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

Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium; Genetic Investigation of ANthropometric Traits (GIANT) Consortium; for the Early Growth Genetics (EGG) Consortium

doi:10.1093/hmg/ddu510

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

Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium
, Genetic Investigation of ANthropometric Traits (GIANT) Consortium
, for the Early Growth Genetics (EGG) Consortium

Erasmus University Medical Center
University of Copenhagen
University of Barcelona
Instituto Salud Carlos III
Pompeu Fabra University (UPF)
MRC Integrative Epidemiology Unit
Karolinska Institutet
University of Pennsylvania
Statens Serum Institut
Division of Endocrinology, Metabolism and Molecular Medicine
Northwestern University Feinberg School of Medicine
University of Helsinki
University Hospital Leipzig
Ludwig-Maximilians-Universität München
Institute of Epidemiology
University of Manchester
Norwegian Institute of Public Health
University of Oulu
University of Kuopio
University Medical Center Groningen
University of Western Australia
University of Queensland
University of Turku
University of Leicester
Harokopio University
University of Oxford
University of Oxford Medical Sciences Division
University of Oulu and Medical Research Center Oulu
University of Exeter Medical School
National University of Singapore
University of Southampton
University of Southampton
School of Social and Community Medicine
University of Bristol
Södersjukhuset
Karolinska Institutet
Children's Hospital of Philadelphia
The University of Pennsylvania
Stanford University School of Medicine
Wellcome Sanger Institute
Analytic and Translational Genetics Unit
Massachusetts General Hospital
Program in Medical and Population Genetics
Centre for Genomic Regulation (CRG) and Pompeu Fabra University
Hospital Del Mar-Instituto Municipal de Asistencia Sanitaria (IMAS)
Foundation for the Promotion of Health and Biomedical Research in the Valencian Region
Sahlgrenska University Hospital
Imperial College London
Imperial College London
Mid Sweden University, Östersund
Oulu University Hospital
Kuopion Yliopistollinen sairaala
Institute for Risk Assessment Sciences
Fimlab Laboratories
Tampere University
Paavo Nurmi Centre
Turku University Hospital
VU University Amsterdam
University of Amsterdam
Amsterdam Neuroscience
University of Turku and Turku University Hospital
The Broad Institute of MIT and Harvard
Boston Children's Hospital
Harvard Medical School
Technical University of Denmark
Harvard T.H. Chan School of Public Health
Tampere University Hospital
Shanghai Rui Jin Hospital
University of Potsdam
the First Affiliated Hospital of Jinan University
Partner Site Munich Heart Alliance
HUS Helsinki University Hospital
Singapore Eye Research Institute
Duke-NUS Medical School
University of Southampton, Faculty of Medicine
Institute of Epidemiology II
Helmholtz Zentrum München German Research Center for Environmental Health
National Institute for Health and Welfare
University Medical Centre Groningen
Churchill Hospital

Research output: Contribution to journal › Article › peer-review

90 Scopus citations

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.

Original language	English
Pages (from-to)	1155-1168
Number of pages	14
Journal	Human Molecular Genetics
Volume	24
Issue number	4
DOIs	https://doi.org/10.1093/hmg/ddu510
State	Published - 15 Feb 2015
Externally published	Yes

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10.1093/hmg/ddu510

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@article{921c170e76b4486aaa3a1ed93e21ec7b,

title = "A novel common variant in DCST2 is associated with length in early life and height in adulthood",

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.",

author = "\{Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium\} and \{Genetic Investigation of ANthropometric Traits (GIANT) Consortium\} and \{for the Early Growth Genetics (EGG) Consortium\} and \{van der Valk\}, \{Ralf J.P.\} and Eskil Kreiner-M{\o}ller and Kooijman, \{Marjolein N.\} and Mo{\'o}nica Guxens and Evangelia Stergiakouli and Annika S{\"a}{\"a}f and Bradfield, \{Jonathan P.\} and Frank Geller and \{Geoffrey Hayes\}, M. and Cousminer, \{Diana L.\} and Antje K{\"o}rner and Elisabeth Thiering and Curtin, \{John A.\} and Ronny Myhre and Ville Huikari and Raimo Joro and Marjan Kerkhof and Warrington, \{Nicole M.\} and Niina Pitk{\"a}nen and Ioanna Ntalla and Momoko Horikoshi and Riitta Veijola and Freathy, \{Rachel M.\} and Teo, \{Yik Ying\} and Barton, \{Sheila J.\} and Evans, \{David M.\} and Kemp, \{John P.\} and Pourcain, \{Beate St\} and Ring, \{Susan M.\} and Smith, \{George Davey\} and Anna Bergstr{\"o}m and Inger Kull and Hakon Hakonarson and Mentch, \{Frank D.\} and Hans Bisgaard and Bo Chawes and Jakob Stokholm and Johannes Waage and Patrick Eriksen and Astrid Sevelsted and Mads Melbye and \{van Duijn\}, \{Cornelia M.\} and Carolina Medina-Gomez and Albert Hofman and \{de Jongste\}, \{Johan C.\} and \{Rob Taal\}, H. and Uitterlinden, \{Andr{\'e} G.\} and Armstrong, \{Loren L.\} and Johan Eriksson and Eleftheria Zeggini",

year = "2015",

month = feb,

day = "15",

doi = "10.1093/hmg/ddu510",

language = "English",

volume = "24",

pages = "1155--1168",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "4",

}

Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium, Genetic Investigation of ANthropometric Traits (GIANT) Consortium & for the Early Growth Genetics (EGG) Consortium 2015, 'A novel common variant in DCST2 is associated with length in early life and height in adulthood', Human Molecular Genetics, vol. 24, no. 4, pp. 1155-1168. https://doi.org/10.1093/hmg/ddu510

A novel common variant in DCST2 is associated with length in early life and height in adulthood. / Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium; Genetic Investigation of ANthropometric Traits (GIANT) Consortium; for the Early Growth Genetics (EGG) Consortium.
In: Human Molecular Genetics, Vol. 24, No. 4, 15.02.2015, p. 1155-1168.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A novel common variant in DCST2 is associated with length in early life and height in adulthood

AU - Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium

AU - Genetic Investigation of ANthropometric Traits (GIANT) Consortium

AU - for the Early Growth Genetics (EGG) Consortium

AU - van der Valk, Ralf J.P.

AU - Kreiner-Møller, Eskil

AU - Kooijman, Marjolein N.

AU - Guxens, Moónica

AU - Stergiakouli, Evangelia

AU - Sääf, Annika

AU - Bradfield, Jonathan P.

AU - Geller, Frank

AU - Geoffrey Hayes, M.

AU - Cousminer, Diana L.

AU - Körner, Antje

AU - Thiering, Elisabeth

AU - Curtin, John A.

AU - Myhre, Ronny

AU - Huikari, Ville

AU - Joro, Raimo

AU - Kerkhof, Marjan

AU - Warrington, Nicole M.

AU - Pitkänen, Niina

AU - Ntalla, Ioanna

AU - Horikoshi, Momoko

AU - Veijola, Riitta

AU - Freathy, Rachel M.

AU - Teo, Yik Ying

AU - Barton, Sheila J.

AU - Evans, David M.

AU - Kemp, John P.

AU - Pourcain, Beate St

AU - Ring, Susan M.

AU - Smith, George Davey

AU - Bergström, Anna

AU - Kull, Inger

AU - Hakonarson, Hakon

AU - Mentch, Frank D.

AU - Bisgaard, Hans

AU - Chawes, Bo

AU - Stokholm, Jakob

AU - Waage, Johannes

AU - Eriksen, Patrick

AU - Sevelsted, Astrid

AU - Melbye, Mads

AU - van Duijn, Cornelia M.

AU - Medina-Gomez, Carolina

AU - Hofman, Albert

AU - de Jongste, Johan C.

AU - Rob Taal, H.

AU - Uitterlinden, André G.

AU - Armstrong, Loren L.

AU - Eriksson, Johan

AU - Zeggini, Eleftheria

PY - 2015/2/15

Y1 - 2015/2/15

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84985023154

U2 - 10.1093/hmg/ddu510

DO - 10.1093/hmg/ddu510

M3 - Article

C2 - 25281659

AN - SCOPUS:84985023154

SN - 0964-6906

VL - 24

SP - 1155

EP - 1168

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 4

ER -

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

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