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

Ralf J. P. van der Valk, Eskil Kreiner-Moller, Marjolein N. Kooijman, Monica Guxens, Evangelia Stergiakouli, Annika Saaf, Jonathan P. Bradfield, Frank Geller, M. Geoffrey Hayes, Diana L. Cousminer, Antje Koerner, Elisabeth Thiering, John A. Curtin, Ronny Myhre, Ville Huikari, Raimo Joro, Marjan Kerkhof, Nicole M. Warrington, Niina Pitkanen, 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 Bergstrom, 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, Andre 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 Lyytikainen, 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 Melen, Struan F. A. Grant, Bjarke Feenstra, William L. Lowe, Elisabeth Widen, 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 Bonnelykke, Vincent 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 x 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; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclastCommon 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 x 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; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 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.show moreshow less

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Author:Ralf J. P. van der Valk, Eskil Kreiner-Moller, Marjolein N. Kooijman, Monica Guxens, Evangelia Stergiakouli, Annika Saaf, Jonathan P. Bradfield, Frank Geller, M. Geoffrey Hayes, Diana L. Cousminer, Antje Koerner, Elisabeth Thiering, John A. Curtin, Ronny Myhre, Ville Huikari, Raimo Joro, Marjan Kerkhof, Nicole M. Warrington, Niina Pitkanen, 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 Bergstrom, 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, Andre 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 Lyytikainen, 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 HocherGND, Mikael Knip, Seang-Mei Saw, John W. Holloway, Erik Melen, Struan F. A. Grant, Bjarke Feenstra, William L. Lowe, Elisabeth Widen, 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 Bonnelykke, Vincent W. V. Jaddoe
DOI:https://doi.org/10.1093/hmg/ddu510
ISSN:0964-6906 (print)
ISSN:1460-2083 (online)
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25281659
Parent Title (English):Human molecular genetics
Publisher:Oxford Univ. Press
Place of publication:Oxford
Document Type:Article
Language:English
Year of first Publication:2015
Year of Completion:2015
Creating Corporation:Early Genetics Lifecourse, Genetic Invest ANthropometric, Early Growth Genetics EGG
Release Date:2017/03/27
Volume:24
Issue:4
Pagenumber:14
First Page:1155
Last Page:1168
Funder:Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust) [085541/Z/08/Z]; Danish Council for Independent Research Medical Sciences (FSS) The Alfred Benzon Foundation; Oak Foundation fellowship; Wellcome Trust [090532]; European Research Council [SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC]; Netherlands Organization for Health Research and Development [VIDI 016.136.367, VIDI 016.136.361]
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft
Peer Review:Referiert