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

Simon Haworth, Chin Yang Shapland, Caroline Hayward, Bram P. Prins, Janine F. Felix, Carolina Medina-Gomez, Fernando Rivadeneira, Carol Wang, Tarunveer S. Ahluwalia, Martine Vrijheid, Mònica Guxens, Jordi Sunyer, Ioanna Tachmazidou, Klaudia Walter, Valentina Iotchkova, Andrew Jackson, Louise Cleal, Jennifer Huffmann, Josine L. Min, Lærke Sass, Paul R. H. J. Timmers, George Davey Smith, Simon E. Fisher, James F. Wilson, Tim J. Cole, Dietmar Fernandez-Orth, Klaus Bønnelykke, Hans Bisgaard, Craig E. Pennell, Vincent W. V. Jaddoe, George Dedoussis, Nicholas Timpson, Eleftheria Zeggini, Veronique Vitart and Beate St Pourcain ()
Additional contact information
Simon Haworth: University of Bristol
Chin Yang Shapland: Max Planck Institute for Psycholinguistics
Caroline Hayward: University of Edinburgh
Bram P. Prins: Wellcome Genome Campus
Janine F. Felix: University Medical Center Rotterdam
Carolina Medina-Gomez: University Medical Center Rotterdam
Fernando Rivadeneira: University Medical Center Rotterdam
Carol Wang: The University of Newcastle
Tarunveer S. Ahluwalia: University of Copenhagen
Martine Vrijheid: ISGlobal
Mònica Guxens: ISGlobal
Jordi Sunyer: ISGlobal
Ioanna Tachmazidou: Wellcome Genome Campus
Klaudia Walter: Wellcome Genome Campus
Valentina Iotchkova: Wellcome Genome Campus
Andrew Jackson: University of Edinburgh
Louise Cleal: University of Edinburgh
Jennifer Huffmann: University of Edinburgh
Josine L. Min: University of Bristol
Lærke Sass: University of Copenhagen
Paul R. H. J. Timmers: University of Edinburgh
George Davey Smith: University of Bristol
Simon E. Fisher: Max Planck Institute for Psycholinguistics
James F. Wilson: University of Edinburgh
Tim J. Cole: UCL Great Ormond Street Institute of Child Health
Dietmar Fernandez-Orth: ISGlobal
Klaus Bønnelykke: University of Copenhagen
Hans Bisgaard: University of Copenhagen
Craig E. Pennell: The University of Newcastle
Vincent W. V. Jaddoe: University Medical Center Rotterdam
George Dedoussis: Harokopio University
Nicholas Timpson: University of Bristol
Eleftheria Zeggini: Wellcome Genome Campus
Veronique Vitart: University of Edinburgh
Beate St Pourcain: University of Bristol

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-018-07863-x

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