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 SassPaul R.H.J. Timmers, UK10K Consortium, George Davey Smith, Tim J. Cole, Nicholas Timpson, Eleftheria Zeggini, Beate St Pourcain*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

19 Citations (Scopus)
212 Downloads (Pure)


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.

Original languageEnglish
Article number357
Number of pages16
JournalNature Communications
Publication statusPublished - 21 Jan 2019


  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Cephalometry
  • Child
  • European Continental Ancestry Group
  • Female
  • Gene Expression Regulation, Developmental
  • Gene Frequency
  • Genetic Loci
  • Genetic Variation
  • Genome, Human
  • Humans
  • Male
  • Middle Aged
  • RNA, Messenger/genetics
  • Skull/anatomy & histology
  • Tumor Suppressor Protein p53/genetics


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