The UK10K project identifies rare variants in health and disease

作者：Writing group, Klaudia Walter, Josine L. Min, Jie Huang, Lucy Crooks, Yasin Memari, Shane McCarthy, John R. B. Perry, Changjiang Xu, Marta Futema, Daniel Lawson, Valentina Iotchkova, Stephan Schiffels, Audrey E. Hendricks, Petr Danecek, Rui Li, James S. Floyd, Louise V. Wain, Inês Barroso, Steve E. Humphries, Matthew E. Hurles, Eleftheria Zeggini, Jeffrey C. Barrett, Vincent Plagnol, J. Brent Richards, Celia M. T. Greenwood, Nicholas J. Timpson, Richard Durbin, Nicole Soranzo, Production group, Senduran Bala, Peter Clapham, Guy Coates, Tony Cox, Allan Daly, Petr Danecek, Yuanping Du, Richard Durbin, Sarah Edkins, Peter Ellis, Paul Flicek, Xiaosen Guo, Xueqin Guo, Liren Huang, David K. Jackson, Christopher Joyce, Thomas Keane, Anja Kolb-Kokocinski, Cordelia Langford, Rui Li, Jieqin Liang, Hong Lin, Ryan Liu, John Maslen, Shane McCarthy, Dawn Muddyman, Michael A. Quail, Jim Stalker, Jianping Sun, Jing Tian, Guangbiao Wang, Jun Wang, Yu Wang, Kim Wong, Pingbo Zhang, Cohorts group, Inês Barroso, Ewan Birney, Chris Boustred, Lu Chen, Gail Clement, Massimiliano Cocca, Petr Danecek, George Davey Smith, Ian N.M. Day, Aaron Day-Williams, Thomas A. Down, Ian Dunham, Richard Durbin, David M. Evans, Tom R. Gaunt, Matthias Geihs, Celia M. T. Greenwood, Deborah Hart, Audrey E. Hendricks, Bryan Howie, Jie Huang, Tim Hubbard, Pirro G. Hysi, Valentina Iotchkova, Yalda Jamshidi, Konrad J. Karczewski, John P. Kemp, Geneviève Lachance, Daniel Lawson, Monkol Lek, Margarida Lopes, Daniel G. MacArthur, Jonathan Marchini, Massimo Mangino, Iain Mathieson, Shane McCarthy, Yasin Memari, Sarah Metrustry, Josine L. Min, Alireza Moayyeri, Dawn Muddyman, Kate Northstone, Kalliope Panoutsopoulou, Lavinia Paternoster, John R. B. Perry, Lydia Quaye, J. Brent Richards, Susan Ring, Graham R. S. Ritchie, Stephan Schiffels, Hashem A. Shihab, So–Youn Shin, Kerrin S. Small, María Soler Artigas, Nicole Soranzo, Lorraine Southam, Timothy D. Spector, Beaté St Pourcain, Gabriela Surdulescu, Ioanna Tachmazidou, Nicholas J. Timpson, Martin D. Tobin, Ana M. Valdes, Peter M. Visscher, Louise V. Wain, Klaudia Walter, Kirsten Ward, Scott G. Wilson, Kim Wong, Jian Yang, Eleftheria Zeggini, Feng Zhang, Hou-Feng Zheng, Neurodevelopmental disorders group, Richard Anney, Muhammad Ayub, Jeffrey C. Barrett, Douglas Blackwood, Patrick F. Bolton, Gerome Breen, David Collier, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Richard Durbin, Louise Gallagher, Daniel Geschwind, Hugh Gurling, Peter Holmans, Irene Lee, Jouko Lönnqvist, Shane McCarthy, Peter McGuffin, Andrew M. McIntosh, Andrew G. McKechanie, Andrew McQuillin, James Morris, Dawn Muddyman, Michael O‘Donovan, Michael J. Owen, Aarno Palotie, Jeremy Parr, Tiina Paunio, Olli Pietiläinen, Karola Rehnström, Sally I. Sharp, David Skuse, David St Clair, Jaana Suvisaari, James Walters, Hywel Williams, Obesity group, Inês Barroso, Elena G. Bochukova, Rebecca Bounds, Anna F. Dominiczak, Richard Durbin, I. Sadaf Farooqi, Audrey E. Hendricks, Julia M. Keogh, Gaëlle Marenne, Shane McCarthy, Andrew D. Morris, Dawn Muddyman, Stephen O’Rahilly, David J. Porteous, Blair H. Smith, Ioanna Tachmazidou, Eleanor Wheeler, Eleftheria Zeggini, Rare disease group, Saeed Al Turki, Carl A. Anderson, Dinu Antony, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Mattia Calissano, Keren Carss, Krishna Chatterjee, Sebahattin Çırak, Catherine Cosgrove, Richard Durbin, David Fitzpatrick, James Floyd, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Detelina Grozeva, Steve E. Humphries, Matthew E. Hurles, Shane McCarthy, Hannah M. Mitchison, Dawn Muddyman, Francesco Muntoni, Stephen O’Rahilly, Alexandros Onoufriadis, Victoria Parker, Felicity Payne, Vincent Plagnol, F. Lucy Raymond, Nicola D. Roberts, David B. Savage, Peter Scambler, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Olivera Spasić-Bošković, Elizabeth Stevens, Margriet van Kogelenberg, Parthiban Vijayarangakannan, Klaudia Walter, Kathleen A. Williamson, Crispian Wilson, Tamieka Whyte, Statistics group, Antonio Ciampi, Celia M. T. Greenwood, Audrey E. Hendricks, Rui Li, Sarah Metrustry, Karim Oualkacha, Ioanna Tachmazidou, Changjiang Xu, Eleftheria Zeggini, Ethics group, Martin Bobrow, Patrick F. Bolton, Richard Durbin, David R. Fitzpatrick, Heather Griffin, Matthew E. Hurles, Jane Kaye, Karen L. Kennedy, Alastair Kent, Dawn Muddyman, Francesco Muntoni, F. Lucy Raymond, Robert K. Semple, Carol Smee, Timothy D. Spector, Nicholas J. Timpson, Incidental findings group, Ruth Charlton, Rosemary Ekong, Marta Futema, Steve E. Humphries, Farrah Khawaja, Luís R. Lopes, Nicola Migone, Stewart J. Payne, Vincent Plagnol, Rebecca C. Pollitt, Sue Povey, Cheryl K. Ridout, Rachel L. Robinson, Richard H. Scott, Adam Shaw, Petros Syrris, Rohan Taylor, Anthony M. Vandersteen, Jeffrey C. Barrett, Inês Barroso, George Davey Smith, Richard Durbin, I. Sadaf Farooqi, David R. Fitzpatrick, Matthew E. Hurles, Jane Kaye, Karen L. Kennedy, Cordelia Langford, Shane McCarthy, Dawn Muddyman, Michael J. Owen, Aarno Palotie, J. Brent Richards, Nicole Soranzo, Timothy D. Spector, Jim Stalker, Nicholas J. Timpson, Eleftheria Zeggini, Lipid meta-analysis group, Antoinette Amuzu, Juan P. Casas, John C. Chambers, Massimiliano Cocca, George Dedoussis, Giovanni Gambaro, Paolo Gasparini, Tom R. Gaunt, Jie Huang, Valentina Iotchkova, Aaron Isaacs, Jon Johnson, Marcus E. Kleber, Jaspal S. Kooner, Claudia Langenberg, Jian’an Luan, Giovanni Malerba, Winfried März, Angela Matchan, Josine L. Min, Richard Morris, Børge G. Nordestgaard, Marianne Benn, Susan Ring, Robert A. Scott, Nicole Soranzo, Lorraine Southam, Nicholas J. Timpson, Daniela Toniolo, Michela Traglia, Anne Tybjærg‐Hansen, Cornelia M. van Duijn, Elisabeth M. van Leeuwen, Anette Varbo, Peter H. Whincup, Gianluigi Zaza, Eleftheria Zeggini, Weihua Zhang · 发表于：Nature · 年份：2015 · DOI：10.1038/nature14962 · 被引用次数：1194 · 研究领域：Genetic Associations and Epidemiology、Epigenetics and DNA Methylation、Genomics and Rare Diseases

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results. Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the ben...