristin Ardlie - Broad InstituteBraxton D Mitchell - University of Maryland, BaltimoreKathleen C Barnes - University of Colorado Anschutz Medical CampusArden Moscati - Icahn School of Medicine at Mount SinaiMyriam Fornage - The University of Texas Health Science Center at HoustonSusan Redline - Harvard UniversityBruce M Psaty - Kaiser Permanente Washington Health Research InstituteEdwin K Silverman - Harvard UniversityScott T Weiss - Harvard UniversityNicholette D Palmer - Wake Forest UniversityRamachandran S Vasan - Boston UniversityEsteban G Burchard - University of California, San FranciscoSharon L R Kardia - University of MichiganJiang He - Tulane UniversityRobert C Kaplan - Albert Einstein College of MedicineNicholas L Smith - University of WashingtonDonna K Arnett - University of KentuckyDavid A Schwartz - University of Colorado BoulderAdolfo Correa - University of Mississippi Medical CenterMariza de Andrade - Mayo ClinicXiuqing Guo - The Lundquist InstituteBarbara A Konkle - University of WashingtonBrian Custer - University of California, San FranciscoJuan M Peralta - The University of Texas at AustinHongsheng Gui - Henry Ford Health SystemDeborah A Meyers - University of ArizonaStephen T McGarvey - Brown UniversityIda Yii-Der Chen - The Lundquist InstituteM Benjamin Shoemaker - Vanderbilt University Medical CenterPatricia A Peyser - University of MichiganJai G Broome - University of WashingtonStephanie M Gogarten - University of WashingtonFei Fei Wang - University of WashingtonQuenna Wong - University of WashingtonMay E Montasser - University of Maryland, BaltimoreMichelle Daya - University of Colorado Anschutz Medical CampusEimear E Kenny - Icahn School of Medicine at Mount SinaiKari E North - University of North Carolina at Chapel HillLenore J Launer - National Institutes of HealthBrian E Cade - Harvard UniversityJoshua C Bis - University of WashingtonMichael H Cho - Harvard UniversityJessica Lasky-Su - Harvard UniversityDonald W Bowden - Wake Forest UniversityL Adrienne Cupples - Boston UniversityAngel C Y Mak - University of California, San FranciscoLewis C Becker - Johns Hopkins UniversityJennifer A Smith - University of MichiganTanika N Kelly - Tulane UniversityStella Aslibekyan - University of Alabama at BirminghamSusan R Heckbert - University of WashingtonHemant K Tiwari - University of Alabama at BirminghamIvana V Yang - University of Colorado BoulderJohn A Heit - Mayo ClinicSteven A Lubitz - Broad InstituteJill M Johnsen - University of WashingtonJoanne E Curran - The University of Texas at AustinSally E Wenzel - University of PittsburghDaniel E Weeks - University of PittsburghDabeeru C Rao - Washington University in St. LouisDawood Darbar - University of Illinois ChicagoJee-Young Moon - Albert Einstein College of MedicineRussell P Tracy - University of VermontErin J Buth - University of WashingtonNicholas Rafaels - University of Colorado BoulderRuth J F Loos - Icahn School of Medicine at Mount SinaiPeter Durda - University of VermontYongmei Liu - Duke UniversityLifang Hou - Northwestern UniversityJiwon Lee - Brigham and Women's HospitalPriyadarshini Kachroo - Harvard UniversityBarry I Freedman - Wake Forest UniversityDaniel Levy - National Institutes of HealthLawrence F Bielak - University of MichiganJames E Hixson - The University of Texas Health Science Center at HoustonJames S Floyd - University of WashingtonEric A Whitsel - University of North Carolina at Chapel HillPatrick T Ellinor - Broad InstituteMarguerite R Irvin - University of Alabama at BirminghamTasha E Fingerlin - National Jewish HealthLaura M Raffield - University of North Carolina at Chapel HillSebastian M Armasu - Mayo ClinicMarsha M Wheeler - University of WashingtonEster C Sabino - Universidade de São PauloJohn Blangero - The University of Texas at AustinL Keoki Williams - Henry Ford Health SystemBruce D Levy - Harvard UniversityWayne Huey-Herng Sheu - Taichung Veterans General HospitalDan M Roden - Vanderbilt University Medical CenterEric Boerwinkle - Baylor College of MedicineJoAnn E Manson - Harvard UniversityRasika A Mathias - Johns Hopkins UniversityPinkal Desai - Cornell UniversityKent D Taylor - UCLA Medical CenterAndrew D Johnson - National Institutes of HealthPaul L Auer - University of Wisconsin–MilwaukeeCharles Kooperberg - Fred Hutch Cancer CenterCathy C Laurie - University of WashingtonThomas W Blackwell - University of MichiganAlbert V Smith - University of MichiganHongyu Zhao - Yale UniversityEthan Lange - University of Colorado Anschutz Medical CampusLeslie Lange - University of Colorado Anschutz Medical CampusStephen S Rich - University of VirginiaJerome I Rotter - Ronald Reagan UCLA Medical CenterJames G Wilson - University of Mississippi Medical CenterPaul Scheet - The University of Texas MD Anderson Cancer CenterJacob O Kitzman - University of MichiganEric S Lander - Massachusetts Institute of TechnologyJesse M Engreitz - Broad InstituteBenjamin L Ebert - Howard Hughes Medical Institute, Boston, MA, USAAlexander P Reiner - University of WashingtonSiddhartha Jaiswal - Stanford UniversityGonçalo Abecasis - University of MichiganVijay G Sankaran - Broad InstituteSekar Kathiresan - Verve Therapeutics (United States)Pradeep Natarajan - Broad InstituteNHLBI Trans-Omics for Precision Medicine Consortium
- Contributors
- Karin Hoth (Contributor) - University of Iowa, PsychiatryRobert Wallace (Contributor) - University of Iowa, Internal Medicine
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.586(7831), pp.763-768
- DOI
- 10.1038/s41586-020-2819-2
- PMID
- 33057201
- PMCID
- PMC7944936
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Grant note
- K01 HL135405 / NHLBI NIH HHS DP2 HL157540 / NHLBI NIH HHS R01 HL120393 / NHLBI NIH HHS K01 HL136700 / NHLBI NIH HHS R01 AI132476 / NIAID NIH HHS R01 HL148565 / NHLBI NIH HHS R35 CA253125 / NCI NIH HHS R01 HL148050 / NHLBI NIH HHS R01 HL139731 / NHLBI NIH HHS R03 HL154284 / NHLBI NIH HHS R01 HL149836 / NHLBI NIH HHS UM1 HG008895 / NHGRI NIH HHS U01 HL089856 / NHLBI NIH HHS R01 HL138737 / NHLBI NIH HHS R01 HL133040 / NHLBI NIH HHS HHSN268201800001C / NHLBI NIH HHS UG3 HL151865 / NHLBI NIH HHS R35 HL135818 / NHLBI NIH HHS UL1 TR001863 / NCATS NIH HHS P01 HL132825 / NHLBI NIH HHS R01 HL117626 / NHLBI NIH HHS T32 HL129982 / NHLBI NIH HHS DP5 OD029586 / NIH HHS R01 HL113323 / NHLBI NIH HHS U01 HL130114 / NHLBI NIH HHS R01 HL091357 / NHLBI NIH HHS U54 GM115428 / NIGMS NIH HHS 18SFRN34250007 / American Heart Association-American Stroke Association K08 HL141601 / NHLBI NIH HHS P50 HL118006 / NHLBI NIH HHS R01 HG009974 / NHGRI NIH HHS R01 HL055673 / NHLBI NIH HHS F30 HL149180 / NHLBI NIH HHS
- Language
- English
- Date published
- 10/2020
- Academic Unit
- Psychiatry; Epidemiology; Iowa Neuroscience Institute; Injury Prevention Research Center; Internal Medicine
- Record Identifier
- 9984293657802771
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