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Record W2620270887 · doi:10.1016/j.ajhg.2017.04.014

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

2017· article· en· W2620270887 on OpenAlexaff
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 Crawford, Cristina Bombieri, Massimiliano Cocca, Aliki‐Eleni Farmaki, Tom R. Gaunt, Marjolein N. Kooijman, Benjamin Lehne, Giovanni Malerba, Satu Männistö, Angela Matchan, Carolina Medina‐Gómez, Sarah Metrustry, Abhishek Nag, Ιωάννα Ντάλλα, Lavinia Paternoster, Nigel W. Rayner, Cinzia Sala, William R. Scott, Hashem A. Shihab, Lorraine Southam, Beaté St Pourcain, Michela Traglia, Katerina Trajanoska, Weihua Zhang, María Soler Artigas, Narinder Bansal, Marianne Benn, Zhongsheng Chen, Petr Danecek, Wei‐Yu Lin, Adam E. Locke, Jian’an Luan, Alisa K. Manning, Antonella Mulas, Carlo Sidore, Anne Tybjærg‐Hansen, Anette Varbo, Magdalena Żołędziewska, Chris Finan, Konstantinos Hatzikotoulas, Audrey E. Hendricks, John P. Kemp, Alireza Moayyeri, Kalliope Panoutsopoulou, Michał Szpak, Scott G. Wilson, Michael Boehnke, Francesco Cucca, Emanuele Di Angelantonio, Claudia Langenberg, Cecilia M. Lindgren, Mark I. McCarthy, Andrew P. Morris, Børge G. Nordestgaard, Robert A. Scott, Martin D. Tobin, Nicholas J. Wareham, Paul R. 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 E. Kleber, Jaspal S. Kooner, Markus Perola, Caroline L. 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

Bibliographic record

VenueThe American Journal of Human Genetics · 2017
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsMcGill UniversityJewish General Hospital
FundersEuropean Regional Development FundEconomic and Social Research CouncilNational Institutes of HealthVersus ArthritisSvenska KulturfondenHögskolan DalarnaSamfundet FolkhälsanVetenskapsrådetMedical Research CouncilSigne ja Ane Gyllenbergin SäätiöKnut och Alice Wallenbergs StiftelseTartu ÜlikoolPaavo Nurmen SäätiöHjärt-LungfondenMinistero dell’Istruzione, dell’Università e della RicercaFolkhälsanin TutkimussäätiöErasmus Universiteit RotterdamZonMwLandstinget DalarnasEuropean CommissionDiabetestutkimussäätiöWellcome TrustNederlandse Organisatie voor Wetenschappelijk OnderzoekNational Institute of Diabetes and Digestive and Kidney DiseasesTekesBritish Heart FoundationNational Institute for Health and Care ResearchNational Heart, Lung, and Blood InstituteHelsingin ja Uudenmaan SairaanhoitopiiriMarcus och Amalia Wallenbergs minnesfondErasmus Medisch CentrumFinska Läkaresällskapet
KeywordsImputation (statistics)Quantitative trait locusBiologyGenetic architectureGeneticsComputational biologyTraitGenome-wide association studyGenomeWhole genome sequencingAnthropometryAllele frequencyAlleleEvolutionary biologyGeneGenotypeComputer scienceSingle-nucleotide polymorphismMachine learningMedicine

Abstract

fetched live from OpenAlex

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.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

How this classification was reachedexpand

Full frame distilled prediction

Teacher imitation

Not calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.

metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: none
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.955
Threshold uncertainty score0.543

Codex and Gemma teacher scores by category

CategoryCodexGemma
Metaresearch0.0010.000
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0000.000
Bibliometrics0.0000.000
Science and technology studies0.0010.000
Scholarly communication0.0000.000
Open science0.0010.000
Research integrity0.0000.000
Insufficient payload (model declined to judge)0.0000.000

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.

Opus teacher head0.030
GPT teacher head0.335
Teacher spread0.305 · how far apart the two teachers sit on this one work
Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one teacher head, not a consensus.

The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical

How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".

Quick stats

Citations218
Published2017
Admission routes1
Has abstractyes

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