Inherited causes of clonal haematopoiesis in 97,691 whole genomes.
Alexander G. Bick,Joshua S. Weinstock,Satish K. Nandakumar,Satish K. Nandakumar,Charles P. Fulco,Charles P. Fulco,Erik L. Bao,Erik L. Bao,Seyedeh M. Zekavat,Seyedeh M. Zekavat,Mindy D. Szeto,Xiaotian Liao,Xiaotian Liao,Matthew Leventhal,Joseph Nasser,Kyle Chang,Cecelia A. Laurie,Bala Bharathi Burugula,Christopher J. Gibson,Amy E. Lin,Margaret A. Taub,François Aguet,Kristin G. Ardlie,Braxton D. Mitchell,Braxton D. Mitchell,Kathleen C. Barnes,Kathleen C. Barnes,Arden Moscati,Myriam Fornage,Susan Redline,Susan Redline,Susan Redline,Bruce M. Psaty,Edwin K. Silverman,Edwin K. Silverman,Scott T. Weiss,Scott T. Weiss,Nicholette D. Palmer,Ramachandran S. Vasan,Esteban G. Burchard,Sharon L.R. Kardia,Jiang He,Robert C. Kaplan,Robert C. Kaplan,Nicholas L. Smith,Nicholas L. Smith,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,Brian E. Cade,Joshua C. Bis,Michael H. Cho,Michael H. Cho,Jessica Lasky-Su,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,Susan R. Heckbert,Hemant K. Tiwari,Ivana V. Yang,John A. Heit,Steven A. Lubitz,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,Priyadarshini Kachroo,Barry I. Freedman,Daniel Levy,Lawrence F. Bielak,James E. Hixson,James S. Floyd,Eric A. Whitsel,Patrick T. Ellinor,Patrick T. Ellinor,Marguerite R. Irvin,Tasha E. Fingerlin,Laura M. Raffield,Sebastian M. Armasu,Marsha M. Wheeler,Ester Cerdeira Sabino,John Blangero,L. Keoki Williams,Bruce D. Levy,Bruce D. Levy,Wayne Huey-Herng Sheu,Dan M. Roden,Eric Boerwinkle,Eric Boerwinkle,JoAnn E. Manson,JoAnn E. Manson,Rasika A. Mathias,Pinkal Desai,Kent D. Taylor,Andrew D. Johnson,Paul L. Auer,Charles Kooperberg,Cathy C. Laurie,Thomas W. Blackwell,Albert V. Smith,Hongyu Zhao,Ethan M. Lange,Leslie A. Lange,Stephen S. Rich,Jerome I. Rotter,James G. Wilson,James G. Wilson,Paul Scheet,Jacob O. Kitzman,Eric S. Lander,Eric S. Lander,Eric S. Lander,Jesse M. Engreitz,Jesse M. Engreitz,Benjamin L. Ebert,Alexander P. Reiner,Alexander P. Reiner,Siddhartha Jaiswal,Gonçalo R. Abecasis,Gonçalo R. Abecasis,Vijay G. Sankaran,Vijay G. Sankaran,Sekar Kathiresan,Pradeep Natarajan,Pradeep Natarajan +165 more
TLDR
Analysis of 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 programme enables simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells.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.read more
Citations
More filters
Journal ArticleDOI
Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association
TL;DR: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update as discussed by the authors .
Journal ArticleDOI
Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.
Daniel Taliun,Daniel N. Harris,Michael D. Kessler,Jedidiah Carlson,Jedidiah Carlson,Zachary A. Szpiech,Raul Torres,Sarah A Gagliano Taliun,André Corvelo,Stephanie M. Gogarten,Hyun Min Kang,Achilleas N. Pitsillides,Jonathon LeFaive,Seung-been Lee,Xiaowen Tian,Brian L. Browning,Sayantan Das,Anne-Katrin Emde,Wayne E. Clarke,Douglas Loesch,Amol C. Shetty,Thomas W. Blackwell,Albert V. Smith,Quenna Wong,Xiaoming Liu,Matthew P. Conomos,Dean Bobo,François Aguet,Christine M. Albert,Alvaro Alonso,Kristin G. Ardlie,Dan E. Arking,Stella Aslibekyan,Paul L. Auer,John Barnard,R. Graham Barr,Lucas Barwick,Lewis C. Becker,Rebecca L. Beer,Emelia J. Benjamin,Lawrence F. Bielak,John Blangero,Michael Boehnke,Donald W. Bowden,Jennifer A. Brody,Esteban G. Burchard,Brian E. Cade,Brian E. Cade,James F. Casella,Brandon Chalazan,Daniel I. Chasman,Daniel I. Chasman,Yii-Der Ida Chen,Michael H. Cho,Seung Hoan Choi,Mina K. Chung,Mina K. Chung,Mina K. Chung,Clary B. Clish,Adolfo Correa,Joanne E. Curran,Brian Custer,Dawood Darbar,Michelle Daya,Mariza de Andrade,Dawn L. DeMeo,Susan K. Dutcher,Patrick T. Ellinor,Leslie S. Emery,Celeste Eng,Diane Fatkin,Diane Fatkin,Diane Fatkin,Tasha E. Fingerlin,Lukas Forer,Myriam Fornage,Nora Franceschini,Christian Fuchsberger,Stephanie M. Fullerton,Soren Germer,Mark T. Gladwin,Daniel J. Gottlieb,Daniel J. Gottlieb,Xiuqing Guo,Michael E. Hall,Jiang He,Nancy L. Heard-Costa,Susan R. Heckbert,Marguerite R. Irvin,Jill M. Johnsen,Andrew D. Johnson,Robert C. Kaplan,Sharon L.R. Kardia,Tanika N. Kelly,Shannon Kelly,Eimear E. Kenny,Douglas P. Kiel,Robert Klemmer,Barbara A. Konkle,Charles Kooperberg,Anna Köttgen,Anna Köttgen,Leslie A. Lange,Jessica Lasky-Su,Daniel Levy,Daniel Levy,Xihong Lin,Keng-Han Lin,Chunyu Liu,Ruth J. F. Loos,Lori Garman,Robert E. Gerszten,Steven A. Lubitz,Kathryn L. Lunetta,Angel C.Y. Mak,Ani Manichaikul,Alisa K. Manning,Alisa K. Manning,Rasika A. Mathias,David D. McManus,Stephen T. McGarvey,James B. Meigs,Deborah A. Meyers,Julie L. Mikulla,Mollie A. Minear,Braxton D. Mitchell,Braxton D. Mitchell,Sanghamitra Mohanty,May E. Montasser,Courtney G. Montgomery,Alanna C. Morrison,Joanne M. Murabito,Andrea Natale,Pradeep Natarajan,Sarah C. Nelson,Kari E. North,Jeffrey R. O'Connell,Nicholette D. Palmer,Nathan Pankratz,Gina M. Peloso,Patricia A. Peyser,Jacob Pleiness,Wendy S. Post,Bruce M. Psaty,D. C. Rao,Susan Redline,Susan Redline,Alexander P. Reiner,Alexander P. Reiner,Dan M. Roden,Jerome I. Rotter,Ingo Ruczinski,Chloé Sarnowski,Sebastian Schoenherr,David A. Schwartz,Jeong-Sun Seo,Sudha Seshadri,Vivien A. Sheehan,Wayne Huey-Herng Sheu,M. Benjamin Shoemaker,Nicholas L. Smith,Nicholas L. Smith,Nicholas L. Smith,Jennifer A. Smith,Nona Sotoodehnia,Adrienne M. Stilp,Weihong Tang,Kent D. Taylor,Marilyn J. Telen,Timothy A. Thornton,Russell P. Tracy,David Van Den Berg,Ramachandran S. Vasan,Karine A. Viaud-Martinez,Scott I. Vrieze,Daniel E. Weeks,Bruce S. Weir,Scott T. Weiss,Lu-Chen Weng,Cristen J. Willer,Yingze Zhang,Xutong Zhao,Donna K. Arnett,Allison E. Ashley-Koch,Kathleen C. Barnes,Eric Boerwinkle,Eric Boerwinkle,Stacey Gabriel,Richard A. Gibbs,Kenneth Rice,Stephen S. Rich,Edwin K. Silverman,Pankaj Qasba,Weiniu Gan,George J. Papanicolaou,Deborah A. Nickerson,Sharon R. Browning,Michael C. Zody,Sebastian Zöllner,James G. Wilson,L. Adrienne Cupples,Cathy C. Laurie,Cashell E. Jaquish,Ryan D. Hernandez,Timothy D. O’Connor,Gonçalo R. Abecasis +205 more
TL;DR: The Trans-Omics for Precision Medicine (TOPMed) project as discussed by the authors aims to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases.
Journal ArticleDOI
Liquid biopsy enters the clinic - implementation issues and future challenges.
TL;DR: In this article, the authors discuss key issues and gaps in technology, clinical trial methodologies and logistics for the eventual integration of liquid biopsy into the clinical workflow, and discuss the potential applications of this technology in cancer screening and diagnosis.
Journal ArticleDOI
Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association
TL;DR: The 2023 Statistical Update as mentioned in this paper provides the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health.
Journal ArticleDOI
Genome-wide enhancer maps link risk variants to disease genes
Joseph Nasser,Drew T. Bergman,Charles P. Fulco,Charles P. Fulco,Philine Guckelberger,Philine Guckelberger,Benjamin R. Doughty,Benjamin R. Doughty,Tejal A. Patwardhan,Tejal A. Patwardhan,Thouis R. Jones,Tung T. Nguyen,Jacob C. Ulirsch,Jacob C. Ulirsch,Fritz Lekschas,Kristy Mualim,Heini M. Natri,Elle M. Weeks,Glen Munson,Michael Kane,Helen Y. Kang,Ang Cui,Ang Cui,John P. Ray,John P. Ray,Thomas Eisenhaure,Ryan L. Collins,Ryan L. Collins,Kushal K. Dey,Hanspeter Pfister,Alkes L. Price,Alkes L. Price,Charles B. Epstein,Anshul Kundaje,Ramnik J. Xavier,Mark J. Daly,Hailiang Huang,Hailiang Huang,Hilary K. Finucane,Hilary K. Finucane,Nir Hacohen,Nir Hacohen,Eric S. Lander,Jesse M. Engreitz,Jesse M. Engreitz +44 more
TL;DR: In this article, the activity-by-contact (ABC) model was applied to create enhancer-gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants.
References
More filters
Journal ArticleDOI
Fitting Linear Mixed-Effects Models Using lme4
TL;DR: In this article, a model is described in an lmer call by a formula, in this case including both fixed-and random-effects terms, and the formula and data together determine a numerical representation of the model from which the profiled deviance or the profeatured REML criterion can be evaluated as a function of some of model parameters.
Journal ArticleDOI
STAR: ultrafast universal RNA-seq aligner
Alexander Dobin,Carrie A. Davis,Felix Schlesinger,Jorg Drenkow,Chris Zaleski,Sonali Jha,Philippe Batut,Mark Chaisson,Thomas R. Gingeras +8 more
TL;DR: The Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure outperforms other aligners by a factor of >50 in mapping speed.
Journal ArticleDOI
Meta-Analysis: A Constantly Evolving Research Integration Tool
TL;DR: The four articles in this special section onMeta-analysis illustrate some of the complexities entailed in meta-analysis methods and contributes both to advancing this methodology and to the increasing complexities that can befuddle researchers.
Linear Mixed-Effects Models using 'Eigen' and S4
TL;DR: The core computational algorithms are implemented using the Eigen C++ library for numerical linear algebra and RcppEigen``glue''.
Journal ArticleDOI
Adjusting batch effects in microarray expression data using empirical Bayes methods
TL;DR: This paper proposed parametric and non-parametric empirical Bayes frameworks for adjusting data for batch effects that is robust to outliers in small sample sizes and performs comparable to existing methods for large samples.
Related Papers (5)
Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes
Siddhartha Jaiswal,Pierre Fontanillas,Jason Flannick,Jason Flannick,Alisa K. Manning,Peter V. Grauman,Brenton G. Mar,Brenton G. Mar,R. Coleman Lindsley,Craig H. Mermel,Noël P. Burtt,Alejandro Chavez,John M. Higgins,Vladislav Moltchanov,Vladislav Moltchanov,Frank C. Kuo,Michael J. Kluk,Brian E. Henderson,Leena Kinnunen,Heikki A. Koistinen,Heikki A. Koistinen,Claes Ladenvall,Gad Getz,Adolfo Correa,Benjamin F. Banahan,Stacey Gabriel,Stacey Gabriel,Sekar Kathiresan,Heather M. Stringham,Mark I. McCarthy,Michael Boehnke,Jaakko Tuomilehto,Jaakko Tuomilehto,Jaakko Tuomilehto,Christopher A. Haiman,Leif Groop,Gil Atzmon,James G. Wilson,Donna Neuberg,David Altshuler,Benjamin L. Ebert +40 more
Clonal Hematopoiesis and risk of atherosclerotic cardiovascular disease
Siddhartha Jaiswal,Pradeep Natarajan,Pradeep Natarajan,Alexander J. Silver,Christopher J. Gibson,Alexander G. Bick,Eugenia Shvartz,Marie McConkey,Namrata Gupta,Stacey Gabriel,Diego Ardissino,Usman Baber,Roxana Mehran,Valentin Fuster,Valentin Fuster,John Danesh,Philippe M. Frossard,Danish Saleheen,Olle Melander,Olle Melander,Galina K. Sukhova,Donna Neuberg,Peter Libby,Sekar Kathiresan,Benjamin L. Ebert +24 more
Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence
Giulio Genovese,Anna K. Kähler,Robert E. Handsaker,Johan Lindberg,Samuel A. Rose,Samuel F. Bakhoum,Kimberly Chambert,Eran Mick,Benjamin M. Neale,Menachem Fromer,Shaun Purcell,Oscar Svantesson,Mikael Landén,Martin Höglund,Sören Lehmann,Stacey Gabriel,Jennifer L. Moran,Eric S. Lander,Patrick F. Sullivan,Pamela Sklar,Henrik Grönberg,Christina M. Hultman,Steven A. McCarroll +22 more
Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice
José J. Fuster,Susan MacLauchlan,María A. Zuriaga,Maya N. Polackal,Allison C. Ostriker,Raja Chakraborty,Chia-Ling Wu,Soichi Sano,Sujatha Muralidharan,Cristina Rius,Jacqueline T Vuong,Sophia Jacob,Varsha Muralidhar,Avril A. B. Robertson,Mark E. Cooper,Vicente Andrés,Karen K. Hirschi,Kathleen A. Martin,Kenneth Walsh +18 more
Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly.
Florian Zink,Simon N. Stacey,Gudmundur L. Norddahl,Michael L. Frigge,Olafur T. Magnusson,Ingileif Jonsdottir,Ingileif Jonsdottir,Thorgeir E. Thorgeirsson,Asgeir Sigurdsson,Sigurjon A. Gudjonsson,Julius Gudmundsson,Jon G. Jonasson,Laufey Tryggvadottir,Thorvaldur Jonsson,Agnar Helgason,Arnaldur Gylfason,Patrick Sulem,Thorunn Rafnar,Unnur Thorsteinsdottir,Unnur Thorsteinsdottir,Daniel F. Gudbjartsson,Daniel F. Gudbjartsson,Gisli Masson,Augustine Kong,Kari Stefansson,Kari Stefansson +25 more