Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Ioanna Tachmazidou, Dániel Süveges, Josine L. Min, Graham R.S. Ritchie, Julia Steinberg, Klaudia Walter, Valentina Iotchkova, Jeremy Schwartzentruber, Jie Huang, Yasin Memari, Shane McCarthy, Andrew A. Crawford, Cristina Bombieri, Massimiliano Cocca, Aliki-Eleni Farmaki, Tom R. Gaunt, Pekka Jousilahti, Marjolein N. Kooijman, Benjamin Lehne, Giovanni MalerbaSatu Männistö, Angela Matchan, Carolina Medina-Gomez, Sarah J. Metrustry, Abhishek Nag, Ioanna Ntalla, Lavinia Paternoster, Nigel W. Rayner, Cinzia Sala, William R. Scott, Hashem A. Shihab, Lorraine Southam, Beate St Pourcain, Michela Traglia, Katerina Trajanoska, Gialuigi Zaza, Weihua Zhang, María S. Artigas, Narinder Bansal, Marianne Benn, Zhongsheng Chen, Petr Danecek, Wei-Yu Lin, Adam Locke, Jian’an Luan, Alisa K. Manning, Antonella Mulas, Carlo Sidore, Anne Tybjaerg-Hansen, Anette Varbo, Magdalena Zoledziewska, Chris Finan, Konstantinos Hatzikotoulas, Audrey E. Hendricks, John P. Kemp, Alireza Moayyeri, Kalliope Panoutsopoulou, Michal Szpak, Scott G. Wilson, Michael Boehnke, Francesco Cucca, Emanuele Di Angelantonio, Claudia Langenberg, Cecilia Lindgren, Mark I. McCarthy, Andrew P. Morris, Børge G. Nordestgaard, Robert A. Scott, Martin D. Tobin, Nicholas J. Wareham, Paul Burton, John C. Chambers, George Davey Smith, George Dedoussis, Janine F. Felix, Oscar H. Franco, Giovanni Gambaro, Paolo Gasparini, Christopher J. Hammond, Albert Hofman, Vincent W.V. Jaddoe, Marcus Kleber, Jaspal S. Kooner, Markus Perola, Caroline Relton, Susan M. Ring, Fernando Rivadeneira, Veikko Salomaa, Timothy D. Spector, Oliver Stegle, Daniela Toniolo, André G. Uitterlinden, Inês Barroso, Celia M.T. Greenwood, John R.B. Perry, Brian R. Walker, Adam S. Butterworth, Yali Xue, Richard Durbin, Kerrin S. Small, Nicole Soranzo, Nicholas J. Timpson, Eleftheria Zeggini

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Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.
Original languageEnglish
Pages (from-to)865–884
JournalAmerican Journal of Human Genetics
Issue number6
Early online date25 May 2017
Publication statusPublished - 1 Jun 2017


  • UK10K
  • genetic association study
  • next-generation whole-genome sequencing
  • imputation
  • UK Biobank
  • anthropometry
  • DXA traits


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