TY - JOUR T1 - Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits. JF - Am J Hum Genet Y1 - 2017 A1 - Tachmazidou, Ioanna A1 - Süveges, Dániel A1 - Min, Josine L A1 - Ritchie, Graham R S A1 - Steinberg, Julia A1 - Walter, Klaudia A1 - Iotchkova, Valentina A1 - Schwartzentruber, Jeremy A1 - Huang, Jie A1 - Memari, Yasin A1 - McCarthy, Shane A1 - Crawford, Andrew A A1 - Bombieri, Cristina A1 - Cocca, Massimiliano A1 - Farmaki, Aliki-Eleni A1 - Gaunt, Tom R A1 - Jousilahti, Pekka A1 - Kooijman, Marjolein N A1 - Lehne, Benjamin A1 - Malerba, Giovanni A1 - Männistö, Satu A1 - Matchan, Angela A1 - Medina-Gomez, Carolina A1 - Metrustry, Sarah J A1 - Nag, Abhishek A1 - Ntalla, Ioanna A1 - Paternoster, Lavinia A1 - Rayner, Nigel W A1 - Sala, Cinzia A1 - Scott, William R A1 - Shihab, Hashem A A1 - Southam, Lorraine A1 - St Pourcain, Beate A1 - Traglia, Michela A1 - Trajanoska, Katerina A1 - Zaza, Gialuigi A1 - Zhang, Weihua A1 - Artigas, María S A1 - Bansal, Narinder A1 - Benn, Marianne A1 - Chen, Zhongsheng A1 - Danecek, Petr A1 - Lin, Wei-Yu A1 - Locke, Adam A1 - Luan, Jian'an A1 - Manning, Alisa K A1 - Mulas, Antonella A1 - Sidore, Carlo A1 - Tybjaerg-Hansen, Anne A1 - Varbo, Anette A1 - Zoledziewska, Magdalena A1 - Finan, Chris A1 - Hatzikotoulas, Konstantinos A1 - Hendricks, Audrey E A1 - Kemp, John P A1 - Moayyeri, Alireza A1 - Panoutsopoulou, Kalliope A1 - Szpak, Michal A1 - Wilson, Scott G A1 - Boehnke, Michael A1 - Cucca, Francesco A1 - Di Angelantonio, Emanuele A1 - Langenberg, Claudia A1 - Lindgren, Cecilia A1 - McCarthy, Mark I A1 - Morris, Andrew P A1 - Nordestgaard, Børge G A1 - Scott, Robert A A1 - Tobin, Martin D A1 - Wareham, Nicholas J A1 - Burton, Paul A1 - Chambers, John C A1 - Smith, George Davey A1 - Dedoussis, George A1 - Felix, Janine F A1 - Franco, Oscar H A1 - Gambaro, Giovanni A1 - Gasparini, Paolo A1 - Hammond, Christopher J A1 - Hofman, Albert A1 - Jaddoe, Vincent W V A1 - Kleber, Marcus A1 - Kooner, Jaspal S A1 - Perola, Markus A1 - Relton, Caroline A1 - Ring, Susan M A1 - Rivadeneira, Fernando A1 - Salomaa, Veikko A1 - Spector, Timothy D A1 - Stegle, Oliver A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Barroso, Inês A1 - Greenwood, Celia M T A1 - Perry, John R B A1 - Walker, Brian R A1 - Butterworth, Adam S A1 - Xue, Yali A1 - Durbin, Richard A1 - Small, Kerrin S A1 - Soranzo, Nicole A1 - Timpson, Nicholas J A1 - Zeggini, Eleftheria KW - Anthropometry KW - Body Height KW - Cohort Studies KW - Databases, Genetic KW - DNA Methylation KW - Female KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lipodystrophy KW - Male KW - Meta-Analysis as Topic KW - Obesity KW - Physical Chromosome Mapping KW - Quantitative Trait Loci KW - Sequence Analysis, DNA KW - Sex Characteristics KW - Syndrome KW - United Kingdom AB -

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.

VL - 100 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28552196?dopt=Abstract ER -