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

van der Valk, Ralf J.P., Kreiner-Moller, Eskil, Kooijman, Marjolein N., Guxens, Monica, Stergiakouli, Evangelia, Saaf, Annika, Bradfield, Jonathan P., Geller, Frank, Hayes, M. Geoffrey, Cousminer, Diana L., Korner, Antje, Thiering, Elisabeth, Curtin, John A., Myhre, Ronny, Huikari, Ville, Joro, Raimo, Kerkhof, Marjan, Warrington, Nicole M., Pitkanen, Niina, Ntalla, Ioanna, Horikoshi, Momoko, Veijola, Riitta, Freathy, Rachel M., Teo, Yik-Ying, Barton, Sheila J., Evans, David M., Kemp, John P., St Pourcain, Beate, Ring, Susan M., Davey Smith, George, Bergstrom, Anna, Kull, Inger, Hakonarson, Hakon, Mentch, Frank D., Bisgaard, Hans, Chawes, Bo, Stokholm, Jakob, Waage, Johannes, Eriksen, Patrick, Sevelsted, Astrid, Melbye, Mads, van Duijn, Cornelia M., Medina-Gomez, Carolina, Hofman, Albert, de Jongste, Johan C., Taal, H. Rob, Uitterlinden, André G., Armstrong, Loren L., Eriksson, Johan, Palotie, Aarno, Bustamante, Mariona, Estivill, Xavier, Gonzalez, Juan R., Llop, Sabrina, Kiess, Wieland, Mahajan, Anubha, Flexeder, Claudia, Tiesler, Carla M.T., Murray, Clare S., Simpson, Angela, Magnus, Per, Sengpiel, Verena, Hartikainen, Anna-Liisa, Keinanen-Kiukaanniemi, Sirkka, Lewin, Alexandra, Da Silva Couto Alves, Alexessander, Blakemore, Alexandra I., Buxton, Jessica L., Kaakinen, Marika, Rodriguez, Alina, Sebert, Sylvain, Vaarasmaki, Marja, Lakka, Timo, Lindi, Virpi, Gehring, Ulrike, Postma, Dirkje S., Ang, Wei, Newnham, John P., Lyytikainen, Leo-Pekka, Pahkala, Katja, Raitakari, Olli T., Panoutsopoulou, Kalliope, Zeggini, Eleftheria, Boomsma, Dorret I., Groen-Blokhuis, Maria, Ilonen, Jorma, Franke, Lude, Hirschhorn, Joel N., Pers, Tune H., Liang, Liming, Huang, Jinyan, Hocher, Berthold, Knip, Mikael, Saw, Seang-Mei, Holloway, John W., Melen, Erik, Grant, Struan F.A., Feenstra, Bjarke, Lowe, William L., Widen, Elisabeth, Sergeyev, Elena, Grallert, Harald, Custovic, Adnan, Jacobsson, Bo, Jarvelin, Marjo-Riitta, Atalay, Mustafa, Koppelman, Gerard H., Pennell, Craig E., Niinikoski, Harri, Dedoussis, George V., Mccarthy, Mark I., Frayling, Timothy M., Sunyer, Jordi, Timpson, Nicholas J., Rivadeneira, Fernando, Bonnelykke, Klaus and Jaddoe, Vincent W.V. (2015) A novel common variant in DCST2 is associated with length in early life and height in adulthood. Human Molecular Genetics, 24(4), pp. 1155-1168. ISSN (print) 0964-6906

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Abstract

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.

Item Type: Article
Additional Information: This work was supported by a Sir Henry Wellcome Postdoctoral Fellowship [Wellcome Trust grant 085541/Z/08/Z],The Danish Council for Independent Research Medical Sciences,The Alfred Benzon Foundation, Oak Foundation, Wellcome Trust [grant number: 090532], National Institute for Health Research. European Research Council [grant number: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC], the Netherlands Organization for Health Research and Development [grant numbers: VIDI 016.136.367 and VIDI 016.136.361].
Research Area: Biological sciences
Epidemiology and public health
Faculty, School or Research Centre: Faculty of Science, Engineering and Computing (until 2017) > School of Life Sciences
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Depositing User: Jessica Buxton
Date Deposited: 11 Dec 2017 10:15
Last Modified: 06 Sep 2019 09:51
DOI: https://doi.org/10.1093/hmg/ddu510
URI: http://eprints.kingston.ac.uk/id/eprint/40221

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