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

Authors:
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 Malerba Satu 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

Am J Hum Genet 2017 Jun 25;100(6):865-884. Epub 2017 May 25.

The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. Electronic address:

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.

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http://dx.doi.org/10.1016/j.ajhg.2017.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473732PMC
June 2017
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