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-Gómez; Fernando Rivadeneira; Carol Wang; Tarunveer S. Ahluwalia; Martine Vrijheid; Mònica Guxens; Jordi Sunyer; Ioanna Tachmazidou; Klaudia Walter; Valentina Iotchkova; Andrew Jackson; Louise Cleal; Jennifer Huffman; Josine L. Min; Lærke Sass; Paul R. H. J. Timmers; UK10K Consortium; George  Davey Smith; Simon E. Fisher; James F. Wilson; Tim J. Cole; Dietmar Fernandez-Orth; Klaus Bønnelykke; Hans Bisgaard; Craig E. Pennell; Vincent W. V.  Jaddoe; George  Dedoussis; Nicholas Timpson; Eleftheria Zeggini; Veronique Vitart; Beaté St Pourcain; Andrew G. McKechanie

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-Gómez, Fernando Rivadeneira, Carol Wang, Tarunveer S. Ahluwalia, Martine Vrijheid, Mònica Guxens, Jordi Sunyer, Ioanna Tachmazidou, Klaudia Walter, Valentina Iotchkova, Andrew Jackson, Louise Cleal, Jennifer Huffman, Josine L. Min, Lærke SassPaul R. H. J. Timmers, UK10K Consortium, George Davey Smith, Simon E. Fisher, James F. Wilson, Tim J. Cole, Dietmar Fernandez-Orth, Klaus Bønnelykke, Hans Bisgaard, Craig E. Pennell, Vincent W. V. Jaddoe, George Dedoussis, Nicholas Timpson, Eleftheria Zeggini, Veronique Vitart, Beaté St Pourcain, Andrew G. McKechanie (Member of Consortium)

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 / Materials (for Non-textual outputs)

GENOME-WIDE ASSOCIATION
LD SCORE REGRESSION
GENETIC ARCHITECTURE
COMMON VARIANTS
GROWTH
BRAIN
GWAS
HERITABILITY
IMPUTATION
WEIGHT

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10.1038/s41467-018-07863-xLicence: Creative Commons: Attribution (CC-BY)

Low-frequency variation in TP53 has large effects on head circumference Accepted author manuscript, 34.9 MBLicence: Creative Commons: Attribution (CC-BY)
Low-frequency variation in TP53...
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Final published version, 1.94 MBLicence: Creative Commons: Attribution (CC-BY)

MC_UU_00007/5 From Microcephaly to Genome Stability, Inflammation and Growth Regulation
Jackson, A.
1/04/18 → 31/03/23
Project: Research

Veronique Vitart
- veronique.vitartigmm.ed.acuk
- Deanery of Molecular, Genetic and Population Health Sciences - Senior Scientist
- MRC Human Genetics Unit
Person: Academic: Research Active

Cite this

Haworth, S., Shapland, C. Y., Hayward, C., Prins, B. P., Felix, J. F., Medina-Gómez, C., Rivadeneira, F., Wang, C., Ahluwalia, T. S., Vrijheid, M., Guxens, M., Sunyer, J., Tachmazidou, I., Walter, K., Iotchkova, V., Jackson, A., Cleal, L., Huffman, J., Min, J. L., ... McKechanie, A. G. (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{c42a6b3a5457430eb8990a332844629d,

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 = "GENOME-WIDE ASSOCIATION, LD SCORE REGRESSION, GENETIC ARCHITECTURE, COMMON VARIANTS, GROWTH, BRAIN, GWAS, HERITABILITY, IMPUTATION, WEIGHT",

author = "Simon Haworth and Shapland, {Chin Yang} and Caroline Hayward and Prins, {Bram P.} and Felix, {Janine F.} and Carolina Medina-G{\'o}mez 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 Huffman and Min, {Josine L.} and L{\ae}rke Sass and Timmers, {Paul R. H. J.} and UK10K Consortium and {Davey Smith}, George and Fisher, {Simon E.} and Wilson, {James F.} and Cole, {Tim J.} and Dietmar Fernandez-Orth and Klaus B{\o}nnelykke and Hans Bisgaard and Pennell, {Craig E.} and Jaddoe, {Vincent W. V.} and George Dedoussis and Nicholas Timpson and Eleftheria Zeggini and Veronique Vitart and {St Pourcain}, Beat{\'e} and McKechanie, {Andrew G.}",

year = "2019",

month = jan,

day = "21",

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

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Haworth, S, Shapland, CY, Hayward, C, Prins, BP, Felix, JF, Medina-Gómez, C, Rivadeneira, F, Wang, C, Ahluwalia, TS, Vrijheid, M, Guxens, M, Sunyer, J, Tachmazidou, I, Walter, K, Iotchkova, V, Jackson, A, Cleal, L, Huffman, J, Min, JL, Sass, L, Timmers, PRHJ, UK10K Consortium, Davey Smith, G, Fisher, SE, Wilson, JF, Cole, TJ, Fernandez-Orth, D, Bønnelykke, K, Bisgaard, H, Pennell, CE, Jaddoe, VWV, Dedoussis, G, Timpson, N, Zeggini, E, Vitart, V, St Pourcain, B & McKechanie, AG 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-Gómez, 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 - Huffman, Jennifer

AU - Min, Josine L.

AU - Sass, Lærke

AU - Timmers, Paul R. H. J.

AU - UK10K Consortium

AU - Davey Smith, George

AU - Fisher, Simon E.

AU - Wilson, James F.

AU - Cole, Tim J.

AU - Fernandez-Orth, Dietmar

AU - Bønnelykke, Klaus

AU - Bisgaard, Hans

AU - Pennell, Craig E.

AU - Jaddoe, Vincent W. V.

AU - Dedoussis, George

AU - Timpson, Nicholas

AU - Zeggini, Eleftheria

AU - Vitart, Veronique

AU - St Pourcain, Beaté

A2 - McKechanie, Andrew G.

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 - GENOME-WIDE ASSOCIATION

KW - LD SCORE REGRESSION

KW - GENETIC ARCHITECTURE

KW - COMMON VARIANTS

KW - GROWTH

KW - BRAIN

KW - GWAS

KW - HERITABILITY

KW - IMPUTATION

KW - WEIGHT

U2 - 10.1038/s41467-018-07863-x

DO - 10.1038/s41467-018-07863-x

M3 - Article

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 / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

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Projects

MC_UU_00007/5 From Microcephaly to Genome Stability, Inflammation and Growth Regulation

Profiles

Veronique Vitart

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