Low-frequency variation in TP53 has large effects on head circumference and intracranial volume
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. ,   UK10K consortium, Turki Saeed Al , Anderson Carl A. , Anney Richard , Antony Dinu , Artigas María Soler , Ayub Muhammad , Bala Senduran , Barrett Jeffrey C. , Barroso Inês , Beales Phil , Bentham Jamie , Bhattacharya Shoumo , Birney Ewan , Blackwood Douglas , Bobrow Martin , Bochukova Elena , Bolton Patrick F. , Bounds Rebecca , Boustred Chris , Breen Gerome , Calissano Mattia , Carss Keren , Charlton Ruth , Chatterjee Krishna , Chen Lu , Ciampi Antonio , Cirak Sebahattin , Clapham Peter , Clement Gail , Coates Guy , Cocca Massimiliano , Collier David A. , Cosgrove Catherine , Cox Tony , Craddock Nick , Crooks Lucy , Curran Sarah , Curtis David , Daly Allan , Danecek Petr , Day Ian N. M. , Day-Williams Aaron , Dominiczak Anna , Down Thomas , Du Yuanping , Dunham Ian , Durbin Richard , Edkins Sarah , Ekong Rosemary , Ellis Peter , Evans David M. , Farooqi I. Sadaf , Fitzpatrick David R. , Flicek Paul , Floyd James , Foley A. Reghan , Franklin Christopher S. , Futema Marta , Gallagher Louise , Gaunt Tom R. , Geihs Matthias , Geschwind Daniel , Greenwood Celia M. T. , Griffin Heather , Grozeva Detelina , Guo Xiaosen , Guo Xueqin , Gurling Hugh , Hart Deborah , Hendricks Audrey E. , Holmans Peter , Howie Bryan , Huang Jie , Huang Liren , Hubbard Tim , Humphries Steve E. , Hurles Matthew E. , Hysi Pirro , Jackson David K. , Jamshidi Yalda , Joyce Chris , Karczewski Konrad J. , Kaye Jane , Keane Thomas , Kemp John P. , Kennedy Karen , Kent Alastair , Keogh Julia , Khawaja Farrah , van Kogelenberg Margriet , Kolb-Kokocinski Anja , Lachance Genevieve , Langford Cordelia , Lawson Daniel , Lee Irene , Lek Monkol , Li Rui , Li Yingrui , Liang Jieqin , Lin Hong , Liu Ryan , Lönnqvist Jouko , Lopes Luis R. , Lopes Margarida , MacArthur Daniel G. , Mangino Massimo , Marchini Jonathan , Marenne Gaëlle , Maslen John , Mathieson Iain , McCarthy Shane , McGuffin Peter , McIntosh Andrew M. , McKechanie Andrew G. , McQuillin Andrew , Memari Yasin , Metrustry Sarah , Migone Nicola , Mitchison Hannah M. , Moayyeri Alireza , Morris Andrew , Morris James , Muddyman Dawn , Muntoni Francesco , Northstone Kate , O’Donovan Michael C. , O’Rahilly Stephen , Onoufriadis Alexandros , Oualkacha Karim , Owen Michael J. , Palotie Aarno , Panoutsopoulou Kalliope , Parker Victoria , Parr Jeremy R. , Paternoster Lavinia , Paunio Tiina , Payne Felicity , Payne Stewart J. , Perry John R. B. , Pietilainen Olli , Plagnol Vincent , Pollitt Rebecca C. , Porteous David J. , Povey Sue , Quail Michael A. , Quaye Lydia , Raymond F. Lucy , Rehnström Karola , Richards J. Brent , Ridout Cheryl K. , Ring Susan , Ritchie Graham R. S. , Roberts Nicola , Robinson Rachel L. , Savage David B. , Scambler Peter , Schiffels Stephan , Schmidts Miriam , Schoenmakers Nadia , Scott Richard H. , Semple Robert K. , Serra Eva , Sharp Sally I. , Shaw Adam , Shihab Hashem A. , Shin So-Youn , Skuse David , Small Kerrin S. , Smee Carol , Smith Blair H. , Soranzo Nicole , Southam Lorraine , Spasic-Boskovic Olivera , Spector Timothy D. , St Clair David , Stalker Jim , Stevens Elizabeth , Sun Jianping , Surdulescu Gabriela , Suvisaari Jaana , Syrris Petros , Taylor Rohan , Tian Jing , Tobin Martin D. , Valdes Ana M. , Vandersteen Anthony M. , Vijayarangakannan Parthiban , Visscher Peter M. , Wain Louise V. , Walters James T. R. , Wang Guangbiao , Wang Jun , Wang Yu , Ward Kirsten , Wheeler Eleanor , Whyte Tamieka , Williams Hywel J. , Williamson Kathleen A. , Wilson Crispian , Wilson Scott G. , Wong Kim , Xu ChangJiang , Yang Jian , Zhang Feng , Zhang Pingbo , Zheng Hou-Feng , 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 
Published: January 2019

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.