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

Haworth, S. et al. (2019) Low-frequency variation in TP53 has large effects on head circumference and intracranial volume. Nature Communications, 10, 357. (doi: 10.1038/s41467-018-07863-x) (PMID:30664637) (PMCID:PMC6341110)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Dominiczak, Professor Anna
Authors: Haworth, S., Shapland, C. Y., Hayward, C., Prins, B. P., Felix, J. F., Medina-Gomez, C., Rivadeneira, F., Wang, C., Ahluwalia, T. S., Vrijheid, M., Guxens, M., Sunyer, J., Tachmazidou, I., Walter, K., Iotchkova, V., Jackson, A., Cleal, L., Huffmann, J., Min, J. L., Sass, L., Timmers, P. R. H. J., Davey Smith, G., Fisher, S. E., Wilson, J. F., Cole, T. J., Fernandez-Orth, D., Bønnelykke, K., Bisgaard, H., Pennell, C. E., Jaddoe, V. W. V., Dedoussis, G., Timpson, N., Zeggini, E., Vitart, V., St Pourcain, B., and ,
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Nature Communications
Publisher:Nature Research
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Nature Communications 10:357
Publisher Policy:Reproduced under a Creative Commons License

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