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Record W2808358827 · doi:10.1038/s41467-018-07863-x

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

2019· article· en· W2808358827 on OpenAlexafffund
Simon Haworth, Chin Yang Shapland, Caroline Hayward, Bram P. Prins, Janine F. Felix, Carolina Medina‐Gómez, Fernando Rivadeneira, Carol A. Wang, Tarunveer S. Ahluwalia, Martine Vrijheid, Mònica Guxens, Jordi Sunyer, Ioanna Tachmazidou, Klaudia Walter, Valentina Iotchkova, Andrew P. Jackson, Louise Cleal, Jennifer Huffmann, Josine L. Min, Lærke Sass, Paul R. H. J. Timmers, Saeed Al Turki, Carl A. Anderson, Richard Anney, Dinu Antony, María Soler Artigas, Muhammad Ayub, Senduran Bala, Jeffrey C. Barrett, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena G. Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Ruth Charlton, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebahattin Çırak, Peter Clapham, Gail Clement, Guy Coates, Massimiliano Cocca, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Petr Danecek, Ian N. M. Day, Aaron Day-Williams, Anna F. Dominiczak, Thomas A. Down, Yuanping Du, Ian Dunham, Richard Durbin, Sarah Edkins, Rosemary Ekong, Peter Ellis, David M. Evans, I. Sadaf Farooqi, David Fitzpatrick, Paul Flicek, James Floyd, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Tom R. Gaunt, Matthias Geihs, Daniel Geschwind, Celia M.T. Greenwood, Heather Griffin, Detelina Grozeva, Xiaosen Guo, Xueqin Guo, Hugh Gurling, Deborah Hart, Audrey E. Hendricks, Peter Holmans, Bryan Howie, Jie Huang, Tim Hubbard, Steve E. Humphries, Matthew E. Hurles, Pirro G. Hysi, David K. Jackson, Yalda Jamshidi, Christopher Joyce, Konrad J. Karczewski, Jane Kaye, Thomas Keane, John P. Kemp, Karen L. Kennedy, Alastair Kent, Julia M. Keogh, Farrah Khawaja, Margriet van Kogelenberg, Anja Kolb‐Kokocinski, Geneviève Lachance, Cordelia Langford, Daniel J. Lawson, Irene Lee, Monkol Lek, Rui Li, Yingrui Li, Jieqin Liang, Hong Lin, Ryan Liu, Jouko Lönnqvist, Luís R. Lopes, Margarida Lopes, Daniel G. MacArthur, Massimo Mangino, Jonathan Marchini, Gaëlle Marenne, John Maslen, Iain Mathieson, Shane McCarthy, Peter McGuffin, Andrew M. McIntosh, Andrew G. McKechanie, Andrew McQuillin, Yasin Memari, Sarah Metrustry, Nicola Migone, Hannah M. Mitchison, Alireza Moayyeri, Andrew D. Morris, James Morris, Dawn Muddyman, Francesco Muntoni, Kate Northstone, Michael O‘Donovan, Stephen O’Rahilly, Alexandros Onoufriadis, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Stewart J. Payne, John R. B. Perry, Olli Pietiläinen, Vincent Plagnol, Rebecca C. Pollitt, David J. Porteous, Sue Povey, Michael A. Quail, Lydia Quaye, F. Lucy Raymond, Karola Rehnström, J. Brent Richards, Cheryl K. Ridout, Susan M. Ring, Graham R. S. Ritchie, Nicola Roberts, Rachel L. Robinson, David B. Savage, Peter Scambler, Stephan Schiffels, Miriam Schmidts, Nadia Schoenmakers, Richard H. Scott, Robert K. Semple, Eva Serra, Sally I. Sharp, Adam Shaw, Hashem A. Shihab, So–Youn Shin, David Skuse, Kerrin S. Small, Carol Smee, Blair H. Smith, Nicole Soranzo, Lorraine Southam, Olivera Spasić-Bošković, Timothy D. Spector, David St Clair, Jim Stalker, Elizabeth Stevens, Jianping Sun, Gabriela Surdulescu, Jaana Suvisaari, Petros Syrris, Rohan Taylor, Jing Tian, Martin D. Tobin, Ana M. Valdes, Anthony M. Vandersteen, Parthiban Vijayarangakannan, Peter M. Visscher, Louise V. Wain, James Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Eleanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Scott G. Wilson, Kim Wong, Changjiang Xu, Jian Yang, Pingbo Zhang, Hou‐Feng Zheng, George Davey Smith, Simon E. Fisher, James F. Wilson, Tim Cole, Dietmar Fernández‐Orth, Klaus Bønnelykke, Hans Bisgaard, Craig E. Pennell, Vincent W. V. Jaddoe, George Dedoussis, Nicholas J. Timpson, Eleftheria Zeggini, Véronique Vitart, Beaté St Pourcain

Bibliographic record

VenueNature Communications · 2019
Typearticle
Languageen
FieldMedicine
TopicCancer-related Molecular Pathways
Canadian institutionsUniversité du Québec à MontréalJewish General HospitalMcGill UniversityQueen's University
FundersNIHR Cambridge Biomedical Research CentreDepartment of Epidemiology, Biostatistics and Occupational Health, McGill UniversityInstitute of Psychiatry, Psychology and Neuroscience, King’s College LondonUniversitätsklinikum KölnQueen's UniversityUniversity of BristolUniversity of GlasgowMedical Research CouncilUniversity of SussexUniversity of OxfordJewish General HospitalKing's College LondonDiamantina Institute, University of QueenslandUniversity of LeicesterWellcome TrustCancer Research UKUniversity College LondonBritish Heart FoundationUniversidade de LisboaBroad InstituteTerveyden ja hyvinvoinnin laitosEuropean Molecular Biology LaboratoryLundbeckfondenCardiff UniversityEli Lilly and CompanyNational Cancer Research InstituteCancer Research InstituteMcGill UniversityHelsingin YliopistoAdaptive BiotechnologiesNational Institute for Health and Care ResearchQueen Mary University of LondonSussex Partnership NHS Foundation TrustBiogenUniversity of EdinburghDavid Geffen School of Medicine, University of California, Los AngelesMassachusetts General Hospital
KeywordsGenetic architectureHead circumferenceAlleleGenetic variationBrain sizeAllele frequencyBiologyVariation (astronomy)DemographyGeneticsEvolutionary biologyMedicinePhenotypeGene

Abstract

fetched live from OpenAlex

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

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)0.000
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 score0.712
Threshold uncertainty score0.681

Codex and Gemma teacher scores by category

CategoryCodexGemma
Metaresearch0.0000.000
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0000.000
Bibliometrics0.0000.000
Science and technology studies0.0000.000
Scholarly communication0.0000.000
Open science0.0000.000
Research integrity0.0000.002
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 head0.012
GPT teacher head0.279
Teacher spread0.267 · 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

Citations40
Published2019
Admission routes2
Has abstractyes

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