Second-generation PLINK: rising to the challenge of larger and richer datasets
Christopher C. Chang,Carson C. Chow,Laurent C. A. M. Tellier,Shashaank Vattikuti,Shaun Purcell,James J. Lee +5 more
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TLDR
PLINK as discussed by the authors is a C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics, which has been widely used in the literature.Abstract:
PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for even faster and more scalable implementations of key functions. In addition, GWAS and population-genetic data now frequently contain probabilistic calls, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format.
To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(sqrt(n))-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. This will be followed by PLINK 2.0, which will introduce (a) a new data format capable of efficiently representing probabilities, phase, and multiallelic variants, and (b) extensions of many functions to account for the new types of information.
The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.read more
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Journal ArticleDOI
Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations
Amit Khera,Mark Chaffin,Krishna G. Aragam,Mary E. Haas,Carolina Roselli,Seung Hoan Choi,Pradeep Natarajan,Eric S. Lander,Steven A. Lubitz,Steven A. Lubitz,Patrick T. Ellinor,Patrick T. Ellinor,Sekar Kathiresan +12 more
TL;DR: Genome-wide polygenic risk scores derived from GWAS data for five common diseases can identify subgroups of the population with risk approaching or exceeding that of a monogenic mutation.
Journal ArticleDOI
Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals
James J. Lee,Robbee Wedow,Aysu Okbay,Edward Kong,Omeed Maghzian,Meghan Zacher,Tuan Anh Nguyen-Viet,Peter Bowers,Julia Sidorenko,Julia Sidorenko,Richard Karlsson Linnér,Richard Karlsson Linnér,Mark Alan Fontana,Mark Alan Fontana,Tushar Kundu,Chanwook Lee,Hui Li,Ruoxi Li,Rebecca Royer,Pascal Timshel,Pascal Timshel,Raymond K. Walters,Raymond K. Walters,Emily A. Willoughby,Loic Yengo,Maris Alver,Yanchun Bao,David W. Clark,Felix R. Day,Nicholas A. Furlotte,Peter K. Joshi,Peter K. Joshi,Kathryn E. Kemper,Aaron Kleinman,Claudia Langenberg,Reedik Mägi,Joey W. Trampush,Shefali S. Verma,Yang Wu,Max Lam,Jing Hua Zhao,Zhili Zheng,Zhili Zheng,Jason D. Boardman,Harry Campbell,Jeremy Freese,Kathleen Mullan Harris,Caroline Hayward,Pamela Herd,Pamela Herd,Meena Kumari,Todd Lencz,Todd Lencz,Jian'an Luan,Anil K. Malhotra,Anil K. Malhotra,Andres Metspalu,Lili Milani,Ken K. Ong,John R. B. Perry,David J. Porteous,Marylyn D. Ritchie,Melissa C. Smart,Blair H. Smith,Joyce Y. Tung,Nicholas J. Wareham,James F. Wilson,Jonathan P. Beauchamp,Dalton Conley,Tõnu Esko,Steven F. Lehrer,Steven F. Lehrer,Steven F. Lehrer,Patrik K. E. Magnusson,Sven Oskarsson,Tune H. Pers,Tune H. Pers,Matthew R. Robinson,Matthew R. Robinson,Kevin Thom,Chelsea Watson,Christopher F. Chabris,Michelle N. Meyer,David Laibson,Jian Yang,Magnus Johannesson,Philipp Koellinger,Philipp Koellinger,Patrick Turley,Patrick Turley,Peter M. Visscher,Daniel J. Benjamin,Daniel J. Benjamin,David Cesarini,David Cesarini +94 more
TL;DR: A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance ineducational attainment and 7–10% ofthe variance in cognitive performance, which substantially increases the utility ofpolygenic scores as tools in research.
Journal ArticleDOI
Genomewide Association Study of Severe Covid-19 with Respiratory Failure.
David Ellinghaus,Frauke Degenhardt,Luis Bujanda,Maria Buti,Agustín Albillos,Pietro Invernizzi,J. Fernández,Daniele Prati,Guido Baselli,Rosanna Asselta,Marit Mæhle Grimsrud,Chiara Milani,Fatima Aziz,Jan Christian Kässens,Sandra May,Mareike Wendorff,Lars Wienbrandt,Florian Uellendahl-Werth,Tenghao Zheng,Xiaoli Yi,Raúl de Pablo,Adolfo Garrido Chercoles,Adriana Palom,Alba Estela Garcia-Fernandez,Francisco Rodriguez-Frias,Alberto Zanella,Alessandra Bandera,Alessandro Protti,Alessio Aghemo,Ana Lleo,Andrea Biondi,Andrea Caballero-Garralda,Andrea Gori,Anja Tanck,Anna Carreras Nolla,Anna Latiano,Anna Ludovica Fracanzani,Anna Peschuck,Antonio Julià,Antonio Pesenti,Antonio Voza,David Jiménez,Beatriz Mateos,Beatriz Nafria Jimenez,Carmen Quereda,Cinzia Paccapelo,Christoph Gassner,Claudio Angelini,Cristina Cea,Aurora Solier,David Pestana,Eduardo Muñiz-Diaz,Elena Sandoval,Elvezia Maria Paraboschi,Enrique Navas,Félix García Sánchez,Ferruccio Ceriotti,F. Martinelli-Boneschi,Flora Peyvandi,Francesco Blasi,Luis Téllez,Albert Blanco-Grau,Georg Hemmrich-Stanisak,Giacomo Grasselli,Giorgio Costantino,Giulia Cardamone,Giuseppe Foti,Serena Aneli,Hayato Kurihara,Hesham ElAbd,Ilaria My,Iván Galván-Femenía,Javier Martin,Jeanette Erdmann,José Ferrusquía-Acosta,Koldo Garcia-Etxebarria,Laura Izquierdo-Sanchez,Laura Rachele Bettini,Lauro Sumoy,Leonardo Terranova,Leticia Moreira,Luigi Santoro,Luigia Scudeller,Francisco Mesonero,Luisa Roade,Malte C. Rühlemann,Marco Schaefer,Maria Carrabba,Mar Riveiro-Barciela,Maria Eloina Figuera Basso,Maria Grazia Valsecchi,María Hernández-Tejero,Marialbert Acosta-Herrera,Mariella D'Angiò,Marina Baldini,Marina Cazzaniga,Martin Schulzky,Maurizio Cecconi,Michael Wittig,Michele Ciccarelli,Miguel Rodríguez-Gandía,Monica Bocciolone,Monica Miozzo,Nicola Montano,Nicole Braun,Nicoletta Sacchi,Nilda Martinez,Onur Özer,Orazio Palmieri,Paola Faverio,Paoletta Preatoni,Paolo Bonfanti,Paolo Omodei,Paolo Tentorio,Pedro Castro,Pedro M. Rodrigues,Aaron Blandino Ortiz,Rafael de Cid,Ricard Ferrer,Roberta Gualtierotti,Rosa Nieto,Siegfried Goerg,Salvatore Badalamenti,Sara Marsal,Giuseppe Matullo,Serena Pelusi,Simonas Juzenas,Stefano Aliberti,Valter Monzani,Victor Moreno,Tanja Wesse,Tobias L. Lenz,Tomás Pumarola,Valeria Rimoldi,Silvano Bosari,Wolfgang Albrecht,Wolfgang Peter,Manuel Romero-Gómez,Mauro D'Amato,Stefano Duga,Jesus M. Banales,Johannes R. Hov,Trine Folseraas,Luca Valenti,Andre Franke,Tom H. Karlsen +145 more
TL;DR: A 3p21.31 gene cluster is identified as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and a potential involvement of the ABO blood-group system is confirmed.
Journal ArticleDOI
Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.
Iris E. Jansen,Jeanne E. Savage,Kyoko Watanabe,Julien Bryois,Dylan M. Williams,Stacy Steinberg,Julia Sealock,Ida K. Karlsson,Ida K. Karlsson,Sara Hägg,Lavinia Athanasiu,Lavinia Athanasiu,Nicola Voyle,Petroula Proitsi,Aree Witoelar,Sven Stringer,Dag Aarsland,Dag Aarsland,Ina S. Almdahl,Ina S. Almdahl,Ina S. Almdahl,Fred Andersen,Sverre Bergh,Francesco Bettella,Sigurbjorn Bjornsson,Anne Brækhus,Geir Bråthen,Christiaan de Leeuw,Rahul S. Desikan,Srdjan Djurovic,Srdjan Djurovic,Logan Dumitrescu,Tormod Fladby,Tormod Fladby,Timothy J. Hohman,Palmi V. Jonsson,Steven J. Kiddle,Arvid Rongve,Ingvild Saltvedt,Sigrid Botne Sando,Geir Selbæk,Maryam Shoai,Nathan G. Skene,Nathan G. Skene,Jon Snaedal,Eystein Stordal,Eystein Stordal,Ingun Ulstein,Yunpeng Wang,Linda R. White,John Hardy,Jens Hjerling-Leffler,Patrick F. Sullivan,Patrick F. Sullivan,Wiesje M. van der Flier,Richard Dobson,Lea K. Davis,Hreinn Stefansson,Kari Stefansson,Nancy L. Pedersen,Stephan Ripke,Stephan Ripke,Stephan Ripke,Ole A. Andreassen,Danielle Posthuma,Danielle Posthuma +65 more
TL;DR: A large genome-wide association study of clinically diagnosed AD and AD-by-proxy identifies new loci and functional pathways that contribute to AD risk and adds novel insights into the neurobiology of AD.
Journal ArticleDOI
Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder
Ditte Demontis,Ditte Demontis,Raymond K. Walters,Raymond K. Walters,Joanna Martin,Joanna Martin,Joanna Martin,Manuel Mattheisen,Thomas Damm Als,Thomas Damm Als,Esben Agerbo,Esben Agerbo,Gisli Baldursson,Rich Belliveau,Jonas Bybjerg-Grauholm,Jonas Bybjerg-Grauholm,Marie Bækvad-Hansen,Marie Bækvad-Hansen,Felecia Cerrato,Kimberly Chambert,Claire Churchhouse,Claire Churchhouse,Ashley Dumont,Nicholas Eriksson,Michael J. Gandal,Jacqueline I. Goldstein,Jacqueline I. Goldstein,Katrina L. Grasby,Jakob Grove,Olafur O Gudmundsson,Olafur O Gudmundsson,Christine Søholm Hansen,Christine Søholm Hansen,Christine Søholm Hansen,Mads E. Hauberg,Mads E. Hauberg,Mads V. Hollegaard,Mads V. Hollegaard,Daniel P. Howrigan,Daniel P. Howrigan,Hailiang Huang,Hailiang Huang,Julian Maller,Alicia R. Martin,Alicia R. Martin,Nicholas G. Martin,Jennifer L. Moran,Jonatan Pallesen,Jonatan Pallesen,Duncan S. Palmer,Duncan S. Palmer,Carsten Bøcker Pedersen,Carsten Bøcker Pedersen,Marianne Giørtz Pedersen,Marianne Giørtz Pedersen,Timothy Poterba,Timothy Poterba,Jesper Buchhave Poulsen,Jesper Buchhave Poulsen,Stephan Ripke,Stephan Ripke,Stephan Ripke,Elise B. Robinson,F. Kyle Satterstrom,F. Kyle Satterstrom,Hreinn Stefansson,Christine Stevens,Patrick Turley,Patrick Turley,G. Bragi Walters,G. Bragi Walters,Hyejung Won,Hyejung Won,Margaret J. Wright,Ole A. Andreassen,Philip Asherson,Christie L. Burton,Dorret I. Boomsma,Bru Cormand,Søren Dalsgaard,Barbara Franke,Joel Gelernter,Joel Gelernter,Daniel H. Geschwind,Daniel H. Geschwind,Hakon Hakonarson,Jan Haavik,Jan Haavik,Henry R. Kranzler,Henry R. Kranzler,Jonna Kuntsi,Kate Langley,Klaus-Peter Lesch,Klaus-Peter Lesch,Klaus-Peter Lesch,Christel M. Middeldorp,Christel M. Middeldorp,Andreas Reif,Luis Augusto Rohde,Panos Roussos,Russell Schachar,Pamela Sklar,Edmund J.S. Sonuga-Barke,Patrick F. Sullivan,Patrick F. Sullivan,Anita Thapar,Joyce Y. Tung,Irwin D. Waldman,Sarah E. Medland,Kari Stefansson,Kari Stefansson,Merete Nordentoft,Merete Nordentoft,David M. Hougaard,David M. Hougaard,Thomas Werge,Thomas Werge,Thomas Werge,Ole Mors,Ole Mors,Preben Bo Mortensen,Mark J. Daly,Stephen V. Faraone,Anders D. Børglum,Anders D. Børglum,Benjamin M. Neale,Benjamin M. Neale +126 more
TL;DR: A genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls identifies variants surpassing genome- wide significance in 12 independent loci and implicates neurodevelopmental pathways and conserved regions of the genome as being involved in underlying ADHD biology.
References
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BOOST: A fast approach to detecting gene-gene interactions in genome-wide case-control studies
TL;DR: In this paper, a simple but powerful method, named "BOolean Operation based Screening and Testing" (BOOST), is introduced to discover unknown gene-gene interactions that underlie complex diseases.
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A Fast, Powerful Method for Detecting Identity by Descent
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HAPGEN2: simulation of multiple disease SNPs
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Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool 'CubeX'
TL;DR: Lower allele frequencies, lower sample numbers, population stratification and a possible |D'| value of 1 are particularly susceptible to distortion of sample Hardy-Weinberg equilibrium, which has significant implications for calculation of linkage disequilibrium in small sample sizes and rarer alleles that may have particular disease relevance and require improved approaches for meaningful evaluation.
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Recommended tests for association in 2×2 tables
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PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses
A global reference for human genetic variation.
Adam Auton,Gonçalo R. Abecasis,David Altshuler,Richard Durbin,David R. Bentley,Aravinda Chakravarti,Andrew G. Clark,Peter Donnelly,Evan E. Eichler,Paul Flicek,Stacey Gabriel,Richard A. Gibbs,Eric D. Green,Matthew E. Hurles,Bartha Maria Knoppers,Jan O. Korbel,Eric S. Lander,Charles Lee,Hans Lehrach,Elaine R. Mardis,Gabor T. Marth,Gil McVean,Deborah A. Nickerson,Jeanette Schmidt,Stephen T. Sherry,Jun Wang,Richard K. Wilson,Eric Boerwinkle,Harsha Doddapaneni,Yi Han,Viktoriya Korchina,Christie Kovar,Sandra L. Lee,Donna M. Muzny,Jeffrey G. Reid,Yiming Zhu,Yuqi Chang,Qiang Feng,Qiang Feng,Xiaodong Fang,Xiaodong Fang,Xiaosen Guo,Xiaosen Guo,Min Jian,Min Jian,Hui Jiang,Hui Jiang,Xin Jin,Tianming Lan,Guoqing Li,Jingxiang Li,Yingrui Li,Shengmao Liu,Xiao Liu,Xiao Liu,Yao Lu,Xuedi Ma,Meifang Tang,Bo Wang,Guangbiao Wang,Honglong Wu,Renhua Wu,Xun Xu,Ye Yin,Dandan Zhang,Wenwei Zhang,Jiao Zhao,Meiru Zhao,Xiaole Zheng,Namrata Gupta,Neda Gharani,Lorraine Toji,Norman P. Gerry,Alissa M. 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A reference panel of 64,976 haplotypes for genotype imputation
Shane A. McCarthy,Sayantan Das,Warren W. Kretzschmar,Olivier Delaneau,Andrew R. Wood,Alexander Teumer,Hyun Min Kang,Christian Fuchsberger,Petr Danecek,Kevin Sharp,Yang Luo,C Sidore,Alan Kwong,Nicholas J. Timpson,Seppo Koskinen,Scott I. Vrieze,Laura J. Scott,He Zhang,Anubha Mahajan,Jan H. Veldink,Ulrike Peters,Ulrike Peters,Carlos N. Pato,Cornelia M. van Duijn,Christopher E. Gillies,Ilaria Gandin,Massimo Mezzavilla,Arthur Gilly,Massimiliano Cocca,Michela Traglia,Andrea Angius,Jeffrey C. Barrett,D.I. Boomsma,Kari Branham,Gerome Breen,Gerome Breen,Chad M. Brummett,Fabio Busonero,Harry Campbell,Andrew T. Chan,Sai Chen,Emily Y. Chew,Francis S. Collins,Laura J Corbin,George Davey Smith,George Dedoussis,Marcus Dörr,Aliki-Eleni Farmaki,Luigi Ferrucci,Lukas Forer,Ross M. Fraser,Stacey Gabriel,Shawn Levy,Leif Groop,Leif Groop,Tabitha A. Harrison,Andrew T. Hattersley,Oddgeir L. Holmen,Kristian Hveem,Matthias Kretzler,James Lee,Matt McGue,Thomas Meitinger,David Melzer,Josine L. Min,Karen L. Mohlke,John B. Vincent,Matthias Nauck,Deborah A. Nickerson,Aarno Palotie,Aarno Palotie,Michele T. Pato,Nicola Pirastu,Melvin G. McInnis,J. Brent Richards,J. Brent Richards,Cinzia Sala,Veikko Salomaa,David Schlessinger,Sebastian Schoenherr,P. Eline Slagboom,Kerrin S. Small,Tim D. Spector,Dwight Stambolian,Marcus A. Tuke,Jaakko Tuomilehto,Leonard H. van den Berg,Wouter van Rheenen,Uwe Völker,Cisca Wijmenga,Daniela Toniolo,Eleftheria Zeggini,Paolo Gasparini,Matthew G. Sampson,James F. Wilson,Timothy M. Frayling,Paul I.W. de Bakker,Morris A. Swertz,Steven A. McCarroll,Charles Kooperberg,Annelot M. Dekker,David Altshuler,Cristen J. Willer,William G. Iacono,Samuli Ripatti,Nicole Soranzo,Nicole Soranzo,Klaudia Walter,Anand Swaroop,Francesco Cucca,Carl A. Anderson,Richard M. Myers,Michael Boehnke,Mark I. McCarthy,Mark I. McCarthy,Richard Durbin,Gonçalo R. Abecasis,Jonathan Marchini +117 more