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Hum Mol Genet. 2015 Feb 15;24(4):1155-68. doi: 10.1093/hmg/ddu510. Epub 2014 Oct 3.

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

van der Valk RJ1, Kreiner-Møller E2, Kooijman MN1, Guxens M3, Stergiakouli E4, Sääf A5, Bradfield JP6, Geller F7, Hayes MG8, Cousminer DL9, Körner A10, Thiering E11, Curtin JA12, Myhre R13, Huikari V14, Joro R15, Kerkhof M16, Warrington NM17, Pitkänen N18, Ntalla I19, Horikoshi M20, Veijola R21, Freathy RM22, Teo YY23, Barton SJ24, Evans DM25, Kemp JP25, St Pourcain B26, Ring SM27, Davey Smith G4, Bergström A5, Kull I28, Hakonarson H29, Mentch FD6, Bisgaard H2, Chawes B2, Stokholm J2, Waage J2, Eriksen P2, Sevelsted A2, Melbye M30; Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium, van Duijn CM31, Medina-Gomez C32, Hofman A33, de Jongste JC34, Taal HR35, Uitterlinden AG32; Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Armstrong LL8, Eriksson J9, Palotie A36, Bustamante M37, Estivill X38, Gonzalez JR3, Llop S39, Kiess W10, Mahajan A40, Flexeder C41, Tiesler CM11, Murray CS12, Simpson A12, Magnus P42, Sengpiel V43, Hartikainen AL44, Keinanen-Kiukaanniemi S14, Lewin A45, Da Silva Couto Alves A45, Blakemore AI46, Buxton JL46, Kaakinen M47, Rodriguez A48, Sebert S14, Vaarasmaki M49, Lakka T50, Lindi V15, Gehring U51, Postma DS52, Ang W53, Newnham JP53, Lyytikäinen LP54, Pahkala K55, Raitakari OT56, Panoutsopoulou K57, Zeggini E57, Boomsma DI58, Groen-Blokhuis M58, Ilonen J59, Franke L60, Hirschhorn JN61, Pers TH62, Liang L63, Huang J64, Hocher B65, Knip M66, Saw SM67, Holloway JW68, Melén E69, Grant SF29, Feenstra B7, Lowe WL8, Widén E9, Sergeyev E10, Grallert H70, Custovic A12, Jacobsson B71, Jarvelin MR72, Atalay M15, Koppelman GH73, Pennell CE53, Niinikoski H74, Dedoussis GV75, Mccarthy MI76, Frayling TM22, Sunyer J77, Timpson NJ4, Rivadeneira F32, Bønnelykke K2, Jaddoe VW78; Early Growth Genetics (EGG) Consortium.

Author information

1
Department of Epidemiology, Department of Paediatrics, The Generation R Study Group.
2
Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
3
Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain, CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain.
4
MRC Integrative Epidemiology Unit .
5
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
6
Center for Applied Genomics, Abramson Research Center.
7
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
8
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
9
Institute for Molecular Medicine Finland.
10
Center of Pediatric Research, University Hospital Center Leipzig, University of Leipzig, Leipzig, Germany.
11
Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany, Institute of Epidemiology I.
12
Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
13
Division Epidemiology, Department Genes and Environment.
14
Institute of Health Sciences.
15
Institute of Biomedicine, Physiology.
16
Department of Epidemiology, Groningen Research Institute for Asthma and COPD.
17
School of Women's and Infants' Health, The University of Western Australia, Perth, Australia, University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
18
Research Centre of Applied and Preventive Cardiovascular Medicine.
19
Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK, Department of Nutrition and Dietetics, Harokopio University of Athens, Athens 11527, Greece.
20
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
21
Department of Pediatrics, Medical Research Center.
22
University of Exeter Medical School, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
23
Saw Swee Hock School of Public Health, Life Science Institute, National University of Singapore, Singapore, Genome Institute of Singapore, Agency for Science, Technology and Research.
24
MRC Lifecourse Epidemiology Unit.
25
MRC Integrative Epidemiology Unit , University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
26
MRC Integrative Epidemiology Unit , Avon Longitudinal Study of Parents and Children (ALSPAC), School of Social and Community Medicine, School of Oral and Dental Sciences, University of Bristol, Bristol, UK.
27
MRC Integrative Epidemiology Unit , Avon Longitudinal Study of Parents and Children (ALSPAC), School of Social and Community Medicine.
28
Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden, Sachs' Children's Hospital, Stockholm, Sweden.
29
Center for Applied Genomics, Abramson Research Center, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
30
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark, Department of Medicine, Stanford School of Medicine, Stanford, USA.
31
Department of Epidemiology.
32
Department of Epidemiology, The Generation R Study Group, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
33
Department of Epidemiology, The Generation R Study Group.
34
Department of Paediatrics, The Generation R Study Group.
35
Department of Epidemiology, Department of Paediatrics.
36
Institute for Molecular Medicine Finland, Analytic and Translational Genetics Unit, Department of Medicine, Program in Medical and Population Genetics, Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
37
Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain, CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain, Centre for Genomic Regulation (CRG), Barcelona, Spain.
38
CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain, Centre for Genomic Regulation (CRG), Barcelona, Spain, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
39
CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, FISABIO-Public Health, Valencia, Spain.
40
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
41
Institute of Epidemiology I.
42
Division Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.
43
Department Obstetrics and Gynecology, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.
44
Institute of Clinical Medicine/Obstetrics and Gynecology.
45
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, MRC Health Protection Agency (HPE) Centre for Environment and Health.
46
Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Faculty of Medicine, Imperial College, London W12 0NN, UK.
47
Institute of Health Sciences, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, MRC Health Protection Agency (HPE) Centre for Environment and Health, Biocenter Oulu, University of Oulu, Oulu, Finland.
48
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, MRC Health Protection Agency (HPE) Centre for Environment and Health, Department of Psychology, Mid Sweden University, Östersund, Sweden.
49
Department of Obstetrics and Gynecology and MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
50
Institute of Biomedicine, Physiology, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland, Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
51
Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
52
Groningen Research Institute for Asthma and COPD, Department of Pulmonology.
53
School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
54
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland, Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
55
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
56
Research Centre of Applied and Preventive Cardiovascular Medicine, Department of Clinical Physiology and Nuclear Medicine.
57
Wellcome Trust Sanger Institute, The Morgan Building, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1HH, UK.
58
Department of Biological Psychology, VU University, Amsterdam, The Netherlands, EMGO Institute for Health and Care Research, Amsterdam, The Netherlands, Neuroscience Campus Amsterdam, The Netherlands.
59
Immunogenetics Laboratory, University of Turku, Turku, Finland, Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland.
60
Department of Genetics, University of Groningen, University Medical Centre Groningen, The Netherlands.
61
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, USA, Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA, Department of Genetics, Harvard Medical School, USA.
62
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, USA, Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Denmark.
63
Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
64
Department of Pediatrics, Tampere University Hospital, Tampere, Finland, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
65
Institute of Nutritional Science, University of Potsdam, Germany, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China, Center for Cardiovascular Research/Institute of Pharmacology, Charité, Berlin, Germany.
66
Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland, Department of Pediatrics, Tampere University Hospital, Tampere, Finland, Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
67
Saw Swee Hock School of Public Health, Singapore Eye Research Institute, Singapore, Duke-NUS Graduate Medical School, Singapore.
68
Human Genetics and Genomic Medicine, Human Development & Health, Faculty of Medicine, University of Southampton, UK.
69
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, Sachs' Children's Hospital, Stockholm, Sweden.
70
Institute of Epidemiology II, Research Unit for Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
71
Division Epidemiology, Department Genes and Environment, Department Obstetrics and Gynecology, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.
72
Institute of Health Sciences, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, MRC Health Protection Agency (HPE) Centre for Environment and Health, Biocenter Oulu, University of Oulu, Oulu, Finland, Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O.Box 20, FI-90220, Oulu 90029 OYS, Finland, Department of Children and Young People and Families, National Institute for Health and Welfare, Aapistie 1, Box 310, Oulu FI-90101, Finland and.
73
Groningen Research Institute for Asthma and COPD, Beatrix Children's Hospital, Pediatric Pulmonology and Pediatric Allergy, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
74
Research Centre of Applied and Preventive Cardiovascular Medicine, Department of Pediatrics, Turku University Hospital, Turku, Finland.
75
Department of Nutrition and Dietetics, Harokopio University of Athens, Athens 11527, Greece.
76
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK, Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, UK.
77
Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain, CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
78
Department of Epidemiology, Department of Paediatrics, The Generation R Study Group, v.jaddoe@erasmusmc.nl.

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.

PMID:
25281659
PMCID:
PMC4447786
DOI:
10.1093/hmg/ddu510
[Indexed for MEDLINE]
Free PMC Article

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