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


Por: van der Valk RJ, Kreiner-Møller E, Kooijman MN, Guxens M, Stergiakouli E, Sääf A, Bradfield JP, Geller F, Hayes MG, Cousminer DL, Körner A, Thiering E, Curtin JA, Myhre R, Huikari V, Joro R, Kerkhof M, Warrington NM, Pitkänen N, Ntalla I, Horikoshi M, Veijola R, Freathy RM, Teo YY, Barton SJ, Evans DM, Kemp JP, St Pourcain B, Ring SM, Davey Smith G, Bergström A, Kull I, Hakonarson H, Mentch FD, Bisgaard H, Chawes B, Stokholm J, Waage J, Eriksen P, Sevelsted A, Melbye M, Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium, van Duijn CM, Medina-Gomez C, Hofman A, de Jongste JC, Taal HR, Uitterlinden AG, Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Armstrong LL, Eriksson J, Palotie A, Bustamante M, Estivill X, Gonzalez JR, Llop S, Kiess W, Mahajan A, Flexeder C, Tiesler CM, Murray CS, Simpson A, Magnus P, Sengpiel V, Hartikainen AL, Keinanen-Kiukaanniemi S, Lewin A, Da Silva Couto Alves A, Blakemore AI, Buxton JL, Kaakinen M, Rodriguez A, Sebert S, Vaarasmaki M, Lakka T, Lindi V, Gehring U, Postma DS, Ang W, Newnham JP, Lyytikäinen LP, Pahkala K, Raitakari OT, Panoutsopoulou K, Zeggini E, Boomsma DI, Groen-Blokhuis M, Ilonen J, Franke L, Hirschhorn JN, Pers TH, Liang L, Huang J, Hocher B, Knip M, Saw SM, Holloway JW, Melén E, Grant SF, Feenstra B, Lowe WL, Widén E, Sergeyev E, Grallert H, Custovic A, Jacobsson B, Jarvelin MR, Atalay M, Koppelman GH, Pennell CE, Niinikoski H, Dedoussis GV, Mccarthy MI, Frayling TM, Sunyer J, Timpson NJ, Rivadeneira F, Bønnelykke K, Jaddoe VW and Early Growth Genetics (EGG) Consortium

Fecha de Publicación: 15/02/2015
Resumen:
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; ß = 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.

Direcciones
van der Valk RJ: Department of Epidemiology, Department of Paediatrics, The Generation R Study Group
Kreiner-Møller E: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
Kooijman MN: Department of Epidemiology, Department of Paediatrics, The Generation R Study Group
Guxens M: Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain, CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain
Stergiakouli E: MRC Integrative Epidemiology Unit
Sääf A: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Bradfield JP: Center for Applied Genomics, Abramson Research Center
Geller F: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
Hayes MG: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Cousminer DL: Institute for Molecular Medicine Finland
Körner A: Center of Pediatric Research, University Hospital Center Leipzig, University of Leipzig, Leipzig, Germany
Thiering E: Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany, Institute of Epidemiology I
Curtin JA: 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
Myhre R: Division Epidemiology, Department Genes and Environment
Huikari V: Institute of Health Sciences
Joro R: Institute of Biomedicine, Physiology
Kerkhof M: Department of Epidemiology, Groningen Research Institute for Asthma and COPD
Warrington NM: 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
Pitkänen N: Research Centre of Applied and Preventive Cardiovascular Medicine
Ntalla I: Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK, Department of Nutrition and Dietetics, Harokopio University of Athens, Athens 11527, Greece
Horikoshi M: 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
Veijola R: Department of Pediatrics, Medical Research Center
Freathy RM: University of Exeter Medical School, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK
Teo YY: 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
Barton SJ: MRC Lifecourse Epidemiology Unit
Evans DM: MRC Integrative Epidemiology Unit , University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia
Kemp JP: MRC Integrative Epidemiology Unit , University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia
St Pourcain B: 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
Ring SM: MRC Integrative Epidemiology Unit , Avon Longitudinal Study of Parents and Children (ALSPAC), School of Social and Community Medicine
Davey Smith G: MRC Integrative Epidemiology Unit
Bergström A: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Kull I: Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden, Sachs' Children's Hospital, Stockholm, Sweden
Hakonarson H: 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
Mentch FD: Center for Applied Genomics, Abramson Research Center
Bisgaard H: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
Chawes B: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
Stokholm J: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
Waage J: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
Eriksen P: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
Sevelsted A: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
Melbye M: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark, Department of Medicine, Stanford School of Medicine, Stanford, USA
van Duijn CM: Department of Epidemiology
Medina-Gomez C: Department of Epidemiology, The Generation R Study Group, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Hofman A: Department of Epidemiology, The Generation R Study Group
de Jongste JC: Department of Paediatrics, The Generation R Study Group
Taal HR: Department of Epidemiology, Department of Paediatrics
Uitterlinden AG: Department of Epidemiology, The Generation R Study Group, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Armstrong LL: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Eriksson J: Institute for Molecular Medicine Finland
Palotie A: 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
Bustamante M: 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
Estivill X: 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
Gonzalez JR: Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain, CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain
Llop S: 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
Kiess W: Center of Pediatric Research, University Hospital Center Leipzig, University of Leipzig, Leipzig, Germany
Mahajan A: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Flexeder C: Institute of Epidemiology I
Tiesler CM: Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany, Institute of Epidemiology I
Murray CS: 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
Simpson A: 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
Magnus P: Division Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
Sengpiel V: Department Obstetrics and Gynecology, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden
Hartikainen AL: Institute of Clinical Medicine/Obstetrics and Gynecology
Keinanen-Kiukaanniemi S: Institute of Health Sciences
Lewin A: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, MRC Health Protection Agency (HPE) Centre for Environment and Health
Da Silva Couto Alves A: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, MRC Health Protection Agency (HPE) Centre for Environment and Health
Blakemore AI: Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Faculty of Medicine, Imperial College, London W12 0NN, UK
Buxton JL: Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Faculty of Medicine, Imperial College, London W12 0NN, UK
Kaakinen M: 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
Rodriguez A: 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
Sebert S: Institute of Health Sciences
Vaarasmaki M: Department of Obstetrics and Gynecology and MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
Lakka T: Institute of Biomedicine, Physiology, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland, Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland
Lindi V: Institute of Biomedicine, Physiology
Gehring U: Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
Postma DS: Groningen Research Institute for Asthma and COPD, Department of Pulmonology
Ang W: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia
Newnham JP: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia
Lyytikäinen LP: Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland, Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland
Pahkala K: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia
Raitakari OT: Research Centre of Applied and Preventive Cardiovascular Medicine, Department of Clinical Physiology and Nuclear Medicine
Panoutsopoulou K: Wellcome Trust Sanger Institute, The Morgan Building, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1HH, UK
Zeggini E: Wellcome Trust Sanger Institute, The Morgan Building, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1HH, UK
Boomsma DI: Department of Biological Psychology, VU University, Amsterdam, The Netherlands, EMGO Institute for Health and Care Research, Amsterdam, The Netherlands, Neuroscience Campus Amsterdam, The Netherlands
Groen-Blokhuis M: Department of Biological Psychology, VU University, Amsterdam, The Netherlands, EMGO Institute for Health and Care Research, Amsterdam, The Netherlands, Neuroscience Campus Amsterdam, The Netherlands
Ilonen J: Immunogenetics Laboratory, University of Turku, Turku, Finland, Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland
Franke L: Department of Genetics, University of Groningen, University Medical Centre Groningen, The Netherlands
Hirschhorn JN: 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
Pers TH: 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
Liang L: Department of Pediatrics, Tampere University Hospital, Tampere, Finland
Huang J: 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
Hocher B: 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
Knip M: 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
Saw SM: Saw Swee Hock School of Public Health, Singapore Eye Research Institute, Singapore, Duke-NUS Graduate Medical School, Singapore
Holloway JW: Human Genetics and Genomic Medicine, Human Development & Health, Faculty of Medicine, University of Southampton, UK
Melén E: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, Sachs' Children's Hospital, Stockholm, Sweden
Grant SF: 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
Feenstra B: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
Lowe WL: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Widén E: Institute for Molecular Medicine Finland
Sergeyev E: Center of Pediatric Research, University Hospital Center Leipzig, University of Leipzig, Leipzig, Germany
Grallert H: Institute of Epidemiology II, Research Unit for Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
Custovic A: 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
Jacobsson B: Division Epidemiology, Department Genes and Environment, Department Obstetrics and Gynecology, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden
Jarvelin MR: 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 a
Atalay M: Institute of Biomedicine, Physiology
Koppelman GH: 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
Pennell CE: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia
Niinikoski H: Research Centre of Applied and Preventive Cardiovascular Medicine, Department of Pediatrics, Turku University Hospital, Turku, Finland
Dedoussis GV: Department of Nutrition and Dietetics, Harokopio University of Athens, Athens 11527, Greece
Mccarthy MI: 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
Frayling TM: University of Exeter Medical School, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK
Sunyer J: 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
Timpson NJ: MRC Integrative Epidemiology Unit
Rivadeneira F: Department of Epidemiology, The Generation R Study Group, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Bønnelykke K: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
Jaddoe VW: Department of Epidemiology, Department of Paediatrics, The Generation R Study Group, v.jaddoe@erasmusmc.nl
ISSN: 09646906





HUMAN MOLECULAR GENETICS
Editorial
OXFORD UNIV PRESS, GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND, Reino Unido
Tipo de documento: Article
Volumen: 24 Número: 4
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WOS: 000350138300021
ID de PubMed: 25281659

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