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

Lookup NU author(s): Professor Jeremy Parr

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Abstract

© 2019, The Author(s). 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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Author(s): Haworth S, Shapland CY, Hayward C, Prins BP, Felix JF, Medina-Gomez C, Rivadeneira F, Wang C, Ahluwalia TS, Vrijheid M, Guxens M, Sunyer J, Tachmazidou I, Walter K, Iotchkova V, Jackson A, Cleal L, Huffmann J, Min JL, Sass L, Timmers PRHJ, Turki SA, Anderson CA, Anney R, Antony D, Artigas MS, Ayub M, Bala S, Barrett JC, Barroso I, Beales P, Bentham J, Bhattacharya S, Birney E, Blackwood D, Bobrow M, Bochukova E, Bolton PF, Bounds R, Boustred C, Breen G, Calissano M, Carss K, Charlton R, Chatterjee K, Chen L, Ciampi A, Cirak S, Clapham P, Clement G, Coates G, Cocca M, Collier DA, Cosgrove C, Cox T, Craddock N, Crooks L, Curran S, Curtis D, Daly A, Danecek P, Day INM, Day-Williams A, Dominiczak A, Down T, Du Y, Dunham I, Durbin R, Edkins S, Ekong R, Ellis P, Evans DM, Farooqi IS, Fitzpatrick DR, Flicek P, Floyd J, Foley AR, Franklin CS, Futema M, Gallagher L, Gaunt TR, Geihs M, Geschwind D, Greenwood CMT, Griffin H, Grozeva D, Guo X, Guo X, Gurling H, Hart D, Hendricks AE, Holmans P, Howie B, Huang J, Huang L, Hubbard T, Humphries SE, Hurles ME, Hysi P, Jackson DK, Jamshidi Y, Joyce C, Karczewski KJ, Kaye J, Keane T, Kemp JP, Kennedy K, Kent A, Keogh J, Khawaja F, van Kogelenberg M, Kolb-Kokocinski A, Lachance G, Langford C, Lawson D, Lee I, Lek M, Li R, Li Y, Liang J, Lin H, Liu R, Lonnqvist J, Lopes LR, Lopes M, MacArthur DG, Mangino M, Marchini J, Marenne G, Maslen J, Mathieson I, McCarthy S, McGuffin P, McIntosh AM, McKechanie AG, McQuillin A, Memari Y, Metrustry S, Migone N, Mitchison HM, Moayyeri A, Morris A, Morris J, Muddyman D, Muntoni F, Northstone K, O'Donovan MC, O'Rahilly S, Onoufriadis A, Oualkacha K, Owen MJ, Palotie A, Panoutsopoulou K, Parker V, Parr JR, Paternoster L, Paunio T, Payne F, Payne SJ, Perry JRB, Pietilainen O, Plagnol V, Pollitt RC, Porteous DJ, Povey S, Quail MA, Quaye L, Raymond FL, Rehnstrom K, Richards JB, Ridout CK, Ring S, Ritchie GRS, Roberts N, Robinson RL, Savage DB, Scambler P, Schiffels S, Schmidts M, Schoenmakers N, Scott RH, Semple RK, Serra E, Sharp SI, Shaw A, Shihab HA, Shin S-Y, Skuse D, Small KS, Smee C, Smith BH, Soranzo N, Southam L, Spasic-Boskovic O, Spector TD, St Clair D, Stalker J, Stevens E, Sun J, Surdulescu G, Suvisaari J, Syrris P, Taylor R, Tian J, Tobin MD, Valdes AM, Vandersteen AM, Vijayarangakannan P, Visscher PM, Wain LV, Walters JTR, Wang G, Wang J, Wang Y, Ward K, Wheeler E, Whyte T, Williams HJ, Williamson KA, Wilson C, Wilson SG, Wong K, Xu CJ, Yang J, Zhang F, Zhang P, Zheng H-F, Davey Smith G, Fisher SE, Wilson JF, Cole TJ, Fernandez-Orth D, Bonnelykke K, Bisgaard H, Pennell CE, Jaddoe VWV, Dedoussis G, Timpson N, Zeggini E, Vitart V, St Pourcain B

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2019

Volume: 10

Issue: 1

Online publication date: 21/01/2019

Acceptance date: 12/11/2018

Date deposited: 18/02/2019

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41467-018-07863-x

DOI: 10.1038/s41467-018-07863-x

PubMed id: 30664637

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