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

• Published in: Nature communications Vol. 10; no. 1; p. 357
• Main Authors: Haworth, Simon, Shapland, Chin Yang, Hayward, Caroline, Prins, Bram P., Felix, Janine F., Medina-Gomez, Carolina, Rivadeneira, Fernando, Wang, Carol, Ahluwalia, Tarunveer S., Vrijheid, Martine, Guxens, Mònica, Sunyer, Jordi, Tachmazidou, Ioanna, Walter, Klaudia, Iotchkova, Valentina, Jackson, Andrew, Cleal, Louise, Huffmann, Jennifer, Min, Josine L., Sass, Lærke, Timmers, Paul R. H. J., Davey Smith, George, Fisher, Simon E., Wilson, James F., Cole, Tim J., Fernandez-Orth, Dietmar, Bønnelykke, Klaus, Bisgaard, Hans, Pennell, Craig E., Jaddoe, Vincent W. V., Dedoussis, George, Timpson, Nicholas, Zeggini, Eleftheria, Vitart, Veronique, St Pourcain, Beate
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.01.2019; Nature Publishing Group; Nature Research; Nature Portfolio
• Subjects: 45; 45/43; 631/208/205/2138; 631/378/2571; 631/378/2583; Adolescent; Adult; Adults; Age; Aged; Aged, 80 and over; Alleles; Babies; Cephalometry; Child; Child development; Children; Chromosomes; Female; Frequency spectrum; Frequency variation; Gene Expression Regulation, Developmental; Gene Frequency; Genetic diversity; Genetic factors; Genetic Loci; Genetic Variation; Genoma humà; Genome, Human; Genome-wide association studies; Genomes; Head; Humanities and Social Sciences; Humans; Male; Marcadors bioquímics; Middle Aged; multidisciplinary; p53 Protein; Pediatrics; Regression analysis; RNA, Messenger - genetics; Science; Science (multidisciplinary); Skull; Skull - anatomy & histology; Skull - metabolism; Tumor Suppressor Protein p53 - genetics; White People
• ISSN: 2041-1723; 2041-1723
• 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 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. Size and shape of the brain are, among others, influenced by the dimensions of the skull. Here, the authors report genome-wide association studies for head circumference and intracranial volume in children and adults and the identification of nine common or low-frequency variants associated with these traits.