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

UK10K Consortium

Research output: Contribution to journalArticle

Abstract

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
Volume10
Issue number1
DOIs
Publication statusPublished - 21 Jan 2019

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circumferences
Head
low frequencies
Genetic Models
Human Development
Growth and Development
Gene Frequency
descent
loci
determinants
Alleles
Growth

Cite this

@article{e2fcdf9bcab64e1ebdbdefbfd6061737,
title = "Low-frequency variation in TP53 has large effects on head circumference and intracranial volume",
abstract = "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.",
author = "{UK10K Consortium} and Simon Haworth and Shapland, {Chin Yang} and Caroline Hayward and Prins, {Bram P.} and Felix, {Janine F.} and Carolina Medina-Gomez and Fernando Rivadeneira and Carol Wang and Ahluwalia, {Tarunveer S.} and Martine Vrijheid and M{\`o}nica Guxens and Jordi Sunyer and Ioanna Tachmazidou and Klaudia Walter and Valentina Iotchkova and Andrew Jackson and Louise Cleal and Jennifer Huffmann and Min, {Josine L.} and L{\ae}rke Sass and Timmers, {Paul R.H.J.} and Turki, {Saeed Al} and Anderson, {Carl A.} and Richard Anney and Dinu Antony and Artigas, {Mar{\'i}a Soler} and Muhammad Ayub and Senduran Bala and Barrett, {Jeffrey C.} and In{\^e}s Barroso and Phil Beales and Jamie Bentham and Shoumo Bhattacharya and Ewan Birney and Douglas Blackwood and Martin Bobrow and Elena Bochukova and Bolton, {Patrick F.} and Rebecca Bounds and Chris Boustred and Gerome Breen and Mattia Calissano and Keren Carss and Ruth Charlton and Krishna Chatterjee and Lu Chen and Antonio Ciampi and Sebahattin Cirak and Peter Clapham and Gail Clement and Guy Coates and Massimiliano Cocca and Collier, {David A.} and Catherine Cosgrove and Tony Cox and Nick Craddock and Lucy Crooks and Sarah Curran and Owen, {Michael J.} and Allan Daly and Petr Danecek and Day, {Ian N.M.} and Aaron Day-Williams and Anna Dominiczak and Thomas Down and Yuanping Du and Ian Dunham and Richard Durbin and Sarah Edkins and Rosemary Ekong and Peter Ellis and Evans, {David M.} and Farooqi, {I. Sadaf} and Fitzpatrick, {David R.} and Paul Flicek and James Floyd and Foley, {A. Reghan} and Franklin, {Christopher S.} and Marta Futema and Louise Gallagher and Gaunt, {Tom R.} and Matthias Geihs and Daniel Geschwind and Greenwood, {Celia M.T.} and Heather Griffin and Detelina Grozeva and Xiaosen Guo and Xueqin Guo and Hugh Gurling and Deborah Hart and Hendricks, {Audrey E.} and Peter Holmans and Bryan Howie and Jie Huang and Liren Huang and Tim Hubbard and Humphries, {Steve E.} and Hurles, {Matthew E.} and Pirro Hysi and Jackson, {David K.} and Yalda Jamshidi and Chris Joyce and Karczewski, {Konrad J.} and Jane Kaye and Thomas Keane and Kemp, {John P.} and Karen Kennedy and Alastair Kent and Julia Keogh and Farrah Khawaja and {van Kogelenberg}, Margriet and Anja Kolb-Kokocinski and Genevieve Lachance and Cordelia Langford and Daniel Lawson and Irene Lee and Monkol Lek and Rui Li and Yingrui Li and Jieqin Liang and Hong Lin and Ryan Liu and Jouko L{\"o}nnqvist and Lopes, {Luis R.} and Margarida Lopes and MacArthur, {Daniel G.} and Massimo Mangino and Jonathan Marchini and Ga{\"e}lle Marenne and John Maslen and Iain Mathieson and Shane McCarthy and Peter McGuffin and McIntosh, {Andrew M.} and McKechanie, {Andrew G.} and Andrew McQuillin and Yasin Memari and Sarah Metrustry and Nicola Migone and Mitchison, {Hannah M.} and Alireza Moayyeri and Andrew Morris and James Morris and Dawn Muddyman and Francesco Muntoni and Kate Northstone and O’Donovan, {Michael C.} and Stephen O’Rahilly and Alexandros Onoufriadis and Karim Oualkacha and Owen, {Michael J.} and Aarno Palotie and Kalliope Panoutsopoulou and Victoria Parker and Parr, {Jeremy R.} and Lavinia Paternoster and Tiina Paunio and Felicity Payne and Payne, {Stewart J.} and Perry, {John R.B.} and Olli Pietilainen and Vincent Plagnol and Pollitt, {Rebecca C.} and Porteous, {David J.} and Sue Povey and Quail, {Michael A.} and Lydia Quaye and Raymond, {F. Lucy} and Karola Rehnstr{\"o}m and Richards, {J. Brent} and Ridout, {Cheryl K.} and Susan Ring and Ritchie, {Graham R.S.} and Nicola Roberts and Robinson, {Rachel L.} and Savage, {David B.} and Peter Scambler and Stephan Schiffels and Miriam Schmidts and Nadia Schoenmakers and Scott, {Richard H.} and Semple, {Robert K.} and Eva Serra and Sharp, {Sally I.} and Adam Shaw and Shihab, {Hashem A.} and Shin, {So Youn} and David Skuse and Small, {Kerrin S.} and Carol Smee and Smith, {Blair H.} and Nicole Soranzo and Lorraine Southam and Olivera Spasic-Boskovic and Spector, {Timothy D.} and {St Clair}, David and Jim Stalker and Elizabeth Stevens and Jianping Sun and Gabriela Surdulescu and Jaana Suvisaari and Petros Syrris and Rohan Taylor and Jing Tian and Tobin, {Martin D.} and Valdes, {Ana M.} and Vandersteen, {Anthony M.} and Parthiban Vijayarangakannan and Visscher, {Peter M.} and Wain, {Louise V.} and Walters, {James T.R.} and Guangbiao Wang and Jun Wang and Yu Wang and Kirsten Ward and Eleanor Wheeler and Tamieka Whyte and Williams, {Hywel J.} and Williamson, {Kathleen A.} and Crispian Wilson and Wilson, {Scott G.} and Kim Wong and Xu, {Chang Jiang} and Jian Yang and Feng Zhang and Pingbo Zhang and Zheng, {Hou Feng} and {Davey Smith}, George and Fisher, {Simon E.} and Wilson, {James F.} and Cole, {Tim J.} and Dietmar Fernandez-Orth and Klaus B{\o}nnelykke and Hans Bisgaard and Pennell, {Craig E.} and Jaddoe, {Vincent W.V.} and George Dedoussis and Nicholas Timpson and Eleftheria Zeggini and Veronique Vitart and {St Pourcain}, Beate",
year = "2019",
month = "1",
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doi = "10.1038/s41467-018-07863-x",
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issn = "2041-1723",
publisher = "Nature Publishing Group - Macmillan Publishers",
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Low-frequency variation in TP53 has large effects on head circumference and intracranial volume. / UK10K Consortium.

In: Nature Communications, Vol. 10, No. 1, 357, 21.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

AU - UK10K Consortium

AU - Haworth, Simon

AU - Shapland, Chin Yang

AU - Hayward, Caroline

AU - Prins, Bram P.

AU - Felix, Janine F.

AU - Medina-Gomez, Carolina

AU - Rivadeneira, Fernando

AU - Wang, Carol

AU - Ahluwalia, Tarunveer S.

AU - Vrijheid, Martine

AU - Guxens, Mònica

AU - Sunyer, Jordi

AU - Tachmazidou, Ioanna

AU - Walter, Klaudia

AU - Iotchkova, Valentina

AU - Jackson, Andrew

AU - Cleal, Louise

AU - Huffmann, Jennifer

AU - Min, Josine L.

AU - Sass, Lærke

AU - Timmers, Paul R.H.J.

AU - Turki, Saeed Al

AU - Anderson, Carl A.

AU - Anney, Richard

AU - Antony, Dinu

AU - Artigas, María Soler

AU - Ayub, Muhammad

AU - Bala, Senduran

AU - Barrett, Jeffrey C.

AU - Barroso, Inês

AU - Beales, Phil

AU - Bentham, Jamie

AU - Bhattacharya, Shoumo

AU - Birney, Ewan

AU - Blackwood, Douglas

AU - Bobrow, Martin

AU - Bochukova, Elena

AU - Bolton, Patrick F.

AU - Bounds, Rebecca

AU - Boustred, Chris

AU - Breen, Gerome

AU - Calissano, Mattia

AU - Carss, Keren

AU - Charlton, Ruth

AU - Chatterjee, Krishna

AU - Chen, Lu

AU - Ciampi, Antonio

AU - Cirak, Sebahattin

AU - Clapham, Peter

AU - Clement, Gail

AU - Coates, Guy

AU - Cocca, Massimiliano

AU - Collier, David A.

AU - Cosgrove, Catherine

AU - Cox, Tony

AU - Craddock, Nick

AU - Crooks, Lucy

AU - Curran, Sarah

AU - Owen, Michael J.

AU - Daly, Allan

AU - Danecek, Petr

AU - Day, Ian N.M.

AU - Day-Williams, Aaron

AU - Dominiczak, Anna

AU - Down, Thomas

AU - Du, Yuanping

AU - Dunham, Ian

AU - Durbin, Richard

AU - Edkins, Sarah

AU - Ekong, Rosemary

AU - Ellis, Peter

AU - Evans, David M.

AU - Farooqi, I. Sadaf

AU - Fitzpatrick, David R.

AU - Flicek, Paul

AU - Floyd, James

AU - Foley, A. Reghan

AU - Franklin, Christopher S.

AU - Futema, Marta

AU - Gallagher, Louise

AU - Gaunt, Tom R.

AU - Geihs, Matthias

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AU - Guo, Xiaosen

AU - Guo, Xueqin

AU - Gurling, Hugh

AU - Hart, Deborah

AU - Hendricks, Audrey E.

AU - Holmans, Peter

AU - Howie, Bryan

AU - Huang, Jie

AU - Huang, Liren

AU - Hubbard, Tim

AU - Humphries, Steve E.

AU - Hurles, Matthew E.

AU - Hysi, Pirro

AU - Jackson, David K.

AU - Jamshidi, Yalda

AU - Joyce, Chris

AU - Karczewski, Konrad J.

AU - Kaye, Jane

AU - Keane, Thomas

AU - Kemp, John P.

AU - Kennedy, Karen

AU - Kent, Alastair

AU - Keogh, Julia

AU - Khawaja, Farrah

AU - van Kogelenberg, Margriet

AU - Kolb-Kokocinski, Anja

AU - Lachance, Genevieve

AU - Langford, Cordelia

AU - Lawson, Daniel

AU - Lee, Irene

AU - Lek, Monkol

AU - Li, Rui

AU - Li, Yingrui

AU - Liang, Jieqin

AU - Lin, Hong

AU - Liu, Ryan

AU - Lönnqvist, Jouko

AU - Lopes, Luis R.

AU - Lopes, Margarida

AU - MacArthur, Daniel G.

AU - Mangino, Massimo

AU - Marchini, Jonathan

AU - Marenne, Gaëlle

AU - Maslen, John

AU - Mathieson, Iain

AU - McCarthy, Shane

AU - McGuffin, Peter

AU - McIntosh, Andrew M.

AU - McKechanie, Andrew G.

AU - McQuillin, Andrew

AU - Memari, Yasin

AU - Metrustry, Sarah

AU - Migone, Nicola

AU - Mitchison, Hannah M.

AU - Moayyeri, Alireza

AU - Morris, Andrew

AU - Morris, James

AU - Muddyman, Dawn

AU - Muntoni, Francesco

AU - Northstone, Kate

AU - O’Donovan, Michael C.

AU - O’Rahilly, Stephen

AU - Onoufriadis, Alexandros

AU - Oualkacha, Karim

AU - Owen, Michael J.

AU - Palotie, Aarno

AU - Panoutsopoulou, Kalliope

AU - Parker, Victoria

AU - Parr, Jeremy R.

AU - Paternoster, Lavinia

AU - Paunio, Tiina

AU - Payne, Felicity

AU - Payne, Stewart J.

AU - Perry, John R.B.

AU - Pietilainen, Olli

AU - Plagnol, Vincent

AU - Pollitt, Rebecca C.

AU - Porteous, David J.

AU - Povey, Sue

AU - Quail, Michael A.

AU - Quaye, Lydia

AU - Raymond, F. Lucy

AU - Rehnström, Karola

AU - Richards, J. Brent

AU - Ridout, Cheryl K.

AU - Ring, Susan

AU - Ritchie, Graham R.S.

AU - Roberts, Nicola

AU - Robinson, Rachel L.

AU - Savage, David B.

AU - Scambler, Peter

AU - Schiffels, Stephan

AU - Schmidts, Miriam

AU - Schoenmakers, Nadia

AU - Scott, Richard H.

AU - Semple, Robert K.

AU - Serra, Eva

AU - Sharp, Sally I.

AU - Shaw, Adam

AU - Shihab, Hashem A.

AU - Shin, So Youn

AU - Skuse, David

AU - Small, Kerrin S.

AU - Smee, Carol

AU - Smith, Blair H.

AU - Soranzo, Nicole

AU - Southam, Lorraine

AU - Spasic-Boskovic, Olivera

AU - Spector, Timothy D.

AU - St Clair, David

AU - Stalker, Jim

AU - Stevens, Elizabeth

AU - Sun, Jianping

AU - Surdulescu, Gabriela

AU - Suvisaari, Jaana

AU - Syrris, Petros

AU - Taylor, Rohan

AU - Tian, Jing

AU - Tobin, Martin D.

AU - Valdes, Ana M.

AU - Vandersteen, Anthony M.

AU - Vijayarangakannan, Parthiban

AU - Visscher, Peter M.

AU - Wain, Louise V.

AU - Walters, James T.R.

AU - Wang, Guangbiao

AU - Wang, Jun

AU - Wang, Yu

AU - Ward, Kirsten

AU - Wheeler, Eleanor

AU - Whyte, Tamieka

AU - Williams, Hywel J.

AU - Williamson, Kathleen A.

AU - Wilson, Crispian

AU - Wilson, Scott G.

AU - Wong, Kim

AU - Xu, Chang Jiang

AU - Yang, Jian

AU - Zhang, Feng

AU - Zhang, Pingbo

AU - Zheng, Hou Feng

AU - Davey Smith, George

AU - Fisher, Simon E.

AU - Wilson, James F.

AU - Cole, Tim J.

AU - Fernandez-Orth, Dietmar

AU - Bønnelykke, Klaus

AU - Bisgaard, Hans

AU - Pennell, Craig E.

AU - Jaddoe, Vincent W.V.

AU - Dedoussis, George

AU - Timpson, Nicholas

AU - Zeggini, Eleftheria

AU - Vitart, Veronique

AU - St Pourcain, Beate

PY - 2019/1/21

Y1 - 2019/1/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85060231664&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-07863-x

DO - 10.1038/s41467-018-07863-x

M3 - Article

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 357

ER -