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

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., SASS, L., TIMMERS, P.R.H.J., TURKI, S.A., ANDERSON, C.A., ANNEY, R., ANTONY, D., ARTIGAS, M.S., AYUB, M., BALA, S., BARRETT, J.C., BARROSO, I., BEALES, P., BENTHAM, J., BHATTACHARYA, S., BIRNEY, E., BLACKWOOD, D., BOBROW, M., BOCHUKOVA, E., BOLTON, P.F., 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, D.A., COSGROVE, C., COX, T., CRADDOCK, N., CROOKS, Lucy, CURRAN, S., CURTIS, D., DALY, A., DANECEK, P., DAY, I.N.M., DAY-WILLIAMS, A., DOMINICZAK, A., DOWN, T., DU, Y., DUNHAM, I., DURBIN, R., EDKINS, S., EKONG, R., ELLIS, P., EVANS, D.M., FAROOQI, I.S., FITZPATRICK, D.R., FLICEK, P., FLOYD, J., FOLEY, A.R., FRANKLIN, C.S., FUTEMA, M., GALLAGHER, L., GAUNT, T.R., GEIHS, M., GESCHWIND, D., GREENWOOD, C.M.T., GRIFFIN, H., GROZEVA, D., GUO, X., GUO, X., GURLING, H., HART, D., HENDRICKS, A.E., HOLMANS, P., HOWIE, B., HUANG, J., HUANG, L., HUBBARD, T., HUMPHRIES, S.E., HURLES, M.E., HYSI, P. and JACKSON, D.K. (2019). Low-frequency variation in TP53 has large effects on head circumference and intracranial volume. Nature Communications, 10 (1).

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Open Access URL: https://www.nature.com/articles/s41467-018-07863-x (Published version)
Link to published version:: https://doi.org/10.1038/s41467-018-07863-x
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    Abstract

    © 2019, The Author(s). 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.

    Item Type: Article
    Uncontrolled 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; Skull; Tumor Suppressor Protein p53; UK10K consortium; Skull; Humans; RNA, Messenger; Cephalometry; Gene Expression Regulation, Developmental; Gene Frequency; Alleles; Genome, Human; Adolescent; Adult; Aged; Aged, 80 and over; Middle Aged; Child; European Continental Ancestry Group; Female; Male; Tumor Suppressor Protein p53; Genetic Variation; Genetic Loci
    Identification Number: https://doi.org/10.1038/s41467-018-07863-x
    SWORD Depositor: Symplectic Elements
    Depositing User: Symplectic Elements
    Date Deposited: 28 Apr 2021 15:41
    Last Modified: 28 Apr 2021 15:45
    URI: http://shura.shu.ac.uk/id/eprint/27935

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