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Nat Commun. 2019 Jan 21;10(1):357. doi: 10.1038/s41467-018-07863-x.

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

Collaborators (206)

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, Lönnqvist 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, Rehnström 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 SY, 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 C, Yang J, Zhang F, Zhang P, Zheng HF.

Author information

1
MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.
2
Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD, Nijmegen, The Netherlands.
3
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
4
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.
5
The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, 3000 CA, Rotterdam, The Netherlands.
6
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, 3000 CA, Rotterdam, The Netherlands.
7
Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, 3000 CA, Rotterdam, The Netherlands.
8
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3000 CA, Rotterdam, The Netherlands.
9
School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, NSW, 2308, Australia.
10
Division of Obstetrics and Gynaecology, The University of Western Australia, Crawley, WA, 6009, Australia.
11
COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, 2820, Copenhagen, Denmark.
12
ISGlobal, 08003, Barcelona, Spain.
13
Pompeu Fabra University, Barcelona, 08003, Spain.
14
Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, 28029, Spain.
15
Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre-Sophia Children's Hospital, P.O. Box 2060, Rotterdam, 3000 CB, The Netherlands.
16
IMIM Instituto Hospital del Mar de Investigaciones Médicas, Barcelona, 08003, Spain.
17
MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
18
Center for Population Genomics, Boston VA Healthcare System, 150 S. Huntington Ave, Jamaica Plain, MA, 02130, USA.
19
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9AG, UK.
20
Donders Institute for Brain, Cognition & Behaviour, Radboud University, 6525 EN, Nijmegen, The Netherlands.
21
Faculty of Population Health Sciences, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
22
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671, Athens, Greece.
23
MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK. beate.stpourcain@mpi.nl.
24
Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD, Nijmegen, The Netherlands. beate.stpourcain@mpi.nl.
25
Donders Institute for Brain, Cognition & Behaviour, Radboud University, 6525 EN, Nijmegen, The Netherlands. beate.stpourcain@mpi.nl.

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.

PMID:
30664637
PMCID:
PMC6341110
DOI:
10.1038/s41467-018-07863-x
[Indexed for MEDLINE]
Free PMC Article

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