Low-frequency variation in TP53 has large effects on head circumference and intracranial volume.
Adolescent
Adult
Aged
Aged, 80 and over
Alleles
Cephalometry
Child
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
White People
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 01 2019
21 01 2019
Historique:
received:
06
06
2018
accepted:
12
11
2018
entrez:
22
1
2019
pubmed:
22
1
2019
medline:
6
2
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30664637
doi: 10.1038/s41467-018-07863-x
pii: 10.1038/s41467-018-07863-x
pmc: PMC6341110
doi:
Substances chimiques
RNA, Messenger
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
357Subventions
Organisme : Medical Research Council
ID : MR/R010692/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L010305/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00011/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : G9824984
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/10
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12013/4
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 202802/Z/16/Z
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/10/17/28553
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_U127580972
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12013/3
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/5
Pays : United Kingdom
Investigateurs
Saeed Al Turki
(SA)
Carl A Anderson
(CA)
Richard Anney
(R)
Dinu Antony
(D)
María Soler Artigas
(MS)
Muhammad Ayub
(M)
Senduran Bala
(S)
Jeffrey C Barrett
(JC)
Inês Barroso
(I)
Phil Beales
(P)
Jamie Bentham
(J)
Shoumo Bhattacharya
(S)
Ewan Birney
(E)
Douglas Blackwood
(D)
Martin Bobrow
(M)
Elena Bochukova
(E)
Patrick F Bolton
(PF)
Rebecca Bounds
(R)
Chris Boustred
(C)
Gerome Breen
(G)
Mattia Calissano
(M)
Keren Carss
(K)
Ruth Charlton
(R)
Krishna Chatterjee
(K)
Lu Chen
(L)
Antonio Ciampi
(A)
Sebahattin Cirak
(S)
Peter Clapham
(P)
Gail Clement
(G)
Guy Coates
(G)
Massimiliano Cocca
(M)
David A Collier
(DA)
Catherine Cosgrove
(C)
Tony Cox
(T)
Nick Craddock
(N)
Lucy Crooks
(L)
Sarah Curran
(S)
David Curtis
(D)
Allan Daly
(A)
Petr Danecek
(P)
Ian N M Day
(INM)
Aaron Day-Williams
(A)
Anna Dominiczak
(A)
Thomas Down
(T)
Yuanping Du
(Y)
Ian Dunham
(I)
Richard Durbin
(R)
Sarah Edkins
(S)
Rosemary Ekong
(R)
Peter Ellis
(P)
David M Evans
(DM)
I Sadaf Farooqi
(IS)
David R Fitzpatrick
(DR)
Paul Flicek
(P)
James Floyd
(J)
A Reghan Foley
(AR)
Christopher S Franklin
(CS)
Marta Futema
(M)
Louise Gallagher
(L)
Tom R Gaunt
(TR)
Matthias Geihs
(M)
Daniel Geschwind
(D)
Celia M T Greenwood
(CMT)
Heather Griffin
(H)
Detelina Grozeva
(D)
Xiaosen Guo
(X)
Xueqin Guo
(X)
Hugh Gurling
(H)
Deborah Hart
(D)
Audrey E Hendricks
(AE)
Peter Holmans
(P)
Bryan Howie
(B)
Jie Huang
(J)
Liren Huang
(L)
Tim Hubbard
(T)
Steve E Humphries
(SE)
Matthew E Hurles
(ME)
Pirro Hysi
(P)
David K Jackson
(DK)
Yalda Jamshidi
(Y)
Chris Joyce
(C)
Konrad J Karczewski
(KJ)
Jane Kaye
(J)
Thomas Keane
(T)
John P Kemp
(JP)
Karen Kennedy
(K)
Alastair Kent
(A)
Julia Keogh
(J)
Farrah Khawaja
(F)
Margriet van Kogelenberg
(M)
Anja Kolb-Kokocinski
(A)
Genevieve Lachance
(G)
Cordelia Langford
(C)
Daniel Lawson
(D)
Irene Lee
(I)
Monkol Lek
(M)
Rui Li
(R)
Yingrui Li
(Y)
Jieqin Liang
(J)
Hong Lin
(H)
Ryan Liu
(R)
Jouko Lönnqvist
(J)
Luis R Lopes
(LR)
Margarida Lopes
(M)
Daniel G MacArthur
(DG)
Massimo Mangino
(M)
Jonathan Marchini
(J)
Gaëlle Marenne
(G)
John Maslen
(J)
Iain Mathieson
(I)
Shane McCarthy
(S)
Peter McGuffin
(P)
Andrew M McIntosh
(AM)
Andrew G McKechanie
(AG)
Andrew McQuillin
(A)
Yasin Memari
(Y)
Sarah Metrustry
(S)
Nicola Migone
(N)
Hannah M Mitchison
(HM)
Alireza Moayyeri
(A)
Andrew Morris
(A)
James Morris
(J)
Dawn Muddyman
(D)
Francesco Muntoni
(F)
Kate Northstone
(K)
Michael C O'Donovan
(MC)
Stephen O'Rahilly
(S)
Alexandros Onoufriadis
(A)
Karim Oualkacha
(K)
Michael J Owen
(MJ)
Aarno Palotie
(A)
Kalliope Panoutsopoulou
(K)
Victoria Parker
(V)
Jeremy R Parr
(JR)
Lavinia Paternoster
(L)
Tiina Paunio
(T)
Felicity Payne
(F)
Stewart J Payne
(SJ)
John R B Perry
(JRB)
Olli Pietilainen
(O)
Vincent Plagnol
(V)
Rebecca C Pollitt
(RC)
David J Porteous
(DJ)
Sue Povey
(S)
Michael A Quail
(MA)
Lydia Quaye
(L)
F Lucy Raymond
(FL)
Karola Rehnström
(K)
J Brent Richards
(JB)
Cheryl K Ridout
(CK)
Susan Ring
(S)
Graham R S Ritchie
(GRS)
Nicola Roberts
(N)
Rachel L Robinson
(RL)
David B Savage
(DB)
Peter Scambler
(P)
Stephan Schiffels
(S)
Miriam Schmidts
(M)
Nadia Schoenmakers
(N)
Richard H Scott
(RH)
Robert K Semple
(RK)
Eva Serra
(E)
Sally I Sharp
(SI)
Adam Shaw
(A)
Hashem A Shihab
(HA)
So-Youn Shin
(SY)
David Skuse
(D)
Kerrin S Small
(KS)
Carol Smee
(C)
Blair H Smith
(BH)
Nicole Soranzo
(N)
Lorraine Southam
(L)
Olivera Spasic-Boskovic
(O)
Timothy D Spector
(TD)
David St Clair
(D)
Jim Stalker
(J)
Elizabeth Stevens
(E)
Jianping Sun
(J)
Gabriela Surdulescu
(G)
Jaana Suvisaari
(J)
Petros Syrris
(P)
Rohan Taylor
(R)
Jing Tian
(J)
Martin D Tobin
(MD)
Ana M Valdes
(AM)
Anthony M Vandersteen
(AM)
Parthiban Vijayarangakannan
(P)
Peter M Visscher
(PM)
Louise V Wain
(LV)
James T R Walters
(JTR)
Guangbiao Wang
(G)
Jun Wang
(J)
Yu Wang
(Y)
Kirsten Ward
(K)
Eleanor Wheeler
(E)
Tamieka Whyte
(T)
Hywel J Williams
(HJ)
Kathleen A Williamson
(KA)
Crispian Wilson
(C)
Scott G Wilson
(SG)
Kim Wong
(K)
ChangJiang Xu
(C)
Jian Yang
(J)
Feng Zhang
(F)
Pingbo Zhang
(P)
Hou-Feng Zheng
(HF)
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