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A novel common variant in DCST2 is associated with length in early life and height in adulthood

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posted on 10.02.2016, 12:52 by R. J. P. van der Valk, E. Kreiner-Møller, M. N. Kooijman, M Guxens, E. Stergiakouli, A. Sääf, J. P. Bradfield, F. Geller, M. G. Hayes, D. L. Cousminer, A. Körner, E. Thiering, J. A. Curtin, R. Myhre, V. Huikari, R. Joro, M. Kerkhof, N. M. Warrington, N. Pitkänen, Ioanna Ntalla, M. Horikoshi, R. Veijola, R. M. Freathy, Y-Y. Teo, S. J. Barton, D. M. Evans, J. P. Kemp, B. St Pourcain, S. M. Ring, G. D. Smith, A. Bergström, I. Kull, H. Hakonarson, F. D. Mentch, H. Bisgaard, B. Chawes, J. Stokholm, J. Waage, P. Eriksen, A. Sevelsted, M. Melbye, C. M. van Duijn, C. Medina-Gomez, A. Hofman, J. C. de Jongste, H. R. Taal, A. G. Uitterlinden, L. L. Armstrong, J. Eriksson, A. Palotie, M. Bustamante, X. Estivill, J. R. Gonzalez, S. Llop, W. Kiess, A. Mahajan, C. Flexeder, C. M. T. Tiesler, C. S. Murray, A. Simpson, P. Magnus, V. Sengpiel, A-L. Hartikainen, S. Keinanen-Kiukaanniemi, A. Lewin, A. Da Silva Couto Alves, A. I. Blakemore, J. L. Buxton, M. Kaakinen, A. Rodriguez, S. Sebert, M. Vaarasmaki, T. Lakka, V. Lindi, U. Gehring, D. S. Postma, W. Ang, J. P. Newnham, L-P. Lyytikäinen, K. Pahkala, O. T. Raitakari, K. Panoutsopoulou, E. Zeggini, D. I. Boomsma, M. Groen-Blokhuis, J. Ilonen, L. Franke, J. N. Hirschhorn, T. H. Pers, L. Liang, J. Huang, B. Hocher, M. Knip, Seang-Mei Saw, J. W. Holloway, E. Melén, S. F. A. Grant, B. Feenstra, W. L. Lowe, E. Widén, E. Sergeyev, H. Grallert, A. Custovic, B. Jacobsson, M-R. Jarvelin, M. Atalay, G. H. Koppelman, C. E. Pennell, H. Niinikoski, G. V. Dedoussis, M. I. Mccarthy, T. M. Frayling, J. Sunyer, N. J. Timpson, F. Rivadeneira, K. Bønnelykke, V. W. V. Jaddoe
Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10−6) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10−8, explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10−4) and adult height (N = 127 513; P = 1.45 × 10−5). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Funding

R.M.F. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust grant 085541/Z/08/Z). T.H.P. is supported by The Danish Council for Independent Research Medical Sciences (FSS) The Alfred Benzon Foundation. B.F. is supported by an Oak Foundation fellowship. M.M. is a Wellcome Trust Senior Investigator (Wellcome Trust grant 090532) and a NIHR Senior Investigator. T.M.F. is supported by the European Research Council grant: SZ-245 50371- GLUCOSEGENES-FP7-IDEAS-ERC. F.R. (VIDI 016.136.367) and V.W.V.J. (VIDI 016.136.361) received grants from the Netherlands Organization for Health Research and Development.

History

Citation

Human Molecular Genetics, 2015, Vol. 24, No. 4

Version

VoR (Version of Record)

Published in

Human Molecular Genetics

Publisher

Oxford University Press (OUP)

issn

0964-6906

eissn

1460-2083

Acceptance date

29/09/2014

Copyright date

2014

Available date

10/02/2016

Publisher version

http://hmg.oxfordjournals.org/content/24/4/1155

Notes

Supplementary Material is available at HMG online.

Associated authors

Early Growth Genetics (EGG) Consortium; Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium; Genetic Investigation of ANthropometric Traits (GIANT) Consortium

Language

en

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