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

ABSTRACT: 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.

SUBMITTER: Tachmazidou I

PROVIDER: S-EPMC5473732 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

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

American journal of human genetics 20170525 6

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 previousl ...[more]

PMID: 28552196

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Project description:Selection can create complex patterns of adaptive differentiation among populations in the wild that may be relevant to management. Atlantic cod in the Northwest Atlantic are at a fraction of their historical abundance and a lack of recovery within the Gulf of Maine has created concern regarding the misalignment of fisheries management structures with biological population structure. To address this and investigate genome-wide patterns of variation, we used low-coverage sequencing to perform a region-wide, whole-genome analysis of fine-scale population structure. We sequenced 306 individuals from 20 sampling locations in U.S. and Canadian waters, including the major spawning aggregations in the Gulf of Maine in addition to spawning aggregations from Georges Bank, southern New England, the eastern Scotian Shelf, and St. Pierre Bank. With genotype likelihoods estimated at almost 11 million loci, we found large differences in haplotype frequencies of previously described chromosomal inversions between Canadian and U.S. sampling locations and also among U.S. sampling locations. Our whole-genome resolution also revealed novel outlier peaks, some of which showed significant genetic differentiation among sampling locations. Comparisons between allochronic winter- and spring-spawning populations revealed highly elevated relative (FST ) and absolute (dxy ) genetic differentiation near genes involved in reproduction, particularly genes associated with the brain-pituitary-gonadal axis, which likely control timing of spawning, contributing to prezygotic isolation. We also found genetic differentiation associated with heat shock proteins and other genes of functional relevance, with complex patterns that may point to multifaceted selection pressures and local adaptation among spawning populations. We provide a high-resolution picture of U.S. Atlantic cod population structure, revealing greater complexity than is currently recognized in management. Our genome-scan approach likely underestimates the full suite of adaptive differentiation among sampling locations. Nevertheless, it should inform the revision of stock boundaries to preserve adaptive genetic diversity and evolutionary potential of cod populations.

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

Publications

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

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