Low frequency genetic variation in the TP53 locus has large effects on head circumference and intracranial volume

Abstract

Background: Craniofacial development involves complex growth and differentiation of hard and soft tissues, characterised by cephalocaudal and allometric patterns, and gives rise to the closely related traits of head... [ view full abstract ]

Background: Craniofacial development involves complex growth and differentiation of hard and soft tissues, characterised by cephalocaudal and allometric patterns, and gives rise to the closely related traits of head circumference (HC) and intracranial volume (ICV). Previous studies have identified genetic variants influencing infant HC, but the role of low-frequent and common variation contributing to childhood and final HC is not well understood, nor the nature of genetic determinants that contribute to an underlying joint skeletal and brain-related phenotype (final craniofacial dimension).

Participants and methods: Here we carry out a genome-wide analysis of final HC and final craniofacial dimension studying 11 population based cohorts with either whole genome sequencing information (n=1,762; UK10K consortium), genotype imputation to a joint UK10K/1KG panel (n=8,285) or genotype imputation to the Haplotype Reference Consortium (HRC) panel (n=8,834). All participants were aged 5.5 years or older and of European ancestry, as near final HC is largely determined by the age of 6 years. The entire HC meta-analysis included 18,881 participants, with a replication in a further independent sample of 973 adults, aged 18-85 years. Joint analysis of HC and ICV (craniofacial dimension) included 26,577 additional participants aged 9-98 years from the CHARGE / ENIGMA consortia with a total sample size of 45,458.

Results: We identified and replicated evidence for genetic association between both final HC and final craniofacial dimension and a novel region on chromosome 17p13.1, implicating low frequency variants within TP53. For final HC, the strongest evidence for association was observed at rs35850753 (EAF=0.02; p=2×10^-10), while final craniofacial dimension, based on the joint analysis of HC and ICV, was most strongly associated with rs78378222 (EAF=0.02; p=9×10^-13). Both variants are in partial linkage disequilibrium, and their effect sizes are substantially larger than any previously reported GWAS signals for either HC or ICV alone. Specifically, they reach nearly a fifth and quarter of a SD unit change in final craniofacial dimension and final HC per rare effect allele respectively, an effect that is observable from mid-childhood onwards, but not in infancy. In addition, we identified eight further loci affecting final craniofacial dimension. The genetic variance composition of HC showed considerable genetic stability between infancy and mid-adolescence, with genetic factors operating at the age of 1.5 years explaining 63.1%(SE=0.09%) of the genetic variance at age 15 years. However, we also observed evidence for some developmental changes in the underlying genetic architecture.

Discussion: TP53 encodes the p53 protein, which has anti-proliferative functions, and both rs35850753 and rs78378222 have been robustly linked to neuroblastoma. There is furthermore support from animal and tissue models for a role of TP53 in early neurological patterning, especially neural crest development involving epithelial-mesenchymal transition (EMT), where epithelial cells are converted into individual migratory cells, as well as neural tube closure and early brain development. Together, our findings thus support a role for TP53 transcripts in human craniofacial development and contribute to an improved understanding of the dynamic nature of genetic architectures throughout human growth and development.

Authors

Beate St Pourcain (Max Planck Institute for Psycholinguistics)
Veronique Vitart (MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH16 4UX, UK)
Eleftheria Zeggini (The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK)
George Dedoussis (Department Of Nutrition And Dietetics, School Of Health Science And Education, Harokopio University, Athens 17671, Greece)
Vincent Jaddoe (The Generation R Study Group, Erasmus Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands)
Craig E. Pennell (School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle (UON), Australia)
Klaus Bønnelykke (COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, DK-2820 Copenhagen, Denmark)
David Martinez (ISGlobal, Center for Research in Environmental Epidemiology, 08003, Barcelona, Catalonia, Spain)
Klaudia Walter (The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK)
Andrew Jackson (MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH16 4UX, UK)
Paul Timmers (MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH16 4UX, UK)
James F. Wilson (MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH16 4UX, UK)
Caroline Hayward (MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH16 4UX, UK)
George Davey Smith (MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK)
Josine Min (MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK)
Valentina Iotchkova (The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK)
Tim Cole (UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK)
Members UK10K (Consortium)
Hans Bisgaard (COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, DK-2820 Copenhagen, Denmark)
Simon E. Fisher (Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD Nijmegen, The Netherlands)
Nicholas J Timpson (MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK)
Dietmar Fernandez (ISGlobal, Center for Research in Environmental Epidemiology, 08003, Barcelona, Catalonia, Spain)
Jordi Sunyer (ISGlobal, Center for Research in Environmental Epidemiology, 08003, Barcelona, Catalonia, Spain)
Tarunveer S Ahluwalia (COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, DK-2820 Copenhagen, Denmark)
Carol Wang (School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle (UON), Australia)
Janine Felix (The Generation R Study Group, Erasmus Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands)
Ioanna Tachmazidou (The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK)
Chin Yang Shapland (Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD Nijmegen, The Netherlands)
Simon Haworth (MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK)

Topic Areas

Health (e.g., BMI, Exercise) , Development

Session

OS-2C » Health (13:15 - Thursday, 21st June, Monadnock)

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