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

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

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

Year: 2015
OAI identifier: oai:dspace.library.uu.nl:1874/307742
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