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

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. and 15 moreHaworth, 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., UK10K consortium, Davey Smith, G., Fisher, S. E., Wilson, J. F., Cole, T. J., Fernandez-Orth, D., B√łnnelykke, K., Bisgaard, H., Pennell, C. E., Jaddoe, V. W. V., Dedoussis, G., Timpson, N. J., Zeggini, E., Vitart, V., & St Pourcain, B. (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.
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 affecting these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic influences and low-frequency genetic variation. To understand these influences, 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.
Additional information
Supplementary Information
Publication type
Journal article
Publication date
2019

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