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Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Authors
Alexander Bick,Joshua Weinstock
Satish Nandakumar,Charles Fulco,Erik Bao,Seyedeh Zekavat,Mindy Szeto,Xiaotian Liao,Matthew Leventhal,Joseph Nasser,Yi-Cheng Chang,Cecelia Laurie,Bala Burugula,Christopher Gibson,Abhishek Niroula,Amy Lin,Margaret Taub,C. Gu,Kristin Ardlie,Braxton Mitchell,Kathleen Barnes,Arden Moscati,Myriam Fornage,Susan Redline,Bruce Psaty,Edwin Silverman,Scott Weiss,Nicholette Palmer,Ramachandran Vasan,Esteban Burchard,Sharon Kardia,Jiang He,Robert Kaplan,Nicholas Smith,Donna Arnett,David Schwartz,Adolfo Correa,Mariza Andrade,Xiuqing Guo,Barbara Konkle,Brian Custer,Juan Peralta,Hongsheng Gui,Deborah Meyers,Stephen McGarvey,Ida Chen,Emelia Benjamin,Patricia Peyser,Jai Broome,Stephanie Gogarten,Fei Wang,Quenna Wong,May Montasser,Michelle Daya,Eimear Kenny,Kari North,Lenore Launer,Ulrich Broeckel,Joshua Bis,Michael Cho,Jessica Lasky‐Su,Donald Bowden,L. Cupples,Angel Mak,Lewis Becker,Jennifer Smith,Tanika Kelly,Stella Aslibekyan,Susan Heckbert,H.K. Tiwari,Ivana Yang,John Heit,Steven Lubitz,Jill Johnsen,Joanne Curran,Sally Wenzel,Daniel Weeks,D. Rao,Dawood Darbar,Jee‐Young Moon,Russell Tracy,Erin Buth,Nicholas Rafaels,Ruth Loos,Peter Durda,Yongmei Liu,Lifang Hou,Jiwon Lee,Priyadarshini Kachroo,Barry Freedman,Daniel Levy,Lawrence Bielak,James Hixson,James Floyd,Eric Whitsel,Patrick Ellinor,Marguerite Irvin,Tasha Fingerlin,Laura Raffield,Sebastian Armasu,Marsha Wheeler,Éster Sabino,John Blangero,Lawrence Williams,Melody Duvall,Wayne Sheu,Dan Roden,Eric Boerwinkle,JoAnn Manson,Rasika Mathias,Pinkal Desai,Kent Taylor,Andrew Johnson,Namiko Abe,Christine Albert,Laura Almasy,Alvaro Alonso,Seth Ament,Peter Anderson,Pramod Anugu,Deborah Applebaum‐Bowden,Dan Arking,Allison Ashley‐Koch,Tim Assimes,Dimitrios Avramopoulos,John Barnard,R. Barr,Emily Barron‐Casella,Lucas Barwick,Terri Beaty,Gerald Beck,Diane Becker,Rebecca Beer,Amber Beitelshees,P.V. Benos,Marcos Bezerra,Larry Bielak,Russell Bowler,Jennifer Brody,Karen Bunting,Carlos Bustamante,Jonathan Cardwell,Vincent Carey,Cara Carty,Richard Casaburi,James Casella,Peter Castaldi,Mark Chaffin,Christy Chang,Yi‐Cheng Chang,Daniel Chasman,Sameer Chavan,Bo-Juen Chen,Wei‐Min Chen,Seung Choi,Lee‐Ming Chuang,Mina Chung,Ren‐Hua Chung,Clary Clish,Suzy Comhair,Elaine Cornell,Carolyn Crandall,James Crapo,Jeffrey Curtis,Coleen Damcott,Sayantan Das,Sean David,Colleen Davis,Michael DeBaun,Ranjan Deka,Dawn DeMeo,Scott Devine,Qing Duan,Ravi Duggirala,Susan Dutcher,Charles Eaton,Lynette Ekunwe,Adel Boueiz,Leslie Emery,Serpil Erzurum,Charles Farber,Matthew Flickinger,Nora Franceschini,Chris Frazar,Mao Fu,Stephanie Fullerton,Lucinda Fulton,Stacey Gabriel,Weiniu Gan,Shanshan Gao,Yan Gao,Margery Gass,Bruce Gelb,Xiaoqi Geng,Mark Geraci,Robert Gerszten,Auyon Ghosh,Richard Gibbs,Christopher Gignoux,Mark Gladwin,David Glahn,Da‐Wei Gong,Harald Göring,Sharon Graw,Daniel Grine,Yue Guan,Namrata Gupta,Jeff Haessler,Michael Hall,Daniel Harris,Nicola Hawley,Ben Heavner,Ryan Hernandez,David Herrington,Craig Hersh,Bertha Hidalgo,Brian Hobbs,John Hokanson,Elliott Hong,Karin Hoth,Chao Hsiung,Yi‐Jen Hung,Haley Huston,Chii‐Min Hwu,Rebecca Jackson,Deepti Jain,Cashell Jaquish,Min Jhun,Craig Johnson,Rich Johnston,Kimberly Jones,Hyun Kang,Shannon Kelly,Michael Kessler,Alyna Khan,Wonji Kim,Gregory Hawkins,Holly Kramer,Christoph Lange,Meryl LeBoff,Seunggeun Lee,Wen‐Jane Lee,Jonathon LeFaive,David Levine,Joshua Lewis,Xiaohui Li,Yun Li,Henry Lin,Honghuang Lin,Keng Lin,Xihong Lin,Simin Liu,Yu Liu,Kathryn Lunetta,James Luo,Michael Mahaney,Barry Make,Ani Manichaikul,Lauren Margolin,Lisa Martin,Susan Mathai,Susanne May,Patrick McArdle,Merry‐Lynn McDonald,Sean McFarland,Daniel McGoldrick,Caitlin McHugh,Hao Mei,Luisa Mestroni,Julie Mikulla,Yuan‐I Min,Mollie Minear,Ryan Minster,Matt Moll,Courtney Montgomery,Solomon Musani,Stanford Mwasongwe,Josyf Mychaleckyj,Girish Nadkarni,Rakhi Naik,Take Naseri,Sergeï Nekhai,Sarah Nelson,Bonnie Neltner,Deborah Nickerson,Jeff O’Connell,Tim O’Connor,Heather Ochs‐Balcom,David Paik,James Pankow,George Papanicolaou,Afshin Parsa,Marco Perez,James Perry,Annette Peters,Lawrence Phillips,Toni Pollin,Wendy Post,Julia Becker,Timothy O’Connor,Michael Preuß,Pankaj Qasba,Dandi Qiao,Zhaohui Qin,Laura Rasmussen‐Torvik,Aakrosh Ratan,Robert Reed,Elizabeth Regan,Muagututi‘a Reupena,Kenneth Rice,Carolina Roselli,Ingo Ruczinski,Pamela Russell,Sarah Ruuska,Kathleen Ryan,Danish Saleheen,Shabnam Salimi,Steven Salzberg,William Scott,Christopher Scheller,Ellen Schmidt,Karen Schwander,Frank Sciurba,Christine Seidman,Jonathan Seidman,Vivien Sheehan,Stephanie Sherman,Amol Shetty,Aniket Shetty,Brian Silver,Josh Smith,Tanja Smith,Sylvia Smoller,Beverly Snively,M Snyder,Tamar Sofer,Nona Sotoodehnia,Adrienne Stilp,Garrett Storm,Elizabeth Streeten,Yun Sung,Jody Sylvia,Adam Szpiro,Carole Sztalryd,Daniel Taliun,Hua Tang,Matthew Taylor,Simeon Taylor,Marilyn Telen,Timothy Thornton,Machiko Threlkeld,Lesley Tinker,David Tirschwell,Sarah Tishkoff,Hemant Tiwari,Catherine Tong,Michael Tsai,Dhananjay Vaidya,David Berg,Peter VandeHaar,Scott Vrieze,Tarik Walker,Robert Wallace,Avram Walts,Heming Wang,Karol Watson,Bruce Weir,Lu‐Chen Weng,Jennifer Wessel,Cristen Willer,Kayleen Williams,Carla Wilson,Joseph Wu,Huichun Xu,Lisa Yanek,Rongze Yang,Norann Zaghloul,Yingze Zhang,Snow Zhao,Wei Zhao,Degui Zhi,Xiang Zhou,Xiaofeng Zhu,Michael Zody,Sebastian Zoellner,Paul Auer,Charles Kooperberg,Cathy Laurie,Thomas Blackwell,Albert Hofman,Hongyu Zhao,Ethan Lange,Leslie Lange,Stephen Rich,Jerome Rotter,James Wilson,Paul Scheet,Jacob Kitzman,Eric Lander,J Engreitz,Benjamin Ebert,Alexander Reiner,Siddhartha Jaiswal,Gonçalo Abecasis,Vijay Sankaran,Sekar Kathiresan,Pradeep Natarajan,François Aguet,Colin Palmer,Brian Cade,H Tiwari
+409 authors
,Jee-Young Moon
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Published
Oct 14, 2020
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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. Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

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