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

Simon Haworth; Chin Yang Shapland; Caroline Hayward; Bram P. Prins; Janine F. Felix; Carolina Medina-Gomez; Fernando Rivadeneira; Carol Wang; Tarunveer S. Ahluwalia; Martine Vrijheid; Mònica Guxens; Jordi Sunyer; Ioanna Tachmazidou; Klaudia Walter; Valentina Iotchkova; Andrew Jackson; Louise Cleal; Jennifer Huffmann; Josine L. Min; Lærke Sass; Paul R.H.J. Timmers; UK10K Consortium; George Davey Smith; Tim J. Cole; Nicholas Timpson; Eleftheria Zeggini; Beate St Pourcain

doi:10.1038/s41467-018-07863-x

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

Simon Haworth, Chin Yang Shapland, Caroline Hayward, Bram P. Prins, Janine F. Felix, Carolina Medina-Gomez, Fernando Rivadeneira, Carol Wang, Tarunveer S. Ahluwalia, Martine Vrijheid, Mònica Guxens, Jordi Sunyer, Ioanna Tachmazidou, Klaudia Walter, Valentina Iotchkova, Andrew Jackson, Louise Cleal, Jennifer Huffmann, Josine L. Min, Lærke SassPaul R.H.J. Timmers, UK10K Consortium, George Davey Smith, Tim J. Cole, Nicholas Timpson, Eleftheria Zeggini, Beate St Pourcain^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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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 language	English
Article number	357
Number of pages	16
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-018-07863-x
Publication status	Published - 21 Jan 2019

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Alleles
Cephalometry
Child
European Continental Ancestry Group
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

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Final published version, 1.94 MBLicence: CC BY

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Haworth, S., Shapland, C. Y., Hayward, C., Prins, B. P., Felix, J. F., Medina-Gomez, C., Rivadeneira, F., Wang, C., Ahluwalia, T. S., Vrijheid, M., Guxens, M., Sunyer, J., Tachmazidou, I., Walter, K., Iotchkova, V., Jackson, A., Cleal, L., Huffmann, J., Min, J. L., ... St Pourcain, B. (2019). Low-frequency variation in TP53 has large effects on head circumference and intracranial volume. Nature Communications, 10, Article 357. https://doi.org/10.1038/s41467-018-07863-x

@article{5df9d1a5bc43412180f2f0b4b6e105d0,

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.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Cephalometry, Child, European Continental Ancestry Group, 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",

author = "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 {UK10K Consortium} and Turki, {Saeed Al} and Anderson, {Carl A.} and Chris Boustred and Sarah Curran and Day, {Ian N.M.} and Evans, {David M.} and Gaunt, {Tom R.} and Kemp, {John P.} and Daniel Lawson and Kate Northstone and Lavinia Paternoster and Susan Ring and Shihab, {Hashem A.} and Shin, {So Youn} and Nicole Soranzo and Jing Tian and Tobin, {Martin D.} and Wain, {Louise V.} and {Davey Smith}, George and Wilson, {James F.} and Cole, {Tim J.} and Nicholas Timpson and Eleftheria Zeggini and {St Pourcain}, Beate",

year = "2019",

month = jan,

day = "21",

doi = "10.1038/s41467-018-07863-x",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer Nature",

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Haworth, S , Shapland, CY, Hayward, C, Prins, BP, Felix, JF, Medina-Gomez, C, Rivadeneira, F, Wang, C, Ahluwalia, TS, Vrijheid, M, Guxens, M, Sunyer, J, Tachmazidou, I, Walter, K, Iotchkova, V, Jackson, A, Cleal, L, Huffmann, J, Min, JL, Sass, L, Timmers, PRHJ, UK10K Consortium, Davey Smith, G, Cole, TJ, Timpson, N, Zeggini, E & St Pourcain, B 2019, 'Low-frequency variation in TP53 has large effects on head circumference and intracranial volume', Nature Communications, vol. 10, 357. https://doi.org/10.1038/s41467-018-07863-x

TY - JOUR

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

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 - UK10K Consortium

AU - Turki, Saeed Al

AU - Anderson, Carl A.

AU - Boustred, Chris

AU - Curran, Sarah

AU - Day, Ian N.M.

AU - Evans, David M.

AU - Gaunt, Tom R.

AU - Kemp, John P.

AU - Lawson, Daniel

AU - Northstone, Kate

AU - Paternoster, Lavinia

AU - Ring, Susan

AU - Shihab, Hashem A.

AU - Shin, So Youn

AU - Soranzo, Nicole

AU - Tian, Jing

AU - Tobin, Martin D.

AU - Wain, Louise V.

AU - Davey Smith, George

AU - Wilson, James F.

AU - Cole, Tim J.

AU - Timpson, Nicholas

AU - Zeggini, Eleftheria

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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Alleles

KW - Cephalometry

KW - Child

KW - European Continental Ancestry Group

KW - Female

KW - Gene Expression Regulation, Developmental

KW - Gene Frequency

KW - Genetic Loci

KW - Genetic Variation

KW - Genome, Human

KW - Humans

KW - Male

KW - Middle Aged

KW - RNA, Messenger/genetics

KW - Skull/anatomy & histology

KW - Tumor Suppressor Protein p53/genetics

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 (Academic Journal)

C2 - 30664637

AN - SCOPUS:85060231664

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 357

ER -

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

Abstract

Keywords

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

Abstract

Keywords

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