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
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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.Abstract:
A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation1. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature2-5, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk6. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.read more
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2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
Frank L.J. Visseren,François Mach,Yvo M. Smulders,David Carballo,Konstantinos C. Koskinas,Maria Bäck,Athanase Benetos,Alessandro Biffi,José-Manuel Boavida,Davide Capodanno,Bernard Cosyns,Carolyn Crawford,Constantinos H. Davos,Ileana Desormais,Emanuele Di Angelantonio,Oscar H. Franco,Sigrun Halvorsen,FD Richard Hobbs,Monika Hollander,Ewa A. Jankowska,Matthias Michal,Simona Sacco,Naveed Sattar,Lale Tokgozoglu,Serena Tonstad,Konstantinos P Tsioufis,Ineke van Dis,Isabelle C. Van Gelder,Christoph Wanner,Bryan Williams,Guy De Backer,Vera Regitz-Zagrosek,Anne Hege Aamodt,Magdy Abdelhamid,Victor Aboyans,Christian Albus,Riccardo Asteggiano,Magnus Bäck,Michael A. Borger,Carlos Brotons,Jelena Čelutkienė,Renata Cifkova,Maja Čikeš,Francesco Cosentino,Nikolaos Dagres,Tine De Backer,Dirk De Bacquer,Victoria Delgado,Hester Den Ruijter,Paul Dendale,Heinz Drexel,Volkmar Falk,Laurent Fauchier,Brian A. Ference,Jean Ferrières,Marc Ferrini,Miles Fisher,Danilo Fliser,Zlatko Fras,Dan Gaita,Simona Giampaoli,Stephan Gielen,Ian D. Graham,Catriona Jennings,Torben Jørgensen,Alexandra Kautzky-Willer,Maryam Kavousi,Wolfgang Koenig,Aleksandra Konradi,Dipak Kotecha,Ulf Landmesser,Madalena Lettino,Basil S. Lewis,Aleš Linhart,Maja-Lisa Løchen,Konstantinos Makrilakis,Giuseppe Mancia,Pedro Marques-Vidal,John W. McEvoy,Paul McGreavy,Béla Merkely,Lis Neubeck,Jens Cosedis Nielsen,Joep Perk,Steffen E. Petersen,Anna Sonia Petronio,Massimo F Piepoli,Nana Pogosova,Eva Prescott,Kausik K. Ray,Zeljko Reiner,Dimitrios J. Richter,Lars Rydén,Evgeny Shlyakhto,Marta Sitges,Miguel Sousa-Uva,Isabella Sudano,Monica Tiberi,Rhian M. Touyz,Andrea Ungar,W. M. Monique Verschuren,Olov Wiklund,David A. Wood,José Luis Zamorano,Carolyn A Crawford,Oscar H Franco Duran +105 more
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Clinical use of current polygenic risk scores may exacerbate health disparities.
Alicia R. Martin,Masahiro Kanai,Yoichiro Kamatani,Yukinori Okada,Benjamin M. Neale,Benjamin M. Neale,Mark J. Daly +6 more
TL;DR: To realize the full and equitable potential of polygenic risk scores, greater diversity must be prioritized in genetic studies, and summary statistics must be publically disseminated to ensure that health disparities are not increased for those individuals already most underserved.
Journal ArticleDOI
Applications of machine learning in drug discovery and development.
Jessica Vamathevan,Dominic Clark,Paul Czodrowski,Ian Dunham,Edgardo Ferran,George Lee,Bin Li,Anant Madabhushi,Anant Madabhushi,Parantu K. Shah,Michaela Spitzer,Shanrong Zhao +11 more
TL;DR: The most useful techniques and how machine learning can promote data-driven decision making in drug discovery and development are discussed and major hurdles in the field are highlighted.
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Benefits and limitations of genome-wide association studies.
Vivian W.Y. Tam,Nikunj Patel,Michelle Turcotte,Yohan Bossé,Guillaume Paré,David Meyre,David Meyre +6 more
TL;DR: This Review comprehensively assess the benefits and limitations of GWAS in human populations and discusses the relevance of performing more GWAS, with a focus on the cardiometabolic field.
Journal ArticleDOI
The Missing Diversity in Human Genetic Studies.
TL;DR: This commentary justifies the need to study more diverse populations using both empirical examples and theoretical reasoning for risk prediction of diseases across global populations.
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TL;DR: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and has reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-generation sequencing, deep exome sequencing, and dense microarray genotyping.
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Lee,Jong-Tae Lee,James Leigh,Cheru Tesema Leshargie,Janni Leung,Ricky Leung,Miriam Levi,Yichong Li,Yongmei Li,Darya Li Kappe,Xiaofeng Liang,Misgan Legesse Liben,Stephen S Lim,Shai Linn,Patrick Y Liu,Angela Liu,Shiwei Liu,Yang Liu,Rakesh Lodha,Giancarlo Logroscino,Stephanie J. London,Katharine J Looker,Alan D. Lopez,Alan D. Lopez,Stefan Lorkowski,Paulo A. Lotufo,Nicola Low,Rafael Lozano,Tim C.D. Lucas,Erlyn Rachelle King Macarayan,Hassan Magdy Abd El Razek,Mohammed Magdy Abd El Razek,Mahdi Mahdavi,Marek Majdan,Reza Majdzadeh,Azeem Majeed,Reza Malekzadeh,Reza Malekzadeh,Rajesh Malhotra,Deborah Carvalho Malta,Abdullah Al Mamun,Helena Manguerra,Treh Manhertz,Ana Mantilla,Lorenzo G. Mantovani,Chabila C Mapoma,Laurie B. Marczak,Jose Martinez-Raga,Francisco Rogerlândio Martins-Melo,Ira Martopullo,Winfried März,Manu Raj Mathur,Mohsen Mazidi,Colm McAlinden,Madeline McGaughey,John J. McGrath,John J. McGrath,Martin McKee,Claire McNellan,Suresh Mehata,Man Mohan Mehndiratta,Tefera Chane Mekonnen,Peter Memiah,Ziad A. Memish,Walter Mendoza,Mubarek Abera Mengistie,Desalegn Tadese Mengistu,George A. Mensah,Tuomo J. Meretoja,Atte Meretoja,Haftay Berhane Mezgebe,Renata Micha,Anoushka Millear,Ted R. Miller,Ted R. Miller,Edward J Mills,Mojde Mirarefin,Erkin M. Mirrakhimov,Awoke Misganaw,Shiva Raj Mishra,Philip B. Mitchell,Karzan Abdulmuhsin Mohammad,Alireza Mohammadi,Kedir Endris Mohammed,Shafiu Mohammed,Sanjay K. Mohanty,Ali H. Mokdad,Sarah K Mollenkopf,Lorenzo Monasta,Marcella Montico,Maziar Moradi-Lakeh,Paula Moraga,Rintaro Mori,Chloe Morozoff,Shane D. Morrison,Mark Moses,Cliff Mountjoy-Venning,Kalayu Birhane Mruts,Ulrich O Mueller,Kate Muller,M. E. Murdoch,Gudlavalleti V S Murthy,Kamarul Imran Musa,Jean B. Nachega,Gabriele Nagel,Mohsen Naghavi,Aliya Naheed,Kovin Naidoo,Luigi Naldi,Vinay Nangia,Gopalakrishnan Natarajan,Dumessa Edessa Negasa,Ruxandra Irina Negoi,Ionut Negoi,Charles R. Newton,Charles R. Newton,Josephine W. Ngunjiri,Trang Huyen Nguyen,Quyen Nguyen,Cuong Tat Nguyen,Grant Nguyen,Minh Nguyen,Emma Nichols,Dina Nur Anggraini Ningrum,Dina Nur Anggraini Ningrum,Sandra Nolte,Vuong Minh Nong,Bo Norrving,Jean Jacques Noubiap,Martin O'Donnell,Felix Akpojene Ogbo,In-Hwan Oh,Anselm Okoro,Olanrewaju Oladimeji,Olanrewaju Oladimeji,Tinuke O Olagunju,Andrew T Olagunju,Andrew T Olagunju,Helen E Olsen,Bolajoko O. Olusanya,Jacob Olusegun Olusanya,Kanyin Ong,John Nelson Opio,Eyal Oren,Eyal Oren,Alberto Ortiz,Aaron Osgood-Zimmerman,Majdi Osman,Mayowa O. Owolabi,Mahesh Pa,Rosana E. Pacella,Adrian Pana,Basant Kumar Panda,Christina Papachristou,Christina Papachristou,Eun-Kee Park,Charles D. H. Parry,Mahboubeh Parsaeian,Scott B. Patten,George C Patton,Katherine R. Paulson,Neil Pearce,David M. Pereira,David M. Pereira,Norberto Perico,Konrad Pesudovs,Carrie Beth Peterson,Max Petzold,Michael R. Phillips,David M. Pigott,Julian David Pillay,Christine Pinho,Dietrich Plass,Martin A Pletcher,Svetlana Popova,Richie Poulton,Farshad Pourmalek,Dorairaj Prabhakaran,Noela M Prasad,Narayan Prasad,Carrie Purcell,Mostafa Qorbani,Reginald Quansah,Beatriz Paulina Ayala Quintanilla,Rynaz H S Rabiee,Amir Radfar,Anwar Rafay,Kazem Rahimi,Afarin Rahimi-Movaghar,Vafa Rahimi-Movaghar,Mohammad Hifz Ur Rahman,Mahfuzar Rahman,Rajesh Kumar Rai,Sasa Rajsic,Usha Ram,Chhabi Lal Ranabhat,Zane Rankin,Puja C Rao,P. V. Rao,Salman Rawaf,Sarah E Ray,Robert C. Reiner,Nikolas Reinig,Marissa B Reitsma,Giuseppe Remuzzi,Andre M. N. Renzaho,Serge Resnikoff,Satar Rezaei,Antonio Luiz Pinho Ribeiro,Luca Ronfani,Gholamreza Roshandel,Gholamreza Roshandel,Gregory A. Roth,Ambuj Roy,Enrico Rubagotti,George Mugambage Ruhago,Soheil Saadat,Nafis Sadat,Mahdi Safdarian,Sare Safi,Saeid Safiri,Rajesh Sagar,Ramesh Sahathevan,Joseph Salama,Huda Omer Ba Saleem,Joshua A. Salomon,Sundeep Salvi,Abdallah M. Samy,Juan Sanabria,Juan Sanabria,Damian Santomauro,Itamar S. Santos,João Vasco Santos,Milena M Santric Milicevic,Benn Sartorius,Maheswar Satpathy,Monika Sawhney,Sonia Saxena,Maria Inês Schmidt,Ione Jayce Ceola Schneider,Ben Schöttker,David C. Schwebel,Falk Schwendicke,Soraya Seedat,Sadaf G. Sepanlou,Sadaf G. Sepanlou,Edson Serván-Mori,Tesfaye Setegn,Katya Anne Shackelford,Amira Shaheen,Masood Ali Shaikh,Mansour Shamsipour,Sheikh Mohammed Shariful Islam,Sheikh Mohammed Shariful Islam,Jayendra Sharma,Rajesh Sharma,Jun She,Peilin Shi,Chloe Shields,Girma Temam Shifa,Mika Shigematsu,Yukito Shinohara,Rahman Shiri,Reza Shirkoohi,Shreya Shirude,Kawkab Shishani,Mark G. Shrime,Abla M. Sibai,Inga Dora Sigfusdottir,Inga Dora Sigfusdottir,Diego Augusto Santos Silva,João Pedro Silva,Dayane Gabriele Alves Silveira,Jasvinder A. Singh,Narinder Pal Singh,Dhirendra N Sinha,Eirini Skiadaresi,Vegard Skirbekk,Erica Leigh Slepak,Amber Sligar,David L. Smith,Mari Smith,Badr Hasan Sobaih,Eugene Sobngwi,Reed J D Sorensen,Tatiane Cristina Moraes Sousa,Luciano A. Sposato,Chandrashekhar T Sreeramareddy,Vinay Srinivasan,Jeffrey D. Stanaway,Vasiliki Stathopoulou,Nicholas Steel,Murray B. Stein,Dan J. Stein,Dan J. Stein,Timothy J. Steiner,Timothy J. Steiner,Caitlyn Steiner,S. Steinke,S. Steinke,Mark A. Stokes,Lars Jacob Stovner,Bryan Strub,Michelle L Subart,Mu'awiyyah Babale Sufiyan,Bruno F. Sunguya,Bruno F. Sunguya,Patrick J Sur,Patrick J Sur,Soumya Swaminathan,Bryan L. Sykes,Dillon O Sylte,Rafael Tabarés-Seisdedos,Getachew Redae Taffere,Jukka Takala,Nikhil Tandon,Mohammad Tavakkoli,Nuno Taveira,Hugh R. Taylor,Arash Tehrani-Banihashemi,Tesfalidet Tekelab,Abdullah Sulieman Terkawi,Dawit Jember Tesfaye,Belay Tesssema,Ornwipa Thamsuwan,Katie E Thomas,Amanda G. Thrift,Tenaw Yimer Tiruye,Ruoyan Tobe-Gai,Mette Christophersen Tollånes,Mette Christophersen Tollånes,Marcello Tonelli,Roman Topor-Madry,Roman Topor-Madry,Miguel Tortajada,Mathilde Touvier,Bach Xuan Tran,Suryakant Tripathi,Christopher Troeger,Thomas Truelsen,Derrick Tsoi,Kald Beshir Tuem,Emin Murat Tuzcu,Stefanos Tyrovolas,Kingsley N. Ukwaja,Eduardo A. Undurraga,Eduardo A. Undurraga,Chigozie Jesse Uneke,Rachel L Updike,Olalekan A. Uthman,Benjamin S Chudi Uzochukwu,Job F M van Boven,Santosh Varughese,Tommi Vasankari,S Venkatesh,Narayanaswamy Venketasubramanian,Ramesh Vidavalur,Francesco Saverio Violante,Sergey K Vladimirov,Vasiliy Victorovich Vlassov,Stein Emil Vollset,Fiseha Wadilo,Tolassa Wakayo,Tolassa Wakayo,Yuan-Pang Wang,Marcia R. Weaver,Scott Weichenthal,Elisabete Weiderpass,Robert G. Weintraub,Andrea Werdecker,Ronny Westerman,Harvey Whiteford,Harvey Whiteford,Tissa Wijeratne,Charles Shey Wiysonge,Charles D.A. Wolfe,Charles D.A. Wolfe,Rachel Woodbrook,Anthony D. Woolf,Abdulhalik Workicho,Denis Xavier,Gelin Xu,Simon Yadgir,Mohsen Yaghoubi,Bereket Yakob,Lijing L Yan,Yuichiro Yano,Pengpeng Ye,Hassen Hamid Yimam,Paul S. F. Yip,Naohiro Yonemoto,Seok Jun Yoon,Marcel Yotebieng,Mustafa Z. Younis,Mustafa Z. Younis,Zoubida Zaidi,Maysaa El Sayed Zaki,Elias Asfaw Zegeye,Zerihun Menlkalew Zenebe,Xueying Zhang,Maigeng Zhou,Ben Zipkin,Sanjay Zodpey,Liesl Zühlke,Christopher J L Murray +778 more
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Journal ArticleDOI
Analysis of protein-coding genetic variation in 60,706 humans
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TL;DR: The aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC) provides direct evidence for the presence of widespread mutational recurrence.
Journal ArticleDOI
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
TL;DR: The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility, and 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.
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