An efficient and scalable analysis framework for variant extraction and refinement from population-scale DNA sequence data
TLDR
GotCloud is presented, a pipeline for efficiently detecting and genotyping high-quality variants from large-scale sequencing data that automates sequence alignment, sample-level quality control, variant calling, filtering of likely artifacts using machine-learning techniques, and genotype refinement using haplotype information.Abstract:
The analysis of next-generation sequencing data is computationally and statistically challenging because of the massive volume of data and imperfect data quality. We present GotCloud, a pipeline for efficiently detecting and genotyping high-quality variants from large-scale sequencing data. GotCloud automates sequence alignment, sample-level quality control, variant calling, filtering of likely artifacts using machine-learning techniques, and genotype refinement using haplotype information. The pipeline can process thousands of samples in parallel and requires less computational resources than current alternatives. Experiments with whole-genome and exome-targeted sequence data generated by the 1000 Genomes Project show that the pipeline provides effective filtering against false positive variants and high power to detect true variants. Our pipeline has already contributed to variant detection and genotyping in several large-scale sequencing projects, including the 1000 Genomes Project and the NHLBI Exome Sequencing Project. We hope it will now prove useful to many medical sequencing studies.read more
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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.
Posted ContentDOI
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,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,Quenna Wong,François Aguet,Christine M. Albert,Alvaro Alonso,Kristin G. Ardlie,Stella Aslibekyan,Paul L. Auer,John Barnard,R. Graham Barr,R. Graham Barr,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,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,Diane Fatkin,Diane Fatkin,Diane Fatkin,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,Sharon L.R. Kardia,Tanika N. Kelly,Shannon Kelly,Eimear E. Kenny,Douglas P. Kiel,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,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,Jeong-Sun Seo,Sudha Seshadri,Vivien A. Sheehan,M. Benjamin Shoemaker,Albert V. 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,Ryan D. Hernandez,Timothy D. O’Connor,Gonçalo R. Abecasis +194 more
TL;DR: The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation as well as resources and early insights from the sequence data.
Journal ArticleDOI
Discovery of common and rare genetic risk variants for colorectal cancer
Jeroen R. Huyghe,Stephanie A. Bien,Tabitha A. Harrison,Hyun Min Kang,Sai Chen,Stephanie L. Schmit,David V. Conti,Conghui Qu,Jihyoun Jeon,Christopher K. Edlund,Peyton Greenside,Michael Wainberg,Fredrick R. Schumacher,Joshua D. Smith,David M. Levine,Sarah C. Nelson,Nasa Sinnott-Armstrong,Demetrius Albanes,M. Henar Alonso,Kristin E. Anderson,Coral Arnau-Collell,Volker Arndt,Christina Bamia,Barbara L. Banbury,John A. Baron,Sonja I. Berndt,Stéphane Bézieau,D. Timothy Bishop,Juergen Boehm,Heiner Boeing,Hermann Brenner,Stefanie Brezina,Stephan Buch,Daniel D. Buchanan,Daniel D. Buchanan,Andrea N. Burnett-Hartman,Katja Butterbach,Bette J. Caan,Peter T. Campbell,Christopher S. Carlson,Christopher S. Carlson,Sergi Castellví-Bel,Andrew T. Chan,Andrew T. Chan,Jenny Chang-Claude,Jenny Chang-Claude,Stephen J. Chanock,Maria Dolores Chirlaque,Sang-Hee Cho,Charles M. Connolly,Amanda J. Cross,Katarina Cuk,Keith R. Curtis,Albert de la Chapelle,Kimberly F. Doheny,David Duggan,Douglas F. Easton,Sjoerd G. Elias,Faye Elliott,Dallas R. English,Dallas R. English,Edith J. M. Feskens,Jane C. Figueiredo,Jane C. Figueiredo,Rocky Fischer,Liesel M. FitzGerald,Liesel M. FitzGerald,David Forman,Manish Gala,Steven Gallinger,W. James Gauderman,Graham G. Giles,Graham G. Giles,Elizabeth M. Gillanders,Jian Gong,Phyllis J. Goodman,William M. Grady,John S. Grove,Andrea Gsur,Marc J. Gunter,Robert W. Haile,Jochen Hampe,Heather Hampel,Sophia Harlid,Richard B. Hayes,Philipp Hofer,Michael Hoffmeister,John L. Hopper,John L. Hopper,Wan-Ling Hsu,Wen Yi Huang,Thomas J. Hudson,David J. Hunter,David J. Hunter,Gemma Ibáñez-Sanz,Gregory Idos,Roxann G. Ingersoll,Rebecca D. Jackson,Eric J. Jacobs,Mark A. Jenkins,Amit Joshi,Corinne E. Joshu,Temitope O. Keku,Timothy J. Key,Hyeong Rok Kim,Emiko Kobayashi,Laurence N. Kolonel,Charles Kooperberg,Tilman Kühn,Sébastien Küry,Sun-Seog Kweon,Susanna C. Larsson,Cecelia A. Laurie,Loic Le Marchand,Suzanne M. Leal,Soo-Chin Lee,Flavio Lejbkowicz,Mathieu Lemire,Christopher I. Li,Li Li,Wolfgang Lieb,Yi Lin,Annika Lindblom,Noralane M. Lindor,Hua Ling,Tin Louie,Satu Männistö,Sanford D. Markowitz,Vicente Martín,Giovanna Masala,Caroline McNeil,Marilena Melas,Roger L. Milne,Roger L. Milne,Lorena Moreno,Neil Murphy,Robin Myte,Alessio Naccarati,Polly A. Newcomb,Polly A. Newcomb,Kenneth Offit,Kenneth Offit,Shuji Ogino,Shuji Ogino,N. Charlotte Onland-Moret,Barbara Pardini,Patrick S. Parfrey,Rachel Pearlman,Vittorio Perduca,Vittorio Perduca,Paul D.P. Pharoah,Mila Pinchev,Elizabeth A. Platz,Ross L. Prentice,Elizabeth W. Pugh,Leon Raskin,Gad Rennert,Gad Rennert,Hedy S. Rennert,Hedy S. Rennert,Elio Riboli,Miguel Rodríguez-Barranco,Jane Romm,Lori C. Sakoda,Lori C. Sakoda,Clemens Schafmayer,Robert E. Schoen,Daniela Seminara,Mitul Shah,Tameka Shelford,Min-Ho Shin,Katerina Shulman,Sabina Sieri,Martha L. Slattery,Melissa C. Southey,Zsofia K. Stadler,Christa Stegmaier,Yu Ru Su,Catherine M. Tangen,Stephen N. Thibodeau,Duncan C. Thomas,Sushma S. Thomas,Amanda E. Toland,Antonia Trichopoulou,Cornelia M. Ulrich,David Van Den Berg,Fränzel J.B. Van Duijnhoven,Bethany Van Guelpen,Henk J. van Kranen,Joseph Vijai,Kala Visvanathan,Pavel Vodicka,Pavel Vodicka,Ludmila Vodickova,Ludmila Vodickova,Veronika Vymetalkova,Veronika Vymetalkova,Korbinian Weigl,Korbinian Weigl,Stephanie J. Weinstein,Emily White,Aung Ko Win,Aung Ko Win,C. Roland Wolf,Alicja Wolk,Alicja Wolk,Michael O. Woods,Anna H. Wu,Syed H.E. Zaidi,Brent W. Zanke,Qing Zhang,Wei Zheng,Peter C. Scacheri,John D. Potter,Michael C. Bassik,Anshul Kundaje,Graham Casey,Victor Moreno,Gonçalo R. Abecasis,Deborah A. Nickerson,Stephen B. Gruber,Li Hsu,Li Hsu,Ulrike Peters,Ulrike Peters +224 more
TL;DR: Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.
Journal ArticleDOI
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
TL;DR: 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.
Journal ArticleDOI
Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers
Carlo Sidore,Fabio Busonero,Andrea Maschio,Eleonora Porcu,Silvia Naitza,Magdalena Zoledziewska,Antonella Mulas,Giorgio Pistis,Maristella Steri,Fabrice Danjou,Alan Kwong,Vicente Diego Ortega Del Vecchyo,Charleston W. K. Chiang,Jennifer L. Bragg-Gresham,Maristella Pitzalis,Ramaiah Nagaraja,Brendan Tarrier,Christine Brennan,Sergio Uzzau,Christian Fuchsberger,Rossano Atzeni,Frederic Reinier,Riccardo Berutti,Jie Huang,Nicholas J. Timpson,Daniela Toniolo,Paolo Gasparini,Giovanni Malerba,George Dedoussis,Eleftheria Zeggini,Nicole Soranzo,Chris Jones,Robert H. Lyons,Andrea Angius,Hyun Min Kang,John Novembre,Serena Sanna,David Schlessinger,Francesco Cucca,Gonçalo R. Abecasis +39 more
TL;DR: The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population of Sardinians.
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