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

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UK10K Consortium, Gerome Breen

Original languageEnglish
Article number357
JournalNature Communications
Issue number1
Early online date1 Dec 2019
Accepted/In press12 Nov 2018
E-pub ahead of print1 Dec 2019
Published21 Jan 2020

King's Authors


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.

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