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Inherited causes of clonal haematopoiesis in 97,691 whole genomes
Nature ( IF 64.8 ) Pub Date : 2020-10-14 , DOI: 10.1038/s41586-020-2819-2 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 , Abhishek Niroula , 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 , 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 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 , Dabeeru C. Rao , Dawood Darbar , Jee-Young Moon , Russell P. Tracy , Erin J. 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 , Ester C. Sabino , John Blangero , L. Keoki Williams , 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 , Namiko Abe , Christine Albert , Laura Almasy , Alvaro Alonso , Seth Ament , Peter Anderson , Pramod Anugu , Deborah Applebaum-Bowden , Dan Arking , Allison Ashley-Koch , Stella Aslibekyan , Tim Assimes , Dimitrios Avramopoulos , John Barnard , R. Graham Barr , Emily Barron-Casella , Lucas Barwick , Terri Beaty , Gerald Beck , Diane Becker , Rebecca Beer , Amber Beitelshees , Emelia Benjamin , Panagiotis Benos , Marcos Bezerra , Larry Bielak , Russell Bowler , Jennifer Brody , Ulrich Broeckel , 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 Hoan 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 El Boueiz , Leslie Emery , Serpil Erzurum , Charles Farber , Matthew Flickinger , Nora Franceschini , Chris Frazar , Mao Fu , Stephanie M. Fullerton , Lucinda Fulton , Stacey Gabriel , Weiniu Gan , Shanshan Gao , Yan Gao , Margery Gass , Bruce Gelb , Xiaoqi Geng , Mark Geraci , Soren Germer , Robert Gerszten , Auyon Ghosh , Richard Gibbs , Chris Gignoux , Mark Gladwin , David Glahn , Da-Wei Gong , Harald Goring , Sharon Graw , Daniel Grine , C. Charles Gu , Yue Guan , Namrata Gupta , Jeff Haessler , Michael Hall , Daniel Harris , Nicola L. 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 A. Jhun , Craig Johnson , Rich Johnston , Kimberly Jones , Hyun Min Kang , Shannon Kelly , Michael Kessler , Alyna Khan , Wonji Kim , Greg Kinney , Holly Kramer , Christoph Lange , Meryl LeBoff , Seunggeun Shawn Lee , Wen-Jane Lee , Jonathon LeFaive , David Levine , Joshua Lewis , Xiaohui Li , Yun Li , Henry Lin , Honghuang Lin , Keng Han 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 , Nancy Min , Mollie Minear , Ryan L. Minster , Matt Moll , Courtney Montgomery , Solomon Musani , Stanford Mwasongwe , Josyf C. Mychaleckyj , Girish Nadkarni , Rakhi Naik , Take Naseri , Sergei Nekhai , Sarah C. 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 , Ulrike Peters , Patricia Peyser , Lawrence S. Phillips , Toni Pollin , Wendy Post , Julia Powers Becker , Meher Preethi Boorgula , Michael Preuss , Pankaj Qasba , Dandi Qiao , Zhaohui Qin , Laura Rasmussen-Torvik , Aakrosh Ratan , Robert Reed , Elizabeth Regan , Muagututi‘a Sefuiva Reupena , Ken Rice , Carolina Roselli , Ingo Ruczinski , Pamela Russell , Sarah Ruuska , Kathleen Ryan , Danish Saleheen , Shabnam Salimi , Steven Salzberg , Kevin Sandow , Christopher Scheller , Ellen Schmidt , Karen Schwander , Frank Sciurba , Christine Seidman , Jonathan Seidman , Vivien Sheehan , Stephanie L. Sherman , Amol Shetty , Aniket Shetty , Brian Silver , Josh Smith , Tanja Smith , Sylvia Smoller , Beverly Snively , Michael Snyder , Tamar Sofer , Nona Sotoodehnia , Adrienne M. Stilp , Garrett Storm , Elizabeth Streeten , Jessica Lasky Su , Yun Ju Sung , Jody Sylvia , Adam Szpiro , Carole Sztalryd , Daniel Taliun , Hua Tang , Matthew Taylor , Simeon Taylor , Marilyn Telen , Timothy A. Thornton , Machiko Threlkeld , Lesley Tinker , David Tirschwell , Sarah Tishkoff , Hemant Tiwari , Catherine Tong , Michael Tsai , Dhananjay Vaidya , David Van Den 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 Xueyan Zhao , Wei Zhao , Degui Zhi , Xiang Zhou , Xiaofeng Zhu , Michael Zody , Sebastian Zoellner , 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 ,
Nature ( IF 64.8 ) Pub Date : 2020-10-14 , DOI: 10.1038/s41586-020-2819-2 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 , Abhishek Niroula , 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 , 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 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 , Dabeeru C. Rao , Dawood Darbar , Jee-Young Moon , Russell P. Tracy , Erin J. 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 , Ester C. Sabino , John Blangero , L. Keoki Williams , 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 , Namiko Abe , Christine Albert , Laura Almasy , Alvaro Alonso , Seth Ament , Peter Anderson , Pramod Anugu , Deborah Applebaum-Bowden , Dan Arking , Allison Ashley-Koch , Stella Aslibekyan , Tim Assimes , Dimitrios Avramopoulos , John Barnard , R. Graham Barr , Emily Barron-Casella , Lucas Barwick , Terri Beaty , Gerald Beck , Diane Becker , Rebecca Beer , Amber Beitelshees , Emelia Benjamin , Panagiotis Benos , Marcos Bezerra , Larry Bielak , Russell Bowler , Jennifer Brody , Ulrich Broeckel , 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 Hoan 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 El Boueiz , Leslie Emery , Serpil Erzurum , Charles Farber , Matthew Flickinger , Nora Franceschini , Chris Frazar , Mao Fu , Stephanie M. Fullerton , Lucinda Fulton , Stacey Gabriel , Weiniu Gan , Shanshan Gao , Yan Gao , Margery Gass , Bruce Gelb , Xiaoqi Geng , Mark Geraci , Soren Germer , Robert Gerszten , Auyon Ghosh , Richard Gibbs , Chris Gignoux , Mark Gladwin , David Glahn , Da-Wei Gong , Harald Goring , Sharon Graw , Daniel Grine , C. Charles Gu , Yue Guan , Namrata Gupta , Jeff Haessler , Michael Hall , Daniel Harris , Nicola L. 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 A. Jhun , Craig Johnson , Rich Johnston , Kimberly Jones , Hyun Min Kang , Shannon Kelly , Michael Kessler , Alyna Khan , Wonji Kim , Greg Kinney , Holly Kramer , Christoph Lange , Meryl LeBoff , Seunggeun Shawn Lee , Wen-Jane Lee , Jonathon LeFaive , David Levine , Joshua Lewis , Xiaohui Li , Yun Li , Henry Lin , Honghuang Lin , Keng Han 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 , Nancy Min , Mollie Minear , Ryan L. Minster , Matt Moll , Courtney Montgomery , Solomon Musani , Stanford Mwasongwe , Josyf C. Mychaleckyj , Girish Nadkarni , Rakhi Naik , Take Naseri , Sergei Nekhai , Sarah C. 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 , Ulrike Peters , Patricia Peyser , Lawrence S. Phillips , Toni Pollin , Wendy Post , Julia Powers Becker , Meher Preethi Boorgula , Michael Preuss , Pankaj Qasba , Dandi Qiao , Zhaohui Qin , Laura Rasmussen-Torvik , Aakrosh Ratan , Robert Reed , Elizabeth Regan , Muagututi‘a Sefuiva Reupena , Ken Rice , Carolina Roselli , Ingo Ruczinski , Pamela Russell , Sarah Ruuska , Kathleen Ryan , Danish Saleheen , Shabnam Salimi , Steven Salzberg , Kevin Sandow , Christopher Scheller , Ellen Schmidt , Karen Schwander , Frank Sciurba , Christine Seidman , Jonathan Seidman , Vivien Sheehan , Stephanie L. Sherman , Amol Shetty , Aniket Shetty , Brian Silver , Josh Smith , Tanja Smith , Sylvia Smoller , Beverly Snively , Michael Snyder , Tamar Sofer , Nona Sotoodehnia , Adrienne M. Stilp , Garrett Storm , Elizabeth Streeten , Jessica Lasky Su , Yun Ju Sung , Jody Sylvia , Adam Szpiro , Carole Sztalryd , Daniel Taliun , Hua Tang , Matthew Taylor , Simeon Taylor , Marilyn Telen , Timothy A. Thornton , Machiko Threlkeld , Lesley Tinker , David Tirschwell , Sarah Tishkoff , Hemant Tiwari , Catherine Tong , Michael Tsai , Dhananjay Vaidya , David Van Den 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 Xueyan Zhao , Wei Zhao , Degui Zhi , Xiang Zhou , Xiaofeng Zhu , Michael Zody , Sebastian Zoellner , 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 ,
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. 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.
中文翻译：
97,691 个全基因组中克隆性造血的遗传原因
年龄是大多数慢性人类疾病的主要危险因素，但衰老赋予这种风险的机制在很大程度上是未知的 1 。与年龄相关的获得体细胞突变会导致再生造血干细胞群的克隆扩增，最近与血液癌症 2 – 4 和冠心病 5 有关——这种现象被称为不确定潜能的克隆性造血 (CHIP) 6 。同时分析种系和体细胞全基因组序列提供了识别 CHIP 根本原因的机会。在这里，我们分析了国家心肺血液研究所精准医学跨组学 (TOPMed) 计划中来自不同血统的 97,691 名参与者的高覆盖率全基因组序列，并确定了 4,229 名具有 CHIP 的个体。我们确定了与特定于不同 CHIP 驱动基因的血细胞、脂质和炎症特征的关联。一组全基因组种系遗传变异的关联使得能够识别与 CHIP 状态相关的三个基因位点，包括 TET2 的一个位点，该位点特定于非洲血统的个体。对 TET2 种系基因座的计算机信息体外评估能够识别破坏 TET2 远端增强子的因果变异，从而增加造血干细胞的自我更新。总体而言，我们观察到种系遗传变异塑造造血干细胞功能，通过克隆造血特有的机制以及导致跨组织体细胞突变的共享机制导致 CHIP。分析97，
更新日期：2020-10-14
中文翻译：
97,691 个全基因组中克隆性造血的遗传原因
年龄是大多数慢性人类疾病的主要危险因素，但衰老赋予这种风险的机制在很大程度上是未知的 1 。与年龄相关的获得体细胞突变会导致再生造血干细胞群的克隆扩增，最近与血液癌症 2 – 4 和冠心病 5 有关——这种现象被称为不确定潜能的克隆性造血 (CHIP) 6 。同时分析种系和体细胞全基因组序列提供了识别 CHIP 根本原因的机会。在这里，我们分析了国家心肺血液研究所精准医学跨组学 (TOPMed) 计划中来自不同血统的 97,691 名参与者的高覆盖率全基因组序列，并确定了 4,229 名具有 CHIP 的个体。我们确定了与特定于不同 CHIP 驱动基因的血细胞、脂质和炎症特征的关联。一组全基因组种系遗传变异的关联使得能够识别与 CHIP 状态相关的三个基因位点，包括 TET2 的一个位点，该位点特定于非洲血统的个体。对 TET2 种系基因座的计算机信息体外评估能够识别破坏 TET2 远端增强子的因果变异，从而增加造血干细胞的自我更新。总体而言，我们观察到种系遗传变异塑造造血干细胞功能，通过克隆造血特有的机制以及导致跨组织体细胞突变的共享机制导致 CHIP。分析97，
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